Genomic instability in EBV-transformed lymphoblastoid cell lines
Ji Hee Oh
The Graduate school Yonsei University Graduate Program in Science for Aging
Genomic instability in EBV-transformed lymphoblastoid cell lines
Dissertation
Submmitted to Graduate Program in Science for Aging
And Graduated school Yonsei University
In partial fulfillment of the requirements
For the degree of Doctor of Philosophy
Ji Hee Oh
December 2013
감사의 글
길고도 짧았던 박사 학위 과정을 미흡하나마 논문으로 결실을 맺게 되었습 니다. 그 동안 많은 가르침과 격려 해주신 모든 분들께 이 글을 통하여 감사의 마음을 전합니다.
무엇보다도 부족한 저에게 배움의 기회를 주시고 많은 가르침을 주신 이종 호 교수님께 고개 숙여 깊이 감사 드립니다. 바쁘신 가운데 변함없이 관심 을 가져주신 이수복 교수님, 이승민 교수님께 감사의 인사를 드립니다. 석 사 학위과정 때부터 꾸준히 학문적으로 많은 가르침을 주신 채지숙 교수님, 김오연 교수님, 정지형 교수님께 감사의 인사를 드립니다.
대학원 전 과정 동안 가장 오랜시간동안 도와주고 걱정해 준 진태원군 너 무 고마웠습니다. 박사 학위과정 입학과 졸업을 같이 할 수 있어서 너무 기쁘며 축하합니다. 김윤경 선생님, 박사되고 승급하고 결혼도하고 너무 축하해요. 같이 졸업 준비하면서 고생도 많이 하고 고맙고 고생 많았습니 다.
오랜 시간 동안 학위과정을 할 수 있도록 도와주신 형질연구 과 선생님들 에게 고마운 마음을 전합니다. 김봉조 과장님, 김흥태 연구사님, 이주영 연 구사님 감사합니다. 너무 많은 도움을 항상 받으면서 논문 준비도 같이 해 준 김영진 선생님 진심으로 고맙습니다. 불광동에서부터 지금까지 변치 않 고 항상 많은 도움을 주신 문상훈 박사님 감사합니다. 두 분의 도움으로 논문을 완성할 수 있었습니다. 지금은 떨어져있어 그리운 김남희 선생님, 이은주 박사님, 박미의 박사님, 김동준 선생님, 김광중 박사님, 복정 선생
님의 진심 어린 충고 감사하고 보고 싶습니다. 많은 시간을 같이 보내진 않았지만 항상 옆에 있어준 김연정 선생님, 황미영 선생님, 윤준호 선생님, 허룡 선생님 앞으로도 더욱 많이 서로 도와주고 서로 힘이 되어주는 사이 가 계속 되었으면 좋겠습니다. 국립보건연구원 형질연구과의 황주연 선생 님, 고민진 선생님, 김정민 선생님, 이헌식 선생님, 배재범 선생님, 박수연 선생님, 이영 선생님, 박인규 선생님, 박태준 선생님, 유호영 선생님, 송영 웅 선생님, 최지영 선생님, 한소희 선생님 항상 도와주셔서 감사합니다.
이세상 누구보다 사랑하는 나의 가족에게 고마움과 감사함을 전합니다. 언 제나 부모님의 기대에 미치지는 못하지만 사랑과 믿음으로 묵묵하게 저의 뒷바라지를 해주셨기에 오늘의 제가 있을 수 있었습니다. 크나큰 은혜에 이 결실 조금이나마 부모님께 기쁨을 드리고 싶습니다. 지금은 홀로 해외 에 있는 하나밖에 없는 내 동생, 항상 걱정하고 고맙고 사랑 하다고 전하 고 싶습니다. 항상 내 의견을 존중해주고 양보해주고 언제나 큰 힘이 되 어준 지민기군에게 사랑하고 고마운 마음을 전하고 싶습니다.
저의 이 모든 결실인 부모님께 이 논문을 바칩니다.
2014년 1월 오지희 드림
CONTENTS
List of Figures ································································· v
List of Tables ····························································· vi
List of Appendices ···················································· viii
ABSTRACT ······························································· ix
Ⅰ. BACKGROUND ······················································· 1
1. LYMPHOBLSTOID CELL LINES (LCLs) ····························· 1
1.1. Epstein-Barr Virus (EBV) ············································ 1
1.2. EBV immortalization ················································· 2
1.3. Subculture ······························································· 3
2. GENOMIC ABERRATION ··············································· 3
2.1. Copy number variation (CNV) ···································· 3
2.2. Loss of heterozygosity (LOH) ····································· 4
2.3. Silent LOH ······························································ 4
3. MICROARRAY TECHNOLOGY ······································· 5
i
Ⅱ. GENOTYPE INSTABILITY DURING LONG-
TERM SUBCULTURE OF LYMPHOBLASTOID
CELL LINES ·································································· 6
1. INTRODUCTION ························································· 6
2. SUBJECTS AND METHODS ··········································· 8
2.1. Samples ································································· 8
2.2. Subculture of LCLs ··················································· 9
2.3. Genotyping ··························································· 12
2.4. Examination of genotype concordance ······················· 12
3. RESULTS ··································································· 13
3.1. Estimated genotype instability in LCLs and PBMCs
across sample pairs ·················································· 13
3.1.1. Investigation of concordance of SNP genotypes
between LCLs and PBMCs ································· 13
3.1.2. Test of the concordance of GWAS SNPs ·············· 17
3.1.3. Calculation of genotype concordance between
LCLs and PBMCs ··········································· 19
3.1.4. Identification of the chromosomal regions
vulnerable to genotyping errors ························ 22
ii
3.1.5. Detection of loss of heterozygosity regions ············ 30
4. DISCUSSION ······························································· 36
Ⅲ. INTEGRATED GENOMIC ABERRATION, GENE
EXPRESSION AND miRNA EXPRESSION ANALYSIS
IN LYMPHOBLASTOID CELL LINE DURING LONG-
TERM CELL CULTURE ·········································· 39
1. INTRODUCTION ······················································· 39
2. MATERIALS AND METHODS ······························· 41
2.1. Samples ····································································· 41
2.2. Genotyping ································································· 43
2.3. Gene expression microarray ············································ 43
2.4. miRNA microarray ······················································· 44
2.5. Gene ontology analysis ·················································· 44
3. RESULTS ··································································· 45
3.1. Exome array genotyping ··········································· 45
3.2. CNV and LOH detection ··········································· 45
3.3. Identification of differentially expressed genes ·············· 48
3.4. Functional correlation of DEGs ·································· 51
3.5. Identification of DEGs overlapped with CNVs ·············· 58
iii
3.6. Functional correlation of DEGs overlapped with CNVs··· 61
4. DISCUSSION ······························································· 66
REFERENCES ···························································· 69
ABSTRACT IN KOREAN ·············································· 75
APPENDICES ···························································· 77
iv
List of Figures
Figure 1. Boxplot: Genotype concordance of between PBMC and
LCLs at 6 different propagation stages ·························· 18
Figure 2. Comparison of genotype concordance of LCLs among
SNP based on the chromosomal location. ······················ 23
Figure 3. The LOH observed in chromosome ······························ 25
Figure 4. The LOH identified at different chromosomal regions ···· 31
v
List of Tables
Table 1. Description of samples ··············································· 11
Table 2. Genotype concordance between PBMCs and LCLs from
SNP filtered call rate ················································· 15
Table 3. Estimation of the concordance rate between duplicated6
experiments from the same samples ······························ 16
Table 4. Comparison of genotype concordance of LCLs
among SNP groupings based on missing rate, HWE
p-value, and MAF ······················································ 21
Table 5. LOH with increased numbers of LCL passages through
culture ····································································· 24
Table 6. Description of samples ··············································· 42
Table 7. Detecting LOH regions ··············································· 47
Table 8. Integration of gene expression data in ≥5 samples with
10 top signals ordered by M-value ································· 49
Table 9. Integration of miRNA expression data in ≥5 samples
with 10top signals ordered by M-value··························· 50
vi
Table 10. Functional annotation clusters of significant DEGs
from gene expression data with top clusters ordered
by FDR ··································································· 52
Table 11. Functional annotation clusters of significant DEGs
from miRNA expression data with top clusters ordered
by FDR ··································································· 55
Table 12. Integration of CNVs with gene expression data ·············· 59
Table 13. Integration of CNVs with miRNA expression data·········· 60
Table 14. Functional annotation clusters of significant DEGs
with CNVs from gene expression data ·························· 62
Table 15. Functional annotation clusters of significant DEGs
with CNVs from miRNA expression data ······················ 63
vii
List of Appendices
Appendix Ⅰ. Detection of CNVs by exome chip ························· 78
Appendix Ⅱ. Functional annotation clusters of significant DEGs
from gene expression data ···································· 89
Appendix Ⅲ. Functional annotation clusters of significant
differentially expression genes from miRNA
expression data ················································· 92
Appendix Ⅳ. Functional annotation clusters of significant DEGs
with CNVs from miRNA expression data ··············· 105
viii
ABSTRACT
Genotype instability in EBV-transformed
lymphoblastoid cell lines
Ji Hee Oh
Graduate Program Science for Aging
The Graduate School
Yonsei University
Epstein-Barr virus (EBV)-transformed lymphoblastoid cell lines
(LCLs) promise to address the challenge posed by the limited availability of primary cells needed as a source of genomic DNA for genetic studies. However, the genetic stability of LCLs following prolonged culture has never been rigorously investigated. The impact of genomic aberration on the biological experiments such as gene
ix expression and miRNA expression level has not been explored.
Purposes of current study are to investigate whether genetic instability of LCLs might cause the accumulation of genetic modifications following their long-term subculture and to examine a correlation between genomic aberration and expression level in genes and miRNAs.
To accomplish our goals, we isolated genomic DNA from human peripheral blood mononuclear cells and LCLs collected from 20 individuals and genotyped the DNA samples using the Affymetrix
Gene Chip Human mapping 500K array set and Illumina
HumanExome BeadChip array. Genotype concordance measurements between two sources of DNA from the same individual indicated that genotypic discordance is negligible in early-passage LCLs (<20 passages) but substantial in late-passage LCLs (>50 passages). Analysis of concordance on a chromosome-by chromosome basis identified genomic regions with a high frequency of genotypic errors resulting from the loss of heterozygosity observed in late-passage LCLs.
Discovered genomic aberrations were of 90 regions of copy number variations (CNVs) observed in late-passage LCLs. In addition,
x integrated analysis revealed genomic aberration changed expression levels in genes and miRNAs.
Our findings suggest that, although LCLs harvested during early stages of propagation are a reliable source of genomic DNA for genetic studies, investigations that involve genotyping of the entire genome should not use DNA from late-passage LCLs.
Key words: lymphobastoid cell line; singe-nucleotide polymorphism; genome-wide association study, exome array, gene expression, miRNA, microarray, long-term cell culture
xi
１
Ⅰ. BACKGROUND
1. LYMPHOBLASTOID CELL LINES (LCLs)
Infection of human B cells with EBV in vitro results in their immortalization and the resulting cell lines are named lymphoblasotid cell lines (LCLs). In these cells, EBV establishes mainly a latent infection, characterized by the expression of a limited number of viral proteins. EBV-transformed LCLs can be obtained by explantation of blood or lymphoid tissues from EBV seropositive individuals without need for exogenous infection. In addition, LCLs from EBV seropositive and seronegative donors can be obtained by in vitro infection of peripheral blood mononuclear cells (PBMCs) with EBV.
1.1. Epstein-Barr Virus (EBV)
The Epstein-Barr virus (EBV) confers upon normal lymphocyte derived from bone marrow, is a virus of herpes family, and one of the
１ most common human viruses. It is named after Michael Anthony
Epstein (born 1921) and Yvonne Barr (born 1932), British virologists who together discovered the virus. In 1964 Epstein and Barr isolated a herpesvirus in cultured Burkitt’s lymphoma cells. The virus is approximately 12nm to 180 nm in diameter and is composed of a double helix of DNA wrapped in a protein capsid. The capsid is surrounded by a tegument made of protein, which in turn is surrounded by an envelope made from lipids. The EBV DNA is 192 kilo base pairs long and contains 85 genes.
1.2. EBV immortalization
When EBV infects B cells in vitro, lymphoblastoid cell lines finally appear that are capable of indefinite growth. The growth transformation of these cell lines is the result of viral protein expression.
It is posit that following natural infection with EBV, the virus executes or all repertoire of gene expression programs to establish a persistent infection.
２
1.3. Subculture
In biology, a subculture is a cell made by transporting or cells from a previous culture to fresh growth medium. This functioning is called subculturing or passaging the cells. Subculture is important for both proliferating and non-proliferating cells. Commonly subculture is from a culture of a volume into growth medium of the same volume, this allows long-term continuation of cell line.
2. GENOMIC ABERRATION
2.1. Copy number variation (CNV)
Copy number variation (CNV) is a structural variation, which includes insertions, deletions and duplication. CNVs are alterations of the DNA of a genome. CNVs accord comparatively large regions of the genome that have insertion, deletion and duplication on chromosomes.
This variation reports for approximately 12% of human genomic DNA and each variation may range from about 1 Kb to several megabase in size (1).
３
2.2. Loss of heterozygosity (LOH)
At an exceptional locus heterozygous for a mutant allele and a normal allele, a deletion or diverse mutational event inside of the normal allele makes the cell either hemizygous or homozygous for the deleterious allele (2).
2.3. Silent loss of heterozygosity
Silent loss of heterozygosity (LOH) is a called copy-neutral LOH
(CN-LOH), because no change in copy number arising in the affected individual. Determination of virtual karyotypes using Single nucleotide polymorphism (SNP)-based arrays can provide genome- wide copy number and LOH, including detection of silent LOH. Silent
LOH cannot be detected by arrayCGH, FISH, conventional cytogenetics.
４
3. MICROARRAY TECHNOLOGY
Microarray technology is a developing technology used to study the expression of many genes at once. It involves placing thousands of gene sequences in known locations on a glass slide called a gene chip.
A sample containing DNA or RNA is placed in contract with the gene chip. Complementary base pairing between the sample and the gene sequences on the chip produces light that is measured. Regions on the chip producing light identify genes that are expressed in the sample
(talking glossary of genetic terms, from the national human genome research institute). Several popular microarrays are the Affymetrix
“Gene Chip", Illumina “Bead chip”, Agilent single-channel arrays.
Microarrays can be used to detect DNA or detect RNA that may or may not be translated into proteins. The process of measuring gene expression via cDNA is called expression analysis expression profiling.
５
Ⅱ. GENOTYPE INSTABILITY DURING LONG-
TERM SUBCULTURE OF LYMPHOBLASTOID
CELL LINES
1. INTRODUCTION
High-throughput microarray-based single SNP genotyping greatly facilitates genome-wide association studies (GWAS) to identify human disease-susceptibility loci. Primary cells or tissue samples are the largest sources of genomic DNA for SNP typing. However, the limited availability of these samples restricts the ease and efficiency with which GWAS can be conducted. Given that LCLs, which are human B lymphocytes immortalized by in vitro infection with EBV, are a renewable source of DNA, they have emerged as a promising alternative to the use of primary cells or tissue samples as sources of human genomic DNA. Numerous genetic studies, including several
GWAS currently underway worldwide, have used LCL samples as a
DNA source (1-4). Although LCLs provide a permanent source of ６ human DNA, the genetic stability of LCLs has not been thoroughly studied in the context of genetic and non-genetic factors (5).
It has been reported that LCLs were influenced by non-genetic factors such as the amount of individual response to the EBV, the history of passage in cell culture and culture conditions (5). It is also known that the immortalization process of LCLs by EBV infection has the potential to cause changes in genetics (6). There are several reports that focused on the genetic changes during the lymphocyte transformation. Specifically, the availability of LCL for GWAS has been primarily evaluated with regard to genotype analysis (6). Some studies estimated that EBV-transformation process may produce minor artifacts on genomic structure and LCL would be a reliable resource for
SNP genotyping and detecting copy number variation under the stringent quality control (7, 8). Furthermore, the recent array comparative genomic hybridization analysis of the B-LCL lines and their parental B cells demonstrated that genomic stability was maintained (9). LCL stability during the long-term subculture process, however, has been remained unclear.
In this study, we rigorously investigated whether genetic instability
７ of LCLs might cause the accumulation of genetic modifications following their long-term subculture. Substantial genotypic errors were detected mostly in late-passage, but not in early-passage, LCLs. This suggests that LCLs harvested during early propagation stages (<40 passages) are reliable sources of genomic DNA for SNP genotyping.
2. SUBJECTS AND METHODS
2. 1. Samples
The 20 LCL strains used in this study were chosen from the LCL collection of the Korean HapMap project (http://cdc.go.kr). As the first step in generating LCLs, peripheral blood samples from individuals who were 40–69 years old and part of Korean Genome Epidemiologic
Study (KoGES) cohorts were subjected to Ficoll-Hypaque gradient centrifugation to obtain peripheral blood mononuclear cells (PBMCs).
The PBMCs were prepared according to the protocols suggested for use with the (Amersham Biosciences, Freiburg, Germany). The subsequent infection of PBMCs with Epstein-Barr virus, using
８ procedures described elsewhere (10), eventually generated LCLs. All
LCL strains were cultured in RPMI 1640 medium (Invitrogen, Carlsbad,
CA) supplemented with 10% fetal bovine serum at 37°C in humidified air containing 5% CO2. Culture medium was replaced with fresh RPMI
1640 at each passage.
2.2. Subculture of LCLs
We used continuous subculturing to propagate LCLs until maximal end passage (10). The maximal passage of each LCL strain was determined the cell number did not increase 4 weeks after subculture (11). Under our culture conditions, most of the LCLs we studied stopped proliferating after 160 passages. The 20 LCLs that proliferated after this many passages were classified as immortal, and the three LC lines that stopped proliferating at passages 33, 44, and 48 were classified as non-immortal (Table 1). The LCL strains were grown to take about more than 2 years. The average life span of these non- immortal LCL strains was 41 ± 8 passages. We analyzed LCL samples
９ harvested at six designated propagation stages. These samples were named LCL2 (passage 2), LCL4 (passage 4), p1 (between 10–20 passages), p41 (between 50–60 passages), p100 (between 110–120 passages), and p160 (between 170–180 passages).
１０
Table 1. Description of samples
Sample name Gender Age Immortalization Used for analysis
A1 F 65 Immortal Yes
A2 M 64 Immortal Yes
A3 M 45 Immortal Yes
A4 M 57 Immortal Yes
A5 M 57 Immortal No
A6 M 47 Immortal No
A7 F 45 Non-immortal No
A8 F 53 Immortal Yes
A9 F 58 Non-immortal Yes
A10 F 68 Immortal Yes
K1 F 61 Immortal Yes
K2 F 46 Immortal No
K3 M 64 Immortal Yes
K4 M 41 Non-immortal Yes
K5 M 65 Immortal Yes
K6 M 58 Immortal Yes
K7 F 55 Immortal Yes
K8 M 47 Immortal Yes
K9 M 69 Immortal Yes
K10 F 43 Immortal Yes
１１
2.3. Genotyping
We genotyped PBMC and LCL samples using the GeneChip human mapping 500K array set (Affymetrix, Inc., Santa Clara, CA), which comprises 500,568 SNPs on two arrays, named NSP and STY.
Genotyping was performed according to the manufacturer’s protocol.
2.4. Examination of genotype concordance
Genotypes of all samples were called using the Affymetrix
BRLMM algorithm (12). We examined the genotype concordance between PBMCs and LCLs derived from the same individual by using identity-by-state (IBS) analysis (13). Pairwise IBS distances between
PBMC and LCL were calculated for each of the NSP and STY arrays separately, as well as for the combined array set. We excluded the A5,
A6, A7 and K2 strains from further analysis because concordance testing indicated that these LCL strains likely originated from different blood donors. In total, 16 LCL strains were used for further analyses.
１２
3. RESULTS
3.1. Estimated genotype instability LCLs and PBMCs across sample
pairs
3.1.1. Investigation of concordance of SNP genotypes between LCLs
and PBMCs
We estimated genotype instability in LCLs and PBMCs across
sample pairs from 16 of the 20 strains generated. Overall, the mean
genotype call rates for samples were 98.1%, 98.4%, and 98.3% for the
STY array, the NSP array, and these two arrays combined,
respectively. To investigate the concordance of SNP genotypes
between PBMCs and LCLs at six different propagation stages from
the same line, we calculated the pairwise distance based on IBS
analysis using the 500,568 SNPs (hereafter called original SNPs)
represented in the Affymetrix 500K array set. The mean pairwise IBS
distance of original SNPs between PBMC and LCLs was
approximately 0.995 (Table 2), indicating that LCLs are generally a
１３ reliable source of DNA for genotyping with microarray-based DNA chips. To estimate within sample variation of genotyping, we randomly selected 8 different LCLs and genotyped each sample twice using the separate array chips. Concordance rates between duplicates of the same sample ranged from 0.988 to 0.997. The mean concordance rate for overall test was 0.992 (Table 3). These results suggest that within sample variation resulted from genotyping can be disregarded in the estimation of the concordance rate between the
LCLs and PBMCs.
１４
Table 2 Genotype concordance between PBMCs and LCLs from SNP filtered call rate
No filtering GWAS filtering ID IBS LCL2 LCL4 p1 p41 p100 p160 LCL2 LCL4 p1 p41 p100 p160 A1 0.996 0.997 0.997 0.996 0.996 0.997 0.996 0.997 0.997 0.997 0.997 0.997 A2 0.995 0.996 0.996 0.995 0.992 0.995 0.996 0.997 0.997 0.996 0.993 0.995 A3 0.997 0.998 0.997 0.997 0.994 0.994 0.998 0.998 0.998 0.998 0.993 0.994 A4 0.997 0.995 0.994 0.992 0.996 0.997 0.997 0.996 0.996 0.994 0.997 0.998 A8 0.994 0.993 0.993 0.992 0.991 0.991 0.995 0.994 0.994 0.993 0.992 0.992 A9 0.997 0.995 0.996 0.993 0.997 0.996 0.997 0.994 A10 0.996 0.992 0.996 0.995 0.995 0.994 0.997 0.994 0.997 0.996 0.995 0.994 K1 0.996 0.997 0.997 0.996 0.998 0.998 0.997 0.998 0.997 0.997 0.999 0.998 K3 0.998 0.998 0.998 0.996 0.998 0.998 0.998 0.999 0.998 0.996 0.998 0.998 K4 0.995 0.996 0.996 0.995 0.996 0.997 0.997 0.996 K5 0.997 0.998 0.998 0.996 0.997 0.994 0.998 0.999 0.998 0.996 0.997 0.995 K6 0.995 0.995 0.995 0.994 0.995 0.994 0.996 0.996 0.996 0.995 0.996 0.995 K7 0.997 0.997 0.995 0.996 0.996 0.997 0.997 0.997 0.996 0.996 0.996 0.997 K8 0.994 0.995 0.994 0.993 0.995 0.995 0.995 0.996 0.995 0.994 0.996 0.996 K9 0.988 0.991 0.991 0.994 0.994 0.994 0.991 0.992 0.993 0.994 0.995 0.995 K10 0.998 0.996 0.997 0.994 0.997 0.997 0.998 0.997 0.997 0.995 0.998 0.998 Mean 0.996 0.996 0.996 0.995 0.995 0.995 0.996 0.996 0.996 0.995 0.996 0.996 Total mean 0.995 0.996 GWAS, genome wide association study; IBS, intensity by state １５
Table 3. Estimation of the concordance rate between duplicated experiments from the same samples
Concordance Affymetrix Duplicated Call Average (between 500K Cell ID experiment # rate call rate experiments 1 Array type and 2)
1 0.985 A7 P1 0.970 0.992 2 0.956
1 0.981 A9 LCL4 0.970 0.991 2 0.959 NSP 1 0.981 K7 LCL4 0.970 0.990 2 0.959
1 0.956 K9 LCL4 0.962 0.989 2 0.967
1 0.971 A4 P41 0.970 0.997 2 0.970
1 0.969 A8 P100 0.962 0.988 2 0.954 STY 1 0.965 K2 LCL4 0.964 0.990 2 0.963
1 0.970 K2 P41 0.969 0.997 2 0.969
１６
3.1.2. Test of the concordance of GWAS SNPs
Of the 500,568 SNPs, we further tested the concordance of SNPs that are most frequently used in GWAS (hereafter called GWAS SNPs).
To select GWAS SNPs, we adapted SNPs that had been analyzed in
GWAS for eight quantitative traits as a part of Korea Association
Resource (KARE) Project , which involves using the Affymetrix
Genome-wide Human SNP Array 5.0 to genotype 500,568 SNPs. We selected 352,228 SNPs identified in KARE GWAS after excluding SNPs owing to a high missing genotype rate (>5%), a low minor allele frequency (MAF) (<0.01), and significant deviation from Hardy-
Weinberg equilibrium (HWE) (P < 1×10–6). Overall mean genotype concordance (between PBMC and LCLs) was 0.996 for GWAS SNPs
(Table 2). Concordance tests involving the GWAS SNP set produced results similar to those obtained using the original SNP set (Figure 1).
These results demonstrated that the LCLs are a suitable alternative to
PBMCs as a source of DNA for genotyping experiments, such as
GWAS.
１７
Figure 1. Boxplot: Genotype concordance of original 500,568 SNPs (A) and GWAS SNPs (B) between PBMCs and
LCLs at 6 different propagation stages
１８
3. 1.3. Calculation of genotype concordance between LCLs and
PBMCs
To understand the source of mismatches of the LCLs, we
calculated genotype concordance between PBMCs and LCLs for SNPs
arbitrarily grouped according to the HWE P-value, MAF, and
genotype missing rate (Table 4). The underlying assumption of the
analysis is based on previous reports that SNPs with lower HWE P-
values, lower MAF values, and higher genotype missing rates tend to
be associated with more genotyping errors . We generated four
groups based on the rates of missing genotypes (<1%, between 1–5%,
between 5–10%, and >10%), three groups according to HWE P-values
of SNPs (HWE-P > 1×10–4, 1×10–4 ≥ HWE-P > 1×10–6, and HWE-P ≤
1×10–6), and five groups according to MAF values of SNPs (MAF <
1%, 1% ≤ MAF < 5%, 5% ≤ MAF < 10%, 10% ≤ MAF < 50%, MAF ≥
50%). For grouping, we adopted SNP information on HWE P-values,
MAF values, and genotype missing rates that are available from
KARE genome-wide scan data. Regardless of LCL passage number,
overall results showed no notable difference in concordance among
１９ groups in the same category (0.994 average concordances).
２０
Table 4. Comparison of genotype concordance of LCLs among SNP groupings based on missing rate, HWE p-value, and MAF
Missing rate Group Concordance
≤0.1 0.989
≤0.05 0.992
≤0.01 0.994
<0.01 0.997
HWE Group Concordance
<10–6 0.989
≥10–4 0.992
>10–4 0.996
MAF Group Concordance
≥0.5 0.996
≥0.1 0.995
≥0.05 0.995
≥0.01 0.996
<0.01 0.998
HWE, hardy weinberg equilibrium; MAF, minor allele frequency
２１
3.1.4. Identification of the chromosomal regions vulnerable to
genotyping errors
We also attempted to identify the chromosomal regions most vulnerable to genotyping errors associated with LCL-derived DNA by scrutinizing genotype concordance across entire chromosomes. A high rate of genotype disconcordance between PBMCs and LCLs was observed on chromosomes 6p, 16q, 18p and 22q in the late-passage
LCL strains A3, A10, K3, and A2 (Figure 2). In those LCL strains, LOH was observed on the loci showing the highest rates of genotype disconcordance with PBMCs, suggesting that LOH might be the major cause of genotype errors for late-passage LCLs (> 50 passage) (Table 5,
Figure 3). This result indicated that LCLs at late stages of propagation are not reliable source of DNA for genome analysis
２２
Figure 2. Comparison of genotype concordance of LCLs among SNP based on the chromosomal location. A total of 16 LCL strains at different propagation stages were compared for genotype concordance
２３
Table 5. Loss of heterozygosity with increased numbers of LCL passages through culture
No. of genotype Line Chr Heterozygosity* Passages mismatching with PBMC
A3 6p 884 1.58% P100, P160
A3 16q 1999 0.25% P100, P160
A10 16q 892 3.02% P160
K3 18p 601 0% P41, P100, P160
A2 22q 1376 0.44% P100, P160
* Heterozygosity = (number of heterozygotes) / (number of homozygotes + number of heterozygotes)
Heterozygosity for LCLs was calculated using LCL samples with lowest concordance relative to blood samples.LCL, lymphoblasotid cell line; Chr, chromosome; PBMC, peripheral blood molecular cell
２４
Figure 3A. The loss of heterozygosity (LOH) observed in chromosome 6p in A3 strain. A black bar indicates each variant with a mismatch.
２５
Figure 3B. The loss of heterozygosity (LOH) observed in chromosome 16q in A3 strain. A black bar indicates each variant with a mismatch.
２６
Figure 3C. The loss of heterozygosity (LOH) observed in chromosome 16q in A10 strain. A black bar indicates each variant with a mismatch.
２７
Figure 3D. The loss of heterozygosity (LOH) observed in chromosome 18p in K3 strain. A black bar indicates each variant with a mismatch.
２８
Figure 3E. The loss of heterozygosity (LOH) observed in chromosome 122q in A2 strain. A black bar indicates each variant with a mismatch.
２９
3.1.5. Detection of loss of heterozygosity regions
The presence of LOH regions was further proved by detecting
either the copy number loss of the large chromosomal region from the
analysis of Log R ratio or the heterozygosity loss estimated from the B
allele frequency (about 0.5). Silent LOH showed no change in the Log
R ratio but did substantial loss of heterozygosity in the B allele
frequency (20). In this study, LOH by copy loss was observed on 6p of
A3 (p100 and p160) (Figure 4A) and on 18p of K3 (in P41, P100 and
P160) (Figure 4D). Silent LOH was detected on 16q of A3 (in P100 and
P160) (Figure 4B), 16q of A10 (in P160) (Figure 4C), and 22q of A2 (in
P100 and P160) (Figure 4E).
３０
Figure 4A. The LOH identified at different chromosomal 6p in A3 strain by Log R ratio and B allele frequency analyses.
３１
Figure 4B. The LOH identified at different chromosomal 16q in A3 strain by Log R ratio and B allele frequency analyses.
３２
Figure 4C. The LOH identified at different chromosomal 16q in A10 strain by Log R ratio and B allele frequency analyses.
３３
Figure 4D. The LOH identified at different chromosomal 18p in K3 strain by Log R ratio and B allele frequency analyses.
３４
Figure 4E. The LOH identified at different chromosomal 22q in A2 strain by Log R ratio and B allele frequency analyses.
３５
4. Discussion
We propagated human LCLs through as many as 160 passages and assessed their stability at selected stages of propagation by SNP genotyping. Overall, we observed no notable differences in genotype concordance between PBMCs and LCLs throughout the course of propagation. However, inspection of each chromosome revealed LOH in four late-stage LCLs. Thus, we recommend against using LCLs at a late stage of propagation for genome analysis, especially SNP genotyping. In addition karyotype analysis before genotyping is desirable for LCLs subcultured through >50 passages.
The detection of LOH at a specific chromosomal region should not be relied on concordance rates. When a genotype mismatching occurs due to LOH, the between sample IBS score for one SNP will be 1 as usual. As a result, the between sample IBS distance obtained from concordance analysis at a LOH region will be always 0.5. Therefore,
LOH showed little effect on concordance rates. Indeed, it was estimated that the genotype mismatching caused by LOH occupies only a very small portion (0.27%) among a total of 1,376 mismatches
３６ detected in 22q of A2 (Table 4). In this context, additional measures such as Log R ratio and B allele frequency should be thoroughly examined to analyze LOH in LCLs. Changes in B allele frequency are specifically important variable to detect silent LOH that cannot be detected by Log R ratio alone.
The mechanism underlying genomic aberration observed in LCLs during long-term subculture remains unclear. However, one plausible explanation is a double-strand break induced recombination (21).
Although the frequency of double-strand breaks is strictly regulated by the actions of nonhomologous end joining proteins and tumor suppressor proteins such as p53, double-strand breaks sometimes produce genomic aberrations (22, 23). Besides genomic changes, phenotypic changes such as activation of the NF-κB pathway and carcinogenesis-related genes have been associated with long-term subculturing of LCLs (13). Profiles of these differentially expressed genes can be considered as genetic signatures of LCL immortalization or EBV-induced carcinogenesis. Moreover, differential expression of nine microRNAs during long-term subculture of LCLs has provided a signature of terminal immortalization of LCLs that distinguishes this
３７ from the initial stage of EBV-mediated B-cell transformation (12).
Mohyuddin et al. studied on microsatellite instability between blood and LCLs by analyzing mutation rate of 20 STRs on the non- recombining part of the Y chromosome (24). They reported that mutations were only 0.3% of the analyses. Our study is different from their work in the context of marker type (microsatellite vs. SNP) and test region in the genome (Y chromosome vs. all autosomes). In addition, Mohyuddin et al. did not pay attention to the genomic instability that may be influenced by the propagation stages of LCLs.
Thus, to our knowledge, this is the first study to examine the effect of long-term subculturing on the genomic stability of LCLs. Our findings indicate that EBV transformation does not significantly affect the genotypes of LCLs. However, LCLs subjected to > 50 passages through culture are not recommended for SNP genotyping owing to an unacceptable increase in the frequency of genetic artifacts.
３８
Ⅲ. INTEGRATED GENOMIC ABERRATION, GENE
EXPRESSION AND miRNA EXPRESSION
ANALYSIS IN LYMPHOBLSTOID CELL LINE
DURING LONG-TERM CELL CULTURE
1. INTRODUCTION
Genome-wide association (GWAS) is widely used approach for discovering genetic variants underlying disease susceptibility. GWAS have relied almost exclusively on SNP array platforms, with SNP content selected initially to capture a large portion of common variation in coding and non-coding regions in various populations. For genotyping using SNP microarray, DNA extracted from blood is mainly used and, DNA extracted from LCLs is often used as alternative source.
In our previously study, we investigated the effect of long-term subculturing on the genomic instability of LCL strains using GWAS chip. In summary, late-passage LCLs (> 41 passage) had genomic
３９ aberrations, including LOH.
However, impact of genomic instability occurred during long-term subculture on other biological experiments such as expression profiles of genes and miRNA has not been studied previously. Therefore, we performed integrated analysis comprising genomic copy number variants, gene expression and miRNA.
In this study, we investigated genomic aberrations from late- passage LCLs using exome array and performed integrated analysis combining genomic aberration and expression patterns of gene expression and miRNA expression. Our results would suggest that careful interpretation of gene expression results is required for late- passage LCLs with genomic aberrations.
４０
2. METERIALS AND METHODS
2.1 Samples
Sample from 46 participants were study descriptions were published previously (23). Blood DNAs from 16 individuals were obtained from a part of Korean Genome Epidemiologic Study (KoGES) cohorts. Long-term subculturing of 16 LCL strains to obtain immortalized LCLs was performed as previously described (12).
Among 32 samples 14 strains among them were subcultured for 160 passages. For this study, early- (passage 6) and late-passage (between
170-180 passage) were used for expression profiling and genotyping
(Table 6).
４１
Table 6. Description of samples
Passage Sample ID Gender Age Early (p4) Late (p160)
A01 F 65 O O
A02 M 64 O O
A03 M 45 O O
A04 M 57 O O
A08 F 53 O O
A09 F 58 O X
A10 F 68 O O
K1 F 61 O O
K3 M 64 O O
K4 M 41 O X
K5 M 65 O O
K6 M 58 O O
K7 F 55 O O
K8 M 47 O O
K9 M 69 O O K10 F 43 O O
４２
2.2. Genotyping
We genotyped blood DNA and LCL DNA samples using the
HumanExome BeadChip v1.1 array (Illumina, inc., San Diego, CA) containing 242,901 markers. Genotyping was performed according to the manufacturer’s protocol. The GenTrain 2.0 clustering algorithm of the Iluumina GenomeStudio v2011.1 software was used for genotyping.
Samples with call rate >98% were used to define genotype clusters.
The no-call threshold was also set to 0.15. In addition, we excluded female Y SNPs during calculation of SNP statistics. Subsequently we excluded the A9, K4 strains from further analysis because there is no late passage.
2.3. Gene expression microarray
Gene expression data from LCL strains were published previously
(12). Briefyl, samples using the GeneChip Human Gene 1.0 ST Array
(Affymetrix, inc., Santa Clara, CA) containing 764,885 differential probes. Expression levels of all transcripts on chips were utilized for
４３ data normalization.
2.4. miRNA microarray
miRNA expression data were used from previously published work (11). The Human V2 microRNA expression beadchip (Illumina, inc., San Diego, CA) array was used for miRNA analysis. Quality control process such as quantile normalization was conducted by
Array Assist 5.5.1 software (Stratagene, LA Jolla, CA, USA).
2.5. Gene ontology analysis
To identify functions of CN-expression level associated genes, gene ontology terms were assessed at P-value (<0.05) using Database for
Annotation, Visualization and Integrated Discovery (DAVID)
(http://david.abcc.ncifcrf.gov) (24). For multiple correction, False
Discovery Rate (FDR) and bonferroni corrected P-values were calculated.
４４
3. RESULTS
3.1. Exome array genotyping
We isolated genomic DNA from blood and LCL of 16 individuals and genotyped the DNA samples using the Illumina exome array.
Overall, the mean genotype call rate for samples were 99.9%, 99.9%, and 98.2% for blood DNA, early-passage LCLs and late-passage LCLs, respectively.
3.2. CNV and LOH detection
The detection of CNVs was performed using CNVPartition
(Illumina) (25) and PennCNV (26). We identified 90 autosomal CNV regions of the genomes of 16 individuals. The average CNV size was approximately 14.5 kb (AppendixⅠ). Moreover, LOH was observed on chromosome 6p, 9q, 16q, and 22q in the late-passage LCL strains A02,
A03, A10, and K10 by CNVPartition (Table 7). Detected LOHs were in good agreement with our previous work using GWAS chip, and
４５ further confirmed that LCLs at late stages of propagation are not reliable source of DNA for genome analysis.
４６
Table7. Detecting LOH regions
Sample ID Chr Start End Size Value Comment
A02T 22 17073119 38111900 21038781 2 LOH Region
22 38119272 51181759 13062487 2 LOH Region
A03B 6 32682019 33775446 1093427 2 LOH Region
A03E 6 32682019 33775446 1093427 2 LOH Region
A03T 6 32682019 33775446 1093427 2 LOH Region
16 46637916 71007323 24369407 2 LOH Region
16 71026112 90130152 19104040 2 LOH Region
A10B 6 33194717 34256568 1061851 2 LOH Region
A10E 6 33194717 34256568 1061851 2 LOH Region
A10T 6 33194717 34256568 1061851 2 LOH Region
16 77323247 83712011 6388764 2 LOH Region
K10B 9 90503433 99064254 8560821 2 LOH Region
K10E 9 90503433 99064254 8560821 2 LOH Region
K10T 9 90503433 99064254 8560821 2 LOH Region CNV, copy number variation; LOH, loss of heterozygosity; chr, chromosome
４７
3.3. Identification of differentially expressed genes
We performed gene expression and miRNA microarray experiments for 14 pairs of early passage and late passage LCL strains to identify expression changes during long-term culture. Differentially
Expressed Genes (DEG) list was generated using expression alterations
(log2-fold change M≥1 or M≤-1).
Totally, 792 probe showed expression change in late-passage LCLs compared to matched early-passage LCLs (Table 8). In at least 5 of 14 samples, 20 probes were differentially expressed with greater than 2- fold change (Table 9).
４８
Table 8. Integration of gene expression data in ≥5 samples with 10 top signals ordered by M-value
Rank Sample (N) Probe ID Cytoband Gene symbol Start BP Stop BP M(Min, Max) 1 10 7902541 1q31.1 IFI44L 79086116 79108484 (-7.86, -1.25) 2 11 7981728 14q32.33 IGHV3-52 107042368 107042628 (-7.26, -1.01) 3 5 8071658 22q11.2 IGLV7-46 22724162 22724454 (-7.13, -1.01) 4 9 7981724 14q32.33 IGHV3-43 106925347 106926484 (-7.08, -1.18) 5 10 8043470 2p11.2 IGKV3D-11 90211959 90212242 (-6.63, -1.32) 6 12 7981732 14q32.33 IGHV4-61 107094941 107095600 (-6.58, -1.52) 7 11 8043431 2p11.2 IGKV1D-33 89953061 89954862 (-6.37, -1.29) 8 12 8068713 21q22.3 MX1 42798144 42831141 (-6.22, -1.06) 9 10 7981730 22q11.2 IGLJ3 107048669 107048973 (-6.07, -1.01) 10 14 8112428 5q12 CD180 66478116 66492612 (-5.97, -1.69) Seleted in the top 10 of 792 probes
BP, base pair; M, log-intensity ratios
４９
Table 9. Integration of miRNA expression data in >5 samples with 10 top signals ordered by M-value
Sample Rank Probe ID Chr Position Target Genes M (Min, Max) (N) LRP1, ZEB1, SIP1, DDx5, INPPL1, MED1, E2F5, E2F1, ERBB3, ZEB2, PRKCE, VEGFA, SIGMAR1, IL24, IL32, 1 7 hsa-miR-205 1 207672133 EGLN2, TP73, CYR61, CTGF, ERBB2, LAMC1, LRRK2, TES1, (2.58, 6.21) SRC BMI1, ZEB2, BIRC5, MPL, N4BP1, OTUB1, TEX261, AKT2, 2 5 hsa-miR-708 11 78790792 CD44, TMEM88 (2.06, 6.06) 3 9 hsa-miR-99a 21 16833291 RAVER2, FGFR3, SERPINE1, IGF1R, MTOR (2.38, 5.53) BMPR1B, EIF4EBP1, HMGA2, HMGA1, GLI1, NKIRAS2, SMO, TP53, VDR, SGPL1, BAK1, ERBB3, ERBB2, BMF, KLF13, NTRK3, LIN28A, BFB, MKNK2, AKT1, CYP24A1, hsa-miR- 1688443, RAF1, PRDM1, IRF4, GRIN2A, CDKN2A, KRT7, TP53INP1, 4 10 21, 11 (2.06, 5.17) 125b 121475749 E2F3, IGF2, LIN28B, BBC3, PPP1CA,PRKRA, BCL2, ETS1, RPS6KA1, TNFAIP3, PIGF, BCL3, TBC1D1, DGAT1, FGRF2, ARID3B, TRIM71, SMAD4, MCL1, IL6R, STARD13, ABTB1, HK2, E2F2, MMP13, MAPK14, MUC1, NES hsa-miR- 5 9 8 141811925 ARHGDIA, MPL, N4BP1, E2F6 (-5.15, -2.07) 151-5p 6 8 hsa-miR-326 11 74723820 GLI1, SMO, NOTCH1, NOTCH2, MSH3, PKM, CD9 (2.77, 4.81) hsa-miR-28- 7 12 3 189889275 CDKN1A, MPL, N4BP1, OYUB1, TEX261, E2F6, ZCCHC3 (-4.59, -2.42) 5p hsa-miR- 8 6 11 110888884 BCL2, CREB1, MET, CDK6, CDK4, CCNE2, MYC, HNF4A (2.35, 4.36) 34b* 154656831, MMP13, REST, CDH1, POU2F2, BCL6, ETS1, RAB34, BACE1, PRDM1, NFKB1, FOXO1, NTRK3, NR2E1, ONECUT2, CDX2, 9 7 hsa-miR-9 1, 5, 15 87998499, AP3B1, CCNG1, SRF, SIRT1, TGFB1, SOCS5, ID2, FOXO3, (-4.18, -2.06) 87712266 CCND1, VIM, VEGFA, CHMP2B, STMN1, GRN, CD34 10 6 hsa-miR-30a 6 72170041 BDNF, NOTCH1, BECN1, TNRC6A (-4.12, -2.13) Seleted in the top 10 of 20 probes; Chr, chromosome; M, log-intensity ratios ５０
3.4. Functional correlation of DEGs
To identify functions of differentially expressed genes, we performed Gene Ontology analysis the DAVID. The list of statistically significant GO terms obtained at Benjamini corrected p-values < 0.05.
Table 10 shows list of statistically significant GO term with Benjamini corrected p-values <0.05. Functional annotation results of identified gene show that these gene are mainly related to immune response, regulation of cell proliferation, cell death, and apoptosis (Table 11).
５１
Table 10. Functional annotation clusters of significant differentially expression genes from gene expression data with top 10 clusters ordered by FDR
P- Term Genes Count % Bonferroni FDR Value AQP9, IFI44L, LY9, HLA-DMB, TLR7, SKAP1, IL10, CD96, CXCR4, SEMA7A, CCL3L3, IL1A, LTA, RAB27A, LAIR1, GBP5, NCF2, CMKLR1, NCF4, CCL4L1, GEM, TRAT1, PDCD1LG2, CCR8, CCR7, CCR6, LAX1, LILRB4, FAIM3, AICDA, GBP4, GBP2, GBP1, GPR183, CCL3, TNF, ENPP2, IFITM2, IFITM3, CCR1, OAS3, ACP5, RSAD2, 11.0 1.04E- immune response 81 2.77E-15 2.77E-15 OAS1, OAS2, IL7R, CCL5, CCL4, IFI35, CCL22, CCL20, XBP1, TAP2, 2 18 TAP1, CD24, IGKC, CD27, FYB, PTPRC, CR1, IL2RA, CR2, TNFSF4, IGKV3D-11, IGJ, CD1C, SMAD3, MYO1F, SLAMF7, CD180, AIM2, PSMB9, BTLA, DDX58, CD55, TNFSF10, CYBB, APOL1, RGS1, TGFBR3, IFI6 CCL3, TNF, FUT8, ENPP2, VIM, CCL5, ITGB1, CCL4, EPHB1, IL10, VCAM1, NRCAM, CD9, CCL22, APP, PTK2, CXCR4, ROBO1, LHX2, ROBO2, CD24, SEMA3A, SELPLG, PPAP2B, VNN2, FN1, SYK, PTPRK, 6.03E- cell motion 48 6.53 1.61E-05 8.04E-06 EGR2, ARID5B, ANXA1, CCL4L1, ITGA4, STAT3, ASCL1, CCR6, 09 PARP9, FYN, ITGA5, FOXG1, LRP6, TGFBR3, SDCBP, EFNA5, JAK2, APBB2, FEZ1, MYH10 PTPRC, TNF, CCL4L1, RSAD2, IFI44, STAT1, CCL5, CCL4, TLR7, IFI35, 4.68E- response to virus STAT2, DDX58, IRAK3, PLSCR1, CCL22, ISG15, CXCR4, EIF2AK2, 20 2.72 1.25E-04 4.16E-05 08 MX1, MX2 TNF, ZAK, BLK, TLR7, IL10, TRIB1, STAT4, RASGRP3, CXCR4, PRKACB, RAPGEF2, INSR, CD27, MAP2K6, GHR, SYK, FYB, ZFP36, 6.89E- protein kinase cascade PTPRC, ARHGEF6, STRADB, SMAD1, STAT1, STAT3, STAT2, DAPK1, 39 5.31 1.84E-04 4.60E-05 08 MAP4K3, TNFRSF10A, MAP4K4, DUSP4, PRLR, FYN, LAX1, JAK1, TGFBR3, JAK2, ERC1, LRRK2, F2R GPR183, TNF, BLM, IL7R, ITGB1, TLR7, IL10, VCAM1, CD9, CXCR4, 1.18E- cell activation BCL11A, NDRG1, CD24, DPP4, LTA, KIF13B, SYK, RAB27A, EGR1, 33 4.49 3.16E-04 6.32E-05 07 PTPRC, TNFSF4, SMAD3, MYO1F, SLAMF7, ITGA4, PLSCR1, PRLR, ５２
P- Term Genes Count % Bonferroni FDR Value FYN, LAX1, LCK, RIPK2, AICDA, F2R
SGMS1, TLR7, IL10, CXCR4, CCL3L3, MX1, MX2, IL1A, RAB27A, PLD1, NCF2, CCL4L1, TRAT1, CCR7, CCR6, MNDA, FAIM3, RIPK2, PRF1, CCL3, TNF, CCR1, RSAD2, PXK, CCL5, ITGB1, CCL4, CCL22, CCL20, 1.72E- defense response 53 7.21 4.58E-04 7.63E-05 TAP2, TAP1, CD24, FN1, PTPRC, CR1, IL2RA, TNFSF4, CR2, HCK, 07 RNASE6, ANXA1, MYO1F, SMAD1, SLAMF7, CD180, STAT3, EPHA3, DDX58, CD55, CYBB, APOL1, ALOX5, F2R HNF1B, AQP9, IL10, CREB3L2, PRKACB, CASP1, INSR, LTA, GHR, EGR1, PLD1, EGR2, GRIN2A, LEF1, CD38, BTG2, RIPK2, SORT1, GNB4, EIF2AK2, ME1, PRF1, TNF, CYP1B1, MCL1, ACP5, HSPA1A, CDH1, response to organic 4.04E- HSPA1B, CCL5, LIN28B, TRIB1, IRAK3, BCHE, DGKD, TAP2, PPP3CA, 58 7.89 1.08E-03 1.54E-04 07 substance CD24, CD27, TXNIP, MAP1B, SMAD3, SMAD1, STAT1, STAT3, EPHA3, ABCB4, CYP7B1, DUSP4, PLA2G4A, EPS8, ID2, FYN, TGFBR3, PTCH1, JAK2, MGST1, F2R, VLDLR CCL3, TNF, F13A1, CCR1, ITGB3, PXK, SGMS1, CCL5, TLR7, CCL4, IL10, CD9, CCL22, CCL20, CXCR4, CCL3L3, CD24, IL1A, FN1, RAB27A, CR1, IL2RA, CR2, TNFSF4, MAP1B, ANXA1, GRIN2A, SMAD3, 4.36E- response to wounding 47 6.39 1.16E-03 1.45E-04 CCL4L1, SMAD1, STAT3, CD180, EPHA3, PLSCR1, CD55, CCR7, CYBB, 07 F5, GNAQ, ITGA5, SERPINB2, RIPK2, JAK2, CTSB, ALOX5, MYH10, F2R MEF2C, ZAK, SGMS1, IL10, PCGF2, APP, FOXO3B, CASP1, MX1, IL1A, LTA, MAP2K6, RAB27A, GHR, ARHGEF6, GRIN2A, PIM2, PRKCE, DAPK1, TNFRSF10A, SERPINB9, TNFRSF9, CD38, BTG2, TNFRSF10D, regulation of HIPK2, LCK, SERPINB2, RIPK2, SORT1, FAIM3, CTSB, LRRK2, TNF, 9.02E- 62 8.44 2.40E-03 2.67E-04 programmed cell death SYVN1, MCL1, HSPA1A, CDH1, HSPA1B, ITM2B, VDR, HSPA5, CD24, 07 CD27, TXNIP, PTPRC, IL2RA, ANXA1, SMAD3, MAL, STRADB, SLAMF7, STAT1, ATF5, PLA2G4A, TNFSF10, PRLR, JAK2, APBB2, PERP, IFI6, F2R, TP53INP1 MEF2C, ZAK, SGMS1, IL10, PCGF2, APP, FOXO3B, CASP1, MX1, IL1A, LTA, MAP2K6, RAB27A, GHR, ARHGEF6, GRIN2A, PIM2, PRKCE, 9.99E- regulation of cell death 62 8.44 2.66E-03 2.66E-04 DAPK1, TNFRSF10A, SERPINB9, TNFRSF9, CD38, BTG2, TNFRSF10D, 07 HIPK2, LCK, SERPINB2, RIPK2, SORT1, FAIM3, CTSB, LRRK2, TNF, ５３
P- Term Genes Count % Bonferroni FDR Value SYVN1, MCL1, HSPA1A, CDH1, HSPA1B, ITM2B, VDR, HSPA5, CD24, CD27, TXNIP, PTPRC, IL2RA, ANXA1, SMAD3, MAL, STRADB, SLAMF7, STAT1, ATF5, PLA2G4A, TNFSF10, PRLR, JAK2, APBB2, PERP, IFI6, F2R, TP53INP1 All of functional annotation clusters are shown in appendix Ⅱ
False discovery rate (FDR) are corrected based on Benjamini &Hochberg’s method
５４
Table 11. Functional annotation clusters of significant differentially expression genes from miRNA expression data with top 10 clusters ordered by FDR
Coun P- Term Genes % Bonferroni FDR t Value BMI1, E2F3, CDX2, PPARG, FOXO1, ZEB1, NR2E1, PTEN, TGFB1, GLI1, BDNF, CASP3, CDKN2A, SERPINE1, FOSL1, MYC, TP53, CDK6, IL6R, CDK4, MYCN, SUZ12, SMO, CCND1, HIF1A, 31.6 4.40E- regulation of cell proliferation HNF4A, GRN, VEGFA, LAMC1, FGFR3, GNAI2, ERBB3, 58 1.04E-24 1.04E-24 9 28 ERBB2, SOX2, BMPR2, SOX4, ITGB1, IGF1R, CD9, VDR, BCL2, PRKRA, ZAP70, BCL6, CEBPA, FLT1, BECN1, SMAD4, IGF2, SIRT1, NOTCH2, NOTCH1, CDKN1A, ID2, ETS1, NOTCH4, FABP4, MTOR FOXO1, NFKB1, FOXO3, PTEN, NR2E1, TGFB1, AKT1, BAK1, CASP3, BDNF, CDKN2A, CD44, FOSL1, MYC, TERT, ARHGEF3, GRIN2A, TP53, IL6R, PRKCE, SMO, IGF2R, 28.9 5.43E- regulation of programmed cell death VEGFA, LRRK2, TNFAIP3, MCL1, ERBB3, ERBB2, SOX4, 53 1.29E-19 6.44E-20 6 23 CDH1, SRC, IGF1R, VDR, BCL2, PRKRA, BCL3, BCL6, BMF, ARHGDIA, TEX261, BECN1, CREB1, BIRC5, IGF2, SIRT1, TP73, ATM, NOTCH2, NOTCH1, CDKN1A, ETS1, BBC3, TP53INP1 FOXO1, NFKB1, FOXO3, PTEN, NR2E1, TGFB1, AKT1, BAK1, CASP3, BDNF, CDKN2A, CD44, FOSL1, MYC, TERT, ARHGEF3, GRIN2A, TP53, IL6R, PRKCE, SMO, IGF2R, 28.9 6.43E- regulation of cell death VEGFA, LRRK2, TNFAIP3, MCL1, ERBB3, ERBB2, SOX4, 53 1.52E-19 5.08E-20 6 23 CDH1, SRC, IGF1R, VDR, BCL2, PRKRA, BCL3, BCL6, BMF, ARHGDIA, TEX261, BECN1, CREB1, BIRC5, IGF2, SIRT1, TP73, ATM, NOTCH2, NOTCH1, CDKN1A, ETS1, BBC3, TP53INP1 FOXO1, NFKB1, FOXO3, PTEN, NR2E1, TGFB1, AKT1, BAK1, CASP3, BDNF, CDKN2A, CD44, FOSL1, MYC, TERT, 28.4 2.42E- regulation of apoptosis 52 5.74E-19 1.43E-19 ARHGEF3, GRIN2A, TP53, IL6R, PRKCE, SMO, IGF2R, 2 22 VEGFA, TNFAIP3, MCL1, ERBB3, ERBB2, SOX4, CDH1, SRC, ５５
Coun P- Term Genes % Bonferroni FDR t Value IGF1R, VDR, BCL2, PRKRA, BCL3, BCL6, BMF, ARHGDIA, TEX261, BECN1, CREB1, BIRC5, IGF2, SIRT1, TP73, ATM, NOTCH2, NOTCH1, CDKN1A, ETS1, BBC3, TP53INP1
E2F1, E2F3, CDX2, PPARG, FOXO1, NFKB1, FOXO3, ZEB1, CBFB, TGFB1, GLI1, AKT1, H2AFX, FOSL1, MYC, AKT2, EGR2, TP53, IL6R, CDK4, HMGA1, CCND1, HIF1A, CCND3, HNF4A, positive regulation of macromolecule 28.9 6.34E- VEGFA, PRDM1, LRRK2, MED1, SOX2, ONECUT2, BMPR2, 53 1.50E-18 3.00E-19 metabolic process 6 22 SOX4, EGLN2, SRF, IGF1R, BCL2, BCL3, CEBPA, KLF13, SMAD7, CREB1, SMAD4, IGF2, DDX5, TP73, NOTCH1, ETS1, PLK1, MAPK14, NOTCH4, MTOR, IRF4 BMI1, E2F3, FGFR3, CDX2, GNAI2, ERBB2, SOX2, SOX4, ITGB1, NR2E1, TGFB1, GLI1, IGF1R, BCL2, ZAP70, BCL6, positive regulation of cell 20.2 3.98E- MYC, FOSL1, FLT1, CDK6, IGF2, IL6R, CDK4, MYCN, SUZ12, 37 9.44E-17 1.57E-17 proliferation 2 20 SMO, CDKN1A, CCND1, NOTCH1, HIF1A, ID2, GRN, VEGFA, NOTCH4, FABP4, MTOR, LAMC1 CDX2, SOX2, PPARG, BMPR2, NFKB1, FOXO3, SRF, TGFB1, positive regulation of cell AKT1, BDNF, BCL2, MAPT, ZAP70, ARHGDIA, AP3B1, LPL, 15.3 1.33E- 28 3.14E-15 4.49E-16 differentiation SMAD4, IGF2, SOCS5, IL6R, NTRK3, SMO, NOTCH1, HIF1A, 0 18 ID2, ETS1, MAPK14, BMPR1B E2F1, E2F3, CDX2, SOX2, PPARG, ONECUT2, SOX4, FOXO1, NFKB1, FOXO3, ZEB1, SRF, CBFB, TGFB1, GLI1, AKT1, IGF1R, BCL3, FOSL1, MYC, AKT2, CEBPA, EGR2, KLF13, CREB1, 22.9 1.08E- macromolecule biosynthetic process 42 2.57E-14 3.21E-15 TP53, SMAD4, IGF2, DDX5, CDK4, HMGA1, TP73, NOTCH1, 5 17 HIF1A, HNF4A, ETS1, MAPK14, VEGFA, NOTCH4, MTOR, IRF4, MED1 E2F1, E2F2, CCNG1, ITGB1, PTEN, TGFB1, CCNE2, AKT1, CDC42, BAK1, CASP3, CDKN2A, BCL2, BCL6, H2AFX, MYC, 16.9 2.38E- GO:0051726~regulation of cell cycle 31 5.64E-14 6.27E-15 FOSL1, ROCK2, TP53, CDK6, IGF2, BIRC5, CDK4, ATM, 4 17 CDKN1A, CCND1, ID2, HNF4A, CCND3, ETS1, MAPK14
５６
Coun P- Term Genes % Bonferroni FDR t Value E2F1, E2F3, CDX2, SOX2, PPARG, ONECUT2, SOX4, FOXO1, NFKB1, FOXO3, ZEB1, SRF, CBFB, TGFB1, GLI1, AKT1, IGF1R, GO:0031328~positive regulation of BCL3, FOSL1, MYC, AKT2, CEBPA, EGR2, KLF13, CREB1, 22.9 5.54E- 42 1.31E-13 1.31E-14 cellular biosynthetic process TP53, SMAD4, IGF2, DDX5, CDK4, HMGA1, TP73, NOTCH1, 5 17 HIF1A, HNF4A, ETS1, MAPK14, VEGFA, NOTCH4, MTOR, IRF4, MED1 All of functional annotation clusters are shown in appendix Ⅲ
False discovery rate (FDR) are corrected based on Benjamini &Hochberg’s method
５７
3.5. Identification of DEGs overlapped with CNVs
Differentially expressed genes and miRNAs overlapped with
CNVs were analyzed. In total gene expression level of 24 regions were upregulated (min, max; -5.03, -0.40) and downregulated (0.57) at late passage (Table 12). Moreover, result of miRNA expression change shows that expression of 6 regions identified from 10 individuals was downregulated (Table 13).
５８
Table 12. Integration of CNVs with gene expression data
ID Chr Start BP End BP SNP (N) SIZE CN Start SNP End SNP M K09 1 100174455 100757001 113 582547 1 exm1689665 exm78060 -0.66 K10 1 159148513 159284385 39 135873 1 exm-rs1474747 exm114211 -3.26 A10 2 113496452 113540315 33 43864 1 exm221735 exm221878 -0.68 K10 3 39139755 39230912 130 91158 1 exm301893 exm302596 -3.63 A08 4 84185440 84580859 68 395420 1 exm410159 exm2265728 -0.94 K09 5 36954812 37381773 77 426962 1 exm-rs292182 exm451022 -0.40 A03 6 6145863 8097529 197 1951667 1 exm2244334 exm515512 -1.87 K06 6 24403275 24716516 107 313242 1 exm519703 exm2118208 -0.43 K10 9 90497810 90503734 41 5925 1 exm2248375 exm2259471 -3.50 K08 10 45407004 45499378 32 92375 1 exm821217 exm821439 -0.46 K09 10 98741206 98744853 37 3648 1 exm845634 exm845804 -0.49 K10 10 45407004 45499378 32 92375 1 exm821217 exm821439 -5.03 A02 11 57885990 57996312 58 110323 1 exm911875 exm912245 -0.41 A03 11 55861030 55905194 41 44165 1 exm908626 exm908870 -0.83 A10 11 111896242 112025712 28 129471 1 exm955584 exm955785 -0.69 K10 11 5528864 5530764 23 1901 1 exm883051 exm883154 -3.15 K08 12 121442242 121476693 22 34452 1 exm1044053 exm1044161 -0.60 K05 15 56657796 56756420 29 98625 1 exm1164400 exm1164537 -0.80 K09 15 56657796 56756420 29 98625 1 exm1164400 exm1164537 -1.05 K05 17 29159404 29227513 38 68110 1 exm2252932 exm1309374 -0.76 K06 18 580409 645081 19 64673 1 exm1371438 exm1916048 -0.41 K09 18 28898294 29056170 103 157877 3 exm1380618 exm1381142 0.57 K05 19 37870148 38231008 103 360861 1 exm1460451 exm1461223 -0.56 K09 19 36884211 38231008 201 1346798 1 exm1459363 exm1461223 -0.49 Chr, chromosome; BP, base pair; CN, copy number; M, log-intensity ratios ５９
Table 13. Integration of CNVs with miRNA expression data
SNP ID Chr Start BP End BP Size CN Start SNP End SNP miRNA ID M (N) K05 1 220160514 220445641 61 285128 1 exm1762440 exm2250764 hsa-miR-215 -0.32 hsa-miR-664* -0.93
hsa-miR-664 -0.26 K09 1 220142246 220383822 67 241577 1 exm149901 exm1762674 hsa-miR-664* -0.51 hsa-miR-664 -0.44
K09 4 113356306 113574284 55 217979 1 exm419331 exm419709 hsa-miR-302a* -0.49 K05 7 1012865 1098100 25 85236 1 exm597627 exm597880 hsa-miR-339-5p -0.25 hsa-miR-339-3p -0.50 K07 7 1012865 1523698 90 510834 1 exm597627 exm598508 hsa-miR-339-5p -0.34 hsa-miR-339-3p -0.52
K09 7 1012865 1608938 117 596074 1 exm597627 exm598998 hsa-miR-339-5p -0.03 hsa-miR-339-3p -0.53 K05 9 139089445 139618041 253 528597 1 exm796918 exm799253 hsa-miR-126* -1.68 hsa-miR-126 0.46 K09 15 89803944 90185592 177 381649 1 exm1187273 exm1188286 hsa-miR-9* -0.71 hsa-miR-9 -0.92
K05 15 89803944 90294028 224 490085 1 exm1187273 exm1188609 hsa-miR-9* -3.01 hsa-miR-9 -3.02 K10 17 56383204 56436167 48 52964 1 exm2253099 exm1340286 hsa-miR-142-5p -15.21 hsa-miR-142-3p -15.18 Chr, chromosome; BP, base pair; SNP, single nucleotide polymorphism; CN, copy number; M, log-intensity ratios
６０
3.6. Functional correlation of DEGs overlapped with CNVs
Functional annotation of CNV regions overlapping both gene expression miRNa expression region was conducted using DAVID.
Major functions of CNVs are related to regulation of transcription,
DNA-dependent, regulation of RNA metabolic process, transcription, regulation of transcription, sensory perception of smell, and sensory perception of chemical stimulus at the 80 genes expression changed with CNVs (Table 14). Expression change of CNV overlapping 3,204 predicted target gene was related to intracellular transport, protein localization, cell migration and so on (Table 15).
６１
Table 14. Functional annotation clusters of significant DEGs with CNVs from gene expression data
Term Genes Count % P-Value Bonferroni FDR
HKR1, ZNF57, ZNF345, ZNF829, ZNF540, ZNF420, ZNF607, ZNF527, ZNF566, ZNF529, ZNF568, ZNF567, regulation of transcription, DNA- RREB1, ZFP30, ZNF569, ZNF790, ZNF793, ZNF585A, 27 25.96 4.48.E-06 2.63.E-03 2.63.E-03 dependent ZNF585B, ZFP82, CSRNP1, ZNF461, ZNF570, ZNF571, ZNF382, BMP6, ZNF573 HKR1, ZNF57, ZNF345, ZNF829, ZNF540, ZNF420, ZNF607, ZNF527, ZNF566, ZNF529, ZNF568, ZNF567, regulation of RNA metabolic RREB1, ZFP30, ZNF569, ZNF790, ZNF793, ZNF585A, 27 25.96 6.77.E-06 3.97.E-03 1.99.E-03 process ZNF585B, ZFP82, CSRNP1, ZNF461, ZNF570, ZNF571, ZNF382, BMP6, ZNF573 HKR1, ZNF57, ZNF781, ZNF345, ZNF829, ZNF540, ZNF420, ZNF607, ZNF527, ZNF566, ZNF529, ZNF568, transcription ZNF567, RREB1, ZFP30, ZNF260, ZNF569, ZNF790, 29 27.88 1.06.E-05 6.24.E-03 2.08.E-03 ZNF793, ZNF585A, ZNF22, ZNF585B, ZFP82, CSRNP1, ZNF461, ZNF570, ZNF571, ZNF382, ZNF573
OR9I1, OR8J3, OR8H3, OR8I2, OR10Q1, OR8H2, sensory perception of smell 11 10.58 1.96.E-04 1.09.E-01 2.84.E-02 OR10J3, OR9Q1, OR1S2, OR9Q2, OR1S1
HKR1, ZNF57, ZNF781, ZNF345, ZNF829, ZNF540, ZNF420, ZNF607, ZNF527, ZNF566, ZNF529, ZNF568, ZNF567, RREB1, ZFP30, ZNF260, ZNF569, ZNF790, regulation of transcription 30 28.85 2.04.E-04 1.13.E-01 2.37.E-02 ZNF793, ZNF585A, ZNF22, ZNF585B, ZFP82, CSRNP1, ZNF461, ZNF570, ZNF571, ZNF382, BMP6, ZNF573 sensory perception of chemical OR9I1, OR8J3, OR8H3, OR8I2, OR10Q1, OR8H2, 11 10.58 4.47.E-04 2.31.E-01 4.29.E-02 stimulus OR10J3, OR9Q1, OR1S2, OR9Q2, OR1S1 False discovery rate (FDR) are corrected based on Benjamini &Hochberg’s method ６２
Table 15. Functional annotation clusters of significant DEGs with CNVs from miRNA expression data with top 5 clusters ordered by FDR
Term Genes Count % P-Value Bonferroni FDR SEC31A, CHMP5, C16ORF70, LHCGR, APP, GBF1, ABRA, STAM, TLK1, KIF13B, RAB27A, KIF5B, VPS45, MYH4, OPTN, AP4M1, MYH9, VTI1A, MAPK1, KRT18, ATP2C1, JUN, TXNDC5, TBRG1, F2, TRAPPC4, MRPL45, TRAPPC3, KIF4B, RIMS2, RIMS1, STX12, KIAA1012, TRAM1, SEC23IP, HAP1, RANBP17, OSBPL5, RGPD2, RGPD1, RGPD4, RGPD3, NXF2, TINAGL1, HNRNPA1, CBLB, ATP2A2, MLX, PCNA, SYTL4, BET1L, HGS, NUTF2, GOSR2, SMURF1, RERE, ARSB, SPG7, HTATIP2, PDIA3, FGF9, MYO7A, WASF2, BNIP3, AP3S1, AP1S3, AP1S2, LONP2, GOLGA5, FGF2, DNAJC19, AP3B1, KDELR2, STX1A, ARHGEF2, STX2, MYRIP, PSEN1, NUP205, TOMM20, MGEA5, SORT1, GNAS, BID, YWHAZ, BET1, MUDENG, SET, BCL2, EXOC4, PPP3CB, CHM, RAB11A, BCL6, PEX13, CD24, intracellular RAB2A, FYB, ACTC1, UPF1, IPO11, YWHAB, NLGN1, EXPH5, PPP1R10, STRADB, COG3, COG4, COG5, ERBB2IP, GSK3B, YWHAQ, AP4B1, COG1, DNM2, SSR3, 214 4.45 1.08E-07 5.64E-04 5.64E-04 transport NCBP2, XPO1, GRPEL2, SRP14, NCBP1, GRPEL1, AP4E1, AP1G1, EIF5A, CNO, CSPG5, SRP19, AGXT, KLHL2, TGFB1, PUM1, SLC25A27, SCAMP1, NUP133, ARNTL, TNNT2, COPG2, ARRB1, LYST, VAMP7, USO1, SLC25A37, AKAP6, ERC1, VPS26A, LRPPRC, BAT1, DRD1, ARFGAP3, NAPG, STAM2, ABCA1, NAPB, LMAN1, NPM1, DOPEY1, AP2M1, RHOBTB3, SEC61A2, RAB8A, SMG1, ICMT, PPIF, SLC25A12, TRNT1, UCP3, TSC1, AKTIP, VCP, TOMM70A, NEDD4, RHOT1, SEC13, XPO7, HDAC6, MYH10, COPA, CLTA, ATL2, PEX5, PEX7, NDE1, SLC1A3, ZFYVE16, GOPC, RANBP2, KPNB1, CLINT1, SEC23A, ARL1, SYNRG, HSP90AA1, PRKCI, TIMM23, M6PR, KIF1C, ATG4D, KIF1B, IPO7, ATG4A, IPO4, COPG, STON1, MUTED, TPM1, AP3M2, CEP57, TAP2, BCAP29, PAFAH1B1, EHD1, NEFL, SRP14P1, NXF2B, SFRS13A, MON2, SFRS13B, JAK2 OXA1L, SEC31B, SEC31A, CHMP5, SLC9A2, LHCGR, C16ORF70, GRIN3B, RAB1A, CTNNB1, FAM125A, APOB, VPS13D, KIFAP3, AAGAB, ABRA, STAM, TLK1, NUP35, RAB27A, KIF13B, PTPRK, CD3G, VPS45, GRIN2A, OPTN, AP4M1, MYH9, protein VTI1A, MAPK1, KRT18, CD36, LCA5, RAB19, JUN, BACE2, F2, RAB12, MRPL45, RAB10, RTP1, RAB40C, CCDC91, ARF6, ARF5, RIMS2, RIMS1, RAB40B, STX12, 274 5.70 1.95E-07 1.01E-03 5.08E-04 localization DMD, TNKS, TRAM1, SEC23IP, RANBP17, RGPD4, RGPD3, RAB7L1, DVL1, CBLB, ARF4, PCNA, SYTL4, BET1L, HGS, GOSR2, NUTF2, SMURF1, RERE, MSR1, PDIA3, FGF9, AP1AR, PPARG, AP3S1, AP1S3, BLZF1, AP1S2, LONP2, DNAJC14, RAB6A, COX18, AGAP1, FGF2, DNAJC19, DHCR24, AP3B1, KDELR2, STX1A, ６３
Term Genes Count % P-Value Bonferroni FDR ARHGEF2, STX2, RAB4A, SENP2, ZDHHC15, ZDHHC17, MYRIP, RAB11FIP2, PSEN1, LAX1, NUP205, MGEA5, RAB5A, TOMM20, SORT1, GNAS, EIF5A2, SERP1, BID, RAB3A, SHROOM2, YWHAZ, BET1, MUDENG, UEVLD, MORC3, EXOC4, PPP3CB, CHM, RAB11A, APBA2, BCL6, PEX13, CD24, PCSK5, RAB2A, FYB, IPO11, YWHAB, NLGN1, EXPH5, PPP1R10, STRADB, COG3, COG4, COG5, TEX15, RAB30, COG6, RAB37, GRIA2, ERBB2IP, GSK3B, MCFD2, RAB34, YWHAQ, RAB39, AP4B1, COG1, SSR3, XPO1, SRP14, GRPEL2, GRPEL1, AP4E1, AP1G1, XPO4, EIF5A, SRP19, AGXT, TGFB1, KLHL2, CXCL10, ANK3, RABGEF1, EGFR, SCAMP1, NUP133, ACTN4, SGOL2, LRP1B, ARNTL, TNS4, COPG2, VAMP7, LYST, FGFR1OP, USO1, AKAP6, AKAP7, COL1A1, PDCD6IP, ERC1, VPS26A, CAV1, ARFGAP3, DRD1, AFTPH, NAPG, DRD2, STAM2, SNX7, SNX4, NAPB, ABCA1, SNX3, LMAN1, CHMP2B, KATNA1, NPM1, DOPEY1, SRGN, SEC61A2, AP2M1, PRAF2, RAB8A, MYO1C, LIN7C, ITGA2, ICMT, ATG3, RAB33A, RAB33B, TRNT1, PLEKHA8, VCP, AKTIP, NEDD4, TOMM70A, SEC13, YIPF5, ATG16L1, XPO7, ATG16L2, HDAC6, COPA, CLTA, TLN1, PAX6, PEX5, OS9, PEX7, CDC42, ZFYVE16, GOPC, NECAP1, RANBP2, KPNB1, NSF, SEC23A, SYNRG, PRKCI, STXBP2, STXBP3, TOPORS, TIMM23, BBS2, ATG4D, IPO7, IPO4, ATG4A, COPG, SNX13, SNX10, LCP2, SNX18, STON1, SNX16, RDX, EFCAB4B, CEP57, AP3M2, SH3GLB1, TAP2, BCAP29, SNX24, SNX20, SCG2, NUP153, SRP14P1, SNX25, CENPF, CENPE, CBY1, MON2, ARL17A, VPS24, JAK2 JUB, CTHRC1, PDGFB, RPS6KB1, ENPEP, NR2E1, CXCL12, TGFB1, NRCAM, CD44, GAB2, SYK, TWIST1, PTPRK, SATB2, RET, ROCK1, MDGA1, EMX2, SCYL3, SIX4, MYH9, CTNNA2, ASCL1, HIF1A, CD34, LYST, PDGFRB, OPHN1, RELN, CAV2, CDK5R1, DRD1, CCL2, DRD2, ITGB1, SCRIB, ITGAM, ARX, OVOL2, KATNA1, RAC1, SBDSP1, NKX2-3, FN1, VAV3, TGFBR1, MET, ITGA1, NR4A2, cell migration ITGA4, ITGA6, LAMA5, PTENP1, MYH10, NRP2, CCKAR, NRP1, WASF2, PAX6, 103 2.14 4.07E-07 2.12E-03 7.06E-04 PEX5, ZEB2, PEX7, EDNRB, NDE1, CXCR4, SEMA3C, CAP1, FGF2, ICAM1, CCDC88A, ARHGEF7, ARID5B, NCK2, PSEN1, IL12A, VCAN, ACVR1, CER1, DCC, SHROOM2, FUT8, ABI2, KITLG, PRKDC, CDH2, PEX13, POU3F2, PAFAH1B1, CD24, SCG2, THBS4, APC, SELP, IL6, FLT1, ISL1, COL5A1, LRP6, NEUROD4, APBB2, SELE, LRP5 GRPEL2, SRP14, XPO1, OXA1L, GRPEL1, AP4E1, AP1G1, C16ORF70, LHCGR, EIF5A, GRIN3B, SRP19, AGXT, KLHL2, TGFB1, CTNNB1, ABRA, TLK1, STAM, cellular KIF13B, RAB27A, EGFR, PTPRK, VPS45, OPTN, ARNTL, AP4M1, VTI1A, MAPK1, COPG2, KRT18, JUN, F2, USO1, AKAP6, MRPL45, DRD1, ARFGAP3, NAPG, macromolecule STAM2, RTP1, NAPB, RIMS2, RIMS1, STX12, NPM1, TNKS, SEC23IP, TRAM1, 142 2.95 7.94E-07 4.12E-03 1.03E-03 localization SRGN, AP2M1, SEC61A2, RANBP17, ICMT, DVL1, TRNT1, CBLB, VCP, TOMM70A, NEDD4, SYTL4, PCNA, HGS, SEC13, NUTF2, GOSR2, SMURF1, XPO7, RERE, HDAC6, COPA, CLTA, PDIA3, FGF9, PAX6, AP3S1, PEX5, PEX7, AP1S3, ６４
Term Genes Count % P-Value Bonferroni FDR CDC42, AP1S2, LONP2, ZFYVE16, RANBP2, COX18, KPNB1, FGF2, DNAJC19, AP3B1, SEC23A, KDELR2, STX1A, ARHGEF2, SYNRG, STX2, PRKCI, TOPORS, TIMM23, BBS2, MYRIP, ATG4D, IPO7, ATG4A, NUP205, IPO4, MGEA5, TOMM20, SORT1, COPG, BID, YWHAZ, STON1, STAU1, MUDENG, AP3M2, CEP57, SH3GLB1, MORC3, TAP2, BCAP29, PPP3CB, EXOC4, CHM, RAB11A, BCL6, PEX13, CD24, FYB, SRP14P1, IPO11, NLGN1, YWHAB, EXPH5, PPP1R10, STRADB, COG3, TEX15, ERBB2IP, GSK3B, YWHAQ, JAK2, AP4B1, SSR3 SEC31B, SEC31A, CHMP5, C16ORF70, LHCGR, RAB1A, FAM125A, APOB, AAGAB, ABRA, STAM, TLK1, NUP35, RAB27A, KIF13B, CD3G, VPS45, OPTN, AP4M1, MYH9, VTI1A, MAPK1, KRT18, CD36, LCA5, RAB19, JUN, BACE2, F2, RAB12, MRPL45, RAB10, RAB40C, CCDC91, ARF6, ARF5, RIMS2, RIMS1, RAB40B, STX12, TNKS, TRAM1, SEC23IP, RANBP17, RGPD4, RGPD3, RAB7L1, CBLB, ARF4, PCNA, SYTL4, BET1L, HGS, GOSR2, NUTF2, SMURF1, RERE, MSR1, PDIA3, FGF9, AP1AR, PPARG, AP3S1, AP1S3, BLZF1, AP1S2, LONP2, DNAJC14, RAB6A, AGAP1, FGF2, DNAJC19, AP3B1, KDELR2, STX1A, ARHGEF2, STX2, RAB4A, SENP2, ZDHHC15, ZDHHC17, MYRIP, RAB11FIP2, PSEN1, LAX1, NUP205, MGEA5, RAB5A, TOMM20, SORT1, GNAS, EIF5A2, SERP1, BID, RAB3A, YWHAZ, BET1, MUDENG, UEVLD, EXOC4, PPP3CB, CHM, RAB11A, APBA2, establishment of BCL6, PEX13, CD24, PCSK5, RAB2A, FYB, IPO11, YWHAB, NLGN1, EXPH5, PPP1R10, STRADB, COG3, COG4, COG5, RAB30, COG6, RAB37, ERBB2IP, GRIA2, protein GSK3B, MCFD2, RAB34, YWHAQ, RAB39, AP4B1, COG1, SSR3, XPO1, SRP14, 240 4.99 8.22E-07 4.27E-03 8.55E-04 localization GRPEL2, GRPEL1, AP4E1, AP1G1, XPO4, EIF5A, SRP19, AGXT, KLHL2, TGFB1, CXCL10, ANK3, RABGEF1, SCAMP1, NUP133, ACTN4, LRP1B, ARNTL, COPG2, LYST, VAMP7, USO1, AKAP6, COL1A1, PDCD6IP, ERC1, VPS26A, ARFGAP3, DRD1, AFTPH, NAPG, STAM2, SNX7, SNX4, ABCA1, NAPB, SNX3, LMAN1, CHMP2B, NPM1, DOPEY1, SEC61A2, AP2M1, RAB8A, PRAF2, MYO1C, ITGA2, LIN7C, ICMT, ATG3, RAB33A, RAB33B, TRNT1, PLEKHA8, AKTIP, VCP, NEDD4, TOMM70A, SEC13, YIPF5, ATG16L1, XPO7, ATG16L2, HDAC6, COPA, CLTA, PEX5, PEX7, ZFYVE16, GOPC, NECAP1, RANBP2, KPNB1, NSF, SEC23A, SYNRG, PRKCI, STXBP2, STXBP3, TIMM23, ATG4D, IPO7, ATG4A, IPO4, COPG, SNX13, SNX10, LCP2, SNX18, STON1, SNX16, EFCAB4B, CEP57, AP3M2, TAP2, BCAP29, SNX24, SCG2, SNX20, NUP153, SRP14P1, SNX25, CENPF, CENPE, MON2, ARL17A, VPS24, JAK2 All of functional annotation clusters are shown in appendix Ⅲ
False discovery rate (FDR) are corrected based on Benjamini &Hochberg’s method
６５
4. DISCUSSION
We estimated genomic instability by comparing earl-passage LCL strains, late-passage LCLs, and blood DNA of sample pairs from 16 individuals. Individual genotyping was performed using Illumina exome array. Overall, we observed no differences in genotype call rate between blood DNA and LCL strains. However, we have identified 89
CNV regions and 4 regions LOH in late passage LCLs. Therefore, this analysis further confirmed that DNA extracted from late-passage LCLs would not be reliable source for genome analysis.
We also performed gene expression data analysis for finding altered gene expression during long-term subculturing. The function of differentially expressed genes was related to immune response. The predicted targets of differentially expressed miRNAs was related with regulation of cell proliferation, cell death and apoptosis. Cellular functions associated with apoptosis, immune response, cell death, JAK-
STAT cascade and lymphocyte activation was appeared in biological networks of LCL immortalization (27).
We also identified altered expressions of genes and miRNAs cuased
６６ by genomic aberrations. Gene ontology analysis was performed to study the functions of differentially expressed genes and predicted gene targets of miRNAs. The top cluster was mainly associated to regulation of transcription and sensory perception in expression data and intracellular transport, localization related function in miRNA data.
The principal functions of HSPs encompass intracellular transport, protein folding, and protein oligomerization, as well as the elimination of protein aggregates or improperly folded proteins,
HSP cell surface expression was showned 12% in EBV- immortalized B-cell (28).
A long-term subculture process would generate genomic artifacts in late passage LCLs in this study, we observed that genomic aberrations occurred in late passage LCLs were the reason of altered expression levels of some genes and miRNA.
６７
６８
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７４
국 문 요 약
인체자원의 지속적인 활용을 위한 불멸화 세포주 연구
전 세계적으로 유전체 연구의 기술적 진보를 통하여 인류는 많은 유전 정보를 얻게 되었고, 대용량 유전체 정보를 분석하게 되면서 각 질병에 관 여하는 유전체 마커와 다형성을 확인 후 질병에 관여하는 유전요인과의 연 관성과 유전체 안정성에 대한 영향 조사를 할 수 있게 되었다. 유전체 연 구를 위해서는 혈액 또는 조직 시료에서 추출한 genomic DNA가 필요하다. 하지만, 이들 시료는 유전체 연구활용에 동의한 검진자, 코호트 참여자 등 에게서 확보한 것으로 매우 제한적인 자원이다.
그 양이 제한될 수밖에 없는 인체 유래물에서 직접 추출하는 genomic DNA를 대신하여 관련 유전체 연구에 활용할 수 있는 DNA를 확보할 수 있는 방법으로 B-lymphocyte에 EBV를 감염시켜 형질전환된 immortalized lymphoblastoid 세포주를 만들 수 있다. 이를 불멸화세포주 (lymphoblastoid cell line, LCL)라 한다. 이 세포주는 개인의 유전자형을 그 대로 가지고 있기 때문에 세포주를 배양하여 특정 개인의 유전자형을 가진 DNA를 무한정 생산할 수 있어 유전체 DNA의 재생가능한 공급원으로써 유망한 대안으로 알려져 있다.
LCL은 인간 DNA의 지속적인 공급원이지만 LCL자원은 유전적 및 비유전 적 불안정성을 가지고 있으므로 주의해서 사용해야하며, 장기 계대 배양하
７５
는 과정에서의 유전자 및 miRNA expression level과 같은 생물학적 실험 genomic aberration에 어떤 영향을 주는 밝혀지지 않았다.
이를 알아보기 위해, 총 20명을 대상으로Affymetrix GeneChip Human mapping 500K array와 Illumina HumanExome Beadchip array를 이용하여 genotype 결과를 혈액 DNA와 계대 배양된 LCL DNA들 간에 비교 했을 때 큰 변화를 찾을 수 없었다. 또한, 장기 계대배양에 따를 LCL의 안정성 을 확인하기 위해 각 염색체 별로 비교 분석한 결과, late-passage LCL에서 LOH와 silent LOH를 찾았다. 이런 결과에 영향을 주는 생물학적 배경을 확인하기 위해 유전자들과 miRNA에서 genomic aberration이 발생되는 부 위에서 expression level 을 조사하였다. 주로 Late-passage LCL에서 유전 자 및 miRNA 의 expression level의 차이를 보였다.
요약하자면, 1) 대체가능한 공급원으로서 LCL genomic DNA의 활용가능성 과 2) 장기 계대배양 했을 때의 LCL 유전정보의 안정성을 탐색 하였으며 3) late-passage LCL에서 유전자와 miRNA의 발현 차이와 genomic aberration을 통합 분석하였다. LCL genomic DNA는 유전체 분석을 위한 대체 자원으로 사용 가능하지만 장기 계대배양의 각 단계 중 late- passagedp서 추출한 LCL DNA는 유전체 구조 변이로 인한 유전 정보의 손상으로 관련 연구에 사용하기가 적합하지 않음을 확인하였다. 따라서 공 급으로 LCL genomic DNA를 사용할 때에는 반드시 earl-passage (<40 passage) LCL을 이용하는 것이 유전정보의 안정성을 확보할 수 있다는 점 을 확인할 수 있었다.
핵심이 되는 말: 불멸화세포주, 유전체 구조변이, 유전정보의 안정성, 장기 계대배양
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APPENDICES
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AppendixⅠ. Detection of CNVs by exome chip (89 regions)
Gene SNP C ID Cytoband STARTBP ENDBP LENGTH START.PROBE END.PROBE symbol (N) N FGR, IFI6, FAM76A, 1p36.11- A04E STX12, 27931698 28212428 29 280731 1 exm2260122 exm37173 p35.3 PPP1R8, THEMIS2 A04T 27931698 28212428 29 280731 1 exm2260122 exm37173 CSF1, AHCYL1, A03E 1p13.3 110352477 110655616 33 303140 1 exm-rs10494112 exm82486 STRIP1, ALX3, A03T 110352477 110655616 33 303140 1 exm-rs10494112 exm82486 PROK1, K01E 1p13.3 CYMP, 110993852 111061360 24 67509 1 exm1694244 exm83023 KCNA10 K01T 110993852 111061360 24 67509 1 exm1694244 exm83023 K06E 110993852 111061360 24 67509 1 exm1694244 exm83023 K06T 110993852 111061360 24 67509 1 exm1694244 exm83023 K03E 1p13.3 KCNA10 111059908 111061360 19 1453 1 exm82930 exm83023 K03T 111059908 111061360 19 1453 1 exm82930 exm83023 FLG-AS1, K03E 1q21.3 FLG2, 152300817 152383382 74 82566 1 exm-rs3126085 exm101023 CRNN K03T 152300817 152383382 74 82566 1 exm-rs3126085 exm101023 K06E 1q21.3 FLG-AS1 152323087 152383382 73 60296 1 exm100586 exm101023 K06T 152323087 152383382 73 60296 1 exm100586 exm101023 KIRREL, K01E 1q23.1 LOC646268 158045965 158152941 17 106977 1 exm112063 exm112209 , CD1D K01T 158045965 158152941 17 106977 1 exm112063 exm112209 K03E 158045965 158152941 17 106977 1 exm112063 exm112209 K03T 158045965 158152941 17 106977 1 exm112063 exm112209 K10E 158045965 158152941 17 106977 1 exm112063 exm112209 K10T 158045965 158152941 17 106977 1 exm112063 exm112209 A04E 158045965 158152941 17 106977 1 exm112063 exm112209 A04T 158045965 158152941 17 106977 1 exm112063 exm112209 SPTA1, K03E 1q23.1 158576472 158687836 150 111365 1 exm112944 exm113532 OR6K3 K03T 158576472 158687836 150 111365 1 exm112944 exm113532 CADM3, LOC100131 A04E 1q23.2 159148513 159284385 39 135873 1 exm-rs1474747 exm114211 825, DARC, FCER1A A04T 159148513 159284385 39 135873 1 exm-rs1474747 exm114211 K08E 159272060 159284385 22 12326 1 exm-rs2251746 exm114211 K08T 159272060 159284385 22 12326 1 exm-rs2251746 exm114211 TAGLN2, IGSF9, SLAMF9, A04T 1q23.2 159888640 160012313 52 123674 1 exm1722085 exm115140 LINC01133 , PIGM, KCNJ10 A04E 159888640 160106787 75 218148 1 exm1722085 exm115402 A03E 160000380 160012313 18 11934 1 exm115060 exm115140 A03T 160000380 160012313 18 11934 1 exm115060 exm115140 K03E 160000380 160012313 18 11934 1 exm115060 exm115140 K03T 160000380 160012313 18 11934 1 exm115060 exm115140 K08E 160000380 160012313 18 11934 1 exm115060 exm115140 K08T 160000380 160012313 18 11934 1 exm115060 exm115140 K01E 1q23..3 NOS1AP 161987190 162210610 13 223421 1 exm118723 exm-rs4657178 K01T 161987190 162210610 13 223421 1 exm118723 exm-rs4657178 K03E 1q24.1 DUSP27 167086594 167097799 37 11206 1 exm120168 exm120358 K03T 167086594 167097799 37 11206 1 exm120168 exm120358 FM02, FM01, A03E 1q24.3 171162516 171310901 42 148386 1 exm123130 exm123354 FM04, TOP1P1
７８
Gene SNP C ID Cytoband STARTBP ENDBP LENGTH START.PROBE END.PROBE symbol (N) N A03T 171162516 171310901 42 148386 1 exm123130 exm123354 FM01, K03E 1q24.3 FM04, 171236840 171310901 27 74062 1 exm123223 exm123354 TOP1P1 K03T 171236840 171310901 27 74062 1 exm123223 exm123354 XPR1, A04E 1q25.3 KIAA1614, 180842993 180962499 37 119507 1 exm128327 exm128566 STX6 A04T 180842993 181116023 43 273031 1 exm128327 exm2250338 CNTN2, A03E 1q32.1 TMEM81, 205034959 205064160 27 29202 1 exm141743 exm141860 RBBP5 A03T 205034959 205064160 27 29202 1 exm141743 exm141860 C1orf116, 1q32.1- YOD1, A01E 207195352 207273209 45 77858 1 exm144176 exm144429 q32.2 PFKFB2, C4BPB A01T 207195352 207200929 27 5578 1 exm144176 exm144277 A03E 207195352 207273209 45 77858 1 exm144176 exm144429 A03T 207195352 207273209 45 77858 1 exm144176 exm144429 A04E 207195352 207200929 27 5578 1 exm144176 exm144277 A04T 207195352 207273209 45 77858 1 exm144176 exm144429 K01E 207195352 207273209 45 77858 1 exm144176 exm144429 K01T 207195352 207273209 45 77858 1 exm144176 exm144429 K07T 207195352 207200929 27 5578 1 exm144176 exm144277 K07E 207195352 207273209 45 77858 1 exm144176 exm144429 K08E 207195352 207273209 45 77858 1 exm144176 exm144429 K08T 207195352 207273209 45 77858 1 exm144176 exm144429 K10E 207195352 207273209 45 77858 1 exm144176 exm144429 K10T 207131878 207273209 65 141332 1 exm144091 exm144429 NSL1, K08E 1q32.3 212911779 212970533 10 58755 1 exm147355 exm147423 TATDN3 K08T 212911779 212970533 10 58755 1 exm147355 exm147423 A02E 1q43 RYR2 237753215 237813353 13 60139 1 exm162637 exm2250909 A02T 237753215 237921596 26 168382 1 exm162637 exm2250912 A10E 237753215 237813353 13 60139 1 exm162637 exm2250909 A10T 237753215 237921596 26 168382 1 exm162637 exm2250912 K01E 237753215 237813353 13 60139 1 exm162637 exm2250909 K01T 237753215 237813353 13 60139 1 exm162637 exm2250909 K06E 237753215 237813353 13 60139 1 exm162637 exm2250909 K06T 237753215 237921596 26 168382 1 exm162637 exm2250912 A03E 1q43 RYR2 237753215 237921596 26 168382 1 exm162637 exm2250912 A03T 237753215 237921596 26 168382 1 exm162637 exm2250912 A08E 237753215 237921596 26 168382 1 exm162637 exm2250912 A08T 237753215 237921596 26 168382 1 exm162637 exm2250912 K03E 237753215 237921596 26 168382 1 exm162637 exm2250912 K03T 237753215 237921596 26 168382 1 exm162637 exm2250912 NLRP3, OR2W5, GCSAML, K03E 1q44 247582305 247752518 80 170214 1 exm166248 exm166605 GCSAML- AS1, OR2C3 K03T 247582305 247752518 80 170214 1 exm166248 exm166605 TRIM58, K03E 1q44 OR2T8, 248039555 248263524 64 223970 1 exm166995 exm167468 OR2L13 K03T 248039555 248263524 64 223970 1 exm166995 exm167468 A02E 1q44 OR2G6 248550916 248802243 44 251328 1 exm168133 exm168760 A02T 248550916 248802243 44 251328 1 exm168133 exm168760 A03E 248550916 248570383 24 19468 1 exm168133 exm168262 A03T 248550916 248802243 44 251328 1 exm168133 exm168760 CKAP2L, A03E 2q13 113496452 113540315 33 43864 1 exm221735 exm221878 IL1A A03T 113496452 113540315 33 43864 1 exm221735 exm221878 A08E 113496452 113540315 33 43864 1 exm221735 exm221878 A08T 113496452 113540315 33 43864 1 exm221735 exm221878 K03E 113496452 113540315 33 43864 1 exm221735 exm221878 K03T 113496452 113540315 33 43864 1 exm221735 exm221878 K08E 113496452 113540315 33 43864 1 exm221735 exm221878 ７９
Gene SNP C ID Cytoband STARTBP ENDBP LENGTH START.PROBE END.PROBE symbol (N) N K08T 113496452 113540315 33 43864 1 exm221735 exm221878 TMEM37, A04E 2q14.2 120194492 120236437 24 41946 1 exm223491 exm223610 SCTR A04T 120194492 120236437 24 41946 1 exm223491 exm223610 TMEM37, K03E 2q14.2 SCTR, 120194492 120397369 37 202878 1 exm223491 exm223702 PCDP1 K03T 120194492 120397369 37 202878 1 exm223491 exm223702 GPR39, K10E 2q21.2 LYPD1, 133144392 133547732 66 403341 1 exm-rs16831128 exm228982 NCKAP5 K10T 133144392 133547732 66 403341 1 exm-rs16831128 exm228982 A04E 133531428 133547732 45 16305 1 exm1979798 exm228982 A04T 133531428 133547732 45 16305 1 exm1979798 exm228982 K07E 2q32.2 COL3A1 189849536 189875421 19 25886 1 exm251939 exm252114 K07T 189849536 190682824 134 833289 1 exm251939 exm252866 BOC, K03E 3q13.2 112968708 113023920 41 55213 1 exm2033569 exm338223 WDR52 K03T 112968708 113023920 41 55213 1 exm2033569 exm338223 QTRTD1, DRD3, K03E 3q13.31 ZNF80, 113729789 114069761 48 339973 1 exm339225 exm339543 TIGIT, ZBTB20 K03T 113729789 114069761 48 339973 1 exm339225 exm339543 K08E 113729789 114170272 50 440484 1 exm339225 exm-rs6438208 TOGOT, ZBTB20, K08T 3q13.31 114012913 114170272 14 157360 1 exm339456 exm-rs6438208 ZBTB20- AS1 TIGIT, K10E 3q13.31 114012913 114069761 12 56849 1 exm339456 exm339543 ZBTB20 K10T 114012913 114069761 12 56849 1 exm339456 exm339543 K01T 121641670 122060404 56 418735 1 exm342391 exm342753 K08T 121641670 121725840 28 84171 1 exm342391 exm342557 K01E 121712002 122060404 49 348403 1 exm342468 exm342753 K08E 121712002 121725840 21 13839 1 exm342468 exm342557 K01T 169058009 169587471 56 529463 1 exm-rs2106124 exm2043578 ACTRT3, MYNN, K03E 3q26.2 169485261 169587471 51 102211 1 exm363548 exm2043578 LRRC34, LRRC31 K03T 169485261 169587471 51 102211 1 exm363548 exm2043578 A02E 169539935 169587471 29 47537 1 exm363698 exm2043578 A02T 169539935 169587471 29 47537 1 exm363698 exm2043578 A04E 169539935 169587471 29 47537 1 exm363698 exm2043578 A04T 169539935 169587471 29 47537 1 exm363698 exm2043578 A08E 169539935 169587471 29 47537 1 exm363698 exm2043578 A08T 169539935 169587471 29 47537 1 exm363698 exm2043578 K01E 169539935 169587471 29 47537 1 exm363698 exm2043578 K06E 169539935 169587471 29 47537 1 exm363698 exm2043578 K06T 169539935 169587471 29 47537 1 exm363698 exm2043578 K08E 169539935 169587471 29 47537 1 exm363698 exm2043578 K08T 169539935 169587471 29 47537 1 exm363698 exm2043578 K10E 169539935 169587471 29 47537 1 exm363698 exm2043578 K10T 169539935 169587471 29 47537 1 exm363698 exm2043578 A04E 3q29 CPN2 194061810 194063344 19 1535 1 exm373445 exm373539 A04T 194061810 194063344 19 1535 1 exm373445 exm373539 K03E 194061810 194063344 19 1535 1 exm373445 exm373539 K03T 194061810 194063344 19 1535 1 exm373445 exm373539 K09E 68340623 84580859 1254 16240237 1 exm401975 exm2265728 CENPC, STAP1, UBA6, GNRHR, 4q13.2- K09T TMPRSS11 68340623 70513361 176 2172739 1 exm401975 exm403696 q13.3 D, TMPRSS11 A, TMPRSS11
８０
Gene SNP C ID Cytoband STARTBP ENDBP LENGTH START.PROBE END.PROBE symbol (N) N E, UGT2B17, UGT2B15, UGT2B10, UGT2B7, UGT2B28, UGT2B4, UGT2A1, UGT2A2 CDS1, K09T 4q21.23 85525406 85742624 36 217219 1 exm410604 exm410913 WDFY3 K09E 85525406 85781681 40 256276 1 exm410604 exm410949 K07E 4q22.1 GPRIN3 90034309 90198463 49 164155 1 exm413509 exm2261776 K07T 90168945 90198463 37 29519 1 exm413560 exm2261776 A01E 90168945 90816679 49 647735 1 exm413560 exm2082158 A01T 90168945 90198463 37 29519 1 exm413560 exm2261776 K05E 90168945 90198463 37 29519 1 exm413560 exm2261776 K05T 90168945 90198463 37 29519 1 exm413560 exm2261776 K08E 90168945 90198463 37 29519 1 exm413560 exm2261776 K08T 90168945 90198463 37 29519 1 exm413560 exm2261776 K10E 90168945 90198463 37 29519 1 exm413560 exm2261776 K10T 90168945 90198463 37 29519 1 exm413560 exm2261776 K01E 90168945 90198463 37 29519 1 exm413560 exm2261776 K01T 90168945 90198463 37 29519 1 exm413560 exm2261776 A03E 90168945 90171195 36 2251 1 exm413560 exm413703 A03T 90168945 90171195 36 2251 1 exm413560 exm413703 A04E 90168945 90171195 36 2251 1 exm413560 exm413703 A04T 90168945 90171195 36 2251 1 exm413560 exm413703 K03E 90168945 90171195 36 2251 1 exm413560 exm413703 K03T 90168945 90171195 36 2251 1 exm413560 exm413703 A01E 4q28.1 FAT4 126237639 126242519 31 4881 1 exm423234 exm423413 A01T 126237639 126242519 31 4881 1 exm423234 exm423413 A04E 126237639 126242519 31 4881 1 exm423234 exm423413 A04T 126237639 126242519 31 4881 1 exm423234 exm423413 K08E 126237639 126241071 21 3433 1 exm423234 exm423358 K08T 126237639 126242519 31 4881 1 exm423234 exm423413 ADAMTS1 5p13.3- K03E 2, RXRP3, 33527307 33963885 60 436579 1 exm448386 exm448753 p13.2 SLC45A2 K03T 33527307 33963885 60 436579 1 exm448386 exm448753 ADAMTS1 K08E 5p13.3 33527307 33684121 30 156815 1 exm448386 exm448594 2 K08T 33527307 33684121 30 156815 1 exm448386 exm448594 SRA1, APBB3, CD14, NDUFA2, IK, K03E 5q31.3 WDR55, 139930307 140175529 123 245223 1 exm482388 exm483335 DND1, HARS, HARS2, PCDHA1, PCDHA2 K03T 139930307 140175529 123 245223 1 exm482388 exm483335 K07E 5q31.3 SRA1 139930307 139936823 25 6517 1 exm482388 exm482477 K07T 139930307 139938369 27 8063 1 exm482388 exm482508 SLC17A2, RIM38, HIST1H, K03E 6p22.2 HFE, 25913644 26545696 204 632053 1 exm2118432 exm523321 BTN3A, HCG11, HMGN4 K03T 25913644 26545696 204 632053 1 exm2118432 exm523321 TRIM40, K03T 6p22.1 30089280 30122251 32 32972 1 exm-rs9261438 exm527231 TRIM10 K03E 30089280 30128949 42 39670 1 exm-rs9261438 exm-rs2157678 RAPBP, A01E 6p21.32 33280629 33423341 64 142713 1 exm-rs3106190 exm539065 ZBTB22,
８１
Gene SNP C ID Cytoband STARTBP ENDBP LENGTH START.PROBE END.PROBE symbol (N) N DAXX, KIFC1, CURA, PHF1, ZBTB9 A01T 33280629 33423341 64 142713 1 exm-rs3106190 exm539065 A03E 33280629 33423341 64 142713 1 exm-rs3106190 exm539065 A03T 33280629 33423341 64 142713 1 exm-rs3106190 exm539065 PGK2, A03E 6p12.3 49753706 49819844 27 66139 1 exm554240 exm554341 CRISP1 A03T 49753706 49819844 27 66139 1 exm554240 exm554341 A04E 49753706 49754822 17 1117 1 exm554240 exm554298 A04T 49753706 49819844 27 66139 1 exm554240 exm554341 K03E 49753706 49819844 27 66139 1 exm554240 exm554341 K03T 49753706 49819844 27 66139 1 exm554240 exm554341 ME1, A01E 6q14.2 PRSS35, 84108096 84304096 21 196001 1 exm563472 exm563601 SNAP91 A10E 84108096 84304096 21 196001 1 exm563472 exm563601 A10T 84108096 84375190 23 267095 1 exm563472 exm563642 K03E 84108096 84304096 21 196001 1 exm563472 exm563601 K03T 84108096 84304096 21 196001 1 exm563472 exm563601 K08T 84108096 84304096 21 196001 1 exm563472 exm563601 K08E 84108096 84375190 23 267095 1 exm563472 exm563642 A01T 84233570 84375190 20 141621 1 exm563502 exm563642 K03E 6q25.2 SYNE1 152688391 152786487 68 98097 1 exm588157 exm2114399 K03T 152688391 152786487 68 98097 1 exm588157 exm2114399 A01E 6q27 c6orf118 165693571 165723066 16 29496 1 exm593659 exm593759 A01T 165693571 165723066 16 29496 1 exm593659 exm593759 A03E 165693571 165723066 16 29496 1 exm593659 exm593759 A03T 165693571 165723066 16 29496 1 exm593659 exm593759 A10E 165693571 165723066 16 29496 1 exm593659 exm593759 A10T 165693571 165723066 16 29496 1 exm593659 exm593759 K03E 165693571 165723066 16 29496 1 exm593659 exm593759 K03T 165693571 165723066 16 29496 1 exm593659 exm593759 A03E 6080540 6226685 40 146146 1 exm604102 exm604426 A03T 6154984 6226685 28 71702 1 exm604173 exm604426 KCND2, TSPAN12, K03E 7q31.31 120323727 120655885 19 332159 1 exm2266471 exm652970 ING3, CPED1 K03T 120323727 120655885 19 332159 1 exm2266471 exm652970 A03E 120382604 120655885 18 273282 1 exm652839 exm652970 A03T 120382604 120655885 18 273282 1 exm652839 exm652970 K03E 122634998 122839969 31 204972 1 exm653918 exm654051 K03T 122634998 122839969 31 204972 1 exm653918 exm654051 MEST, A03E 7q32.2 130135210 130368500 17 233291 1 exm657974 exm658157 COPG2 A03T 130135210 130368500 17 233291 1 exm657974 exm658157 K03E 130135210 130368500 17 233291 1 exm657974 exm658157 K06T 130135210 130368500 17 233291 1 exm657974 exm658157 A10E 130295911 130368500 10 72590 1 exm658092 exm658157 A10T 130295911 130368500 10 72590 1 exm658092 exm658157 K01E 130295911 130368500 10 72590 1 exm658092 exm658157 K01T 130295911 130368500 10 72590 1 exm658092 exm658157 K03T 130295911 130368500 10 72590 1 exm658092 exm658157 K06E 130295911 130368500 10 72590 1 exm658092 exm658157 K08E 130295911 130368500 10 72590 1 exm658092 exm658157 K08T 130295911 130368500 10 72590 1 exm658092 exm658157 K10E 130295911 130368500 10 72590 1 exm658092 exm658157 K10T 130295911 130368500 10 72590 1 exm658092 exm658157 K03E 8q11.22 PXDNL 52216762 52325767 34 109006 1 exm-rs7821565 exm700444 K03T 52216762 52325767 34 109006 1 exm-rs7821565 exm700444 A03E 8q22.2 POP1 99135575 99208191 33 72617 1 exm711760 exm711928 A03T 99135575 99208191 33 72617 1 exm711760 exm711928 A03E 8q24.12 NOV 120353267 120435251 11 81985 1 exm-rs2469997 exm717390 A03T 120353267 120435251 11 81985 1 exm-rs2469997 exm717390 K01E 120353267 120435251 11 81985 1 exm-rs2469997 exm717390 K01T 120353267 120435251 11 81985 1 exm-rs2469997 exm717390
８２
Gene SNP C ID Cytoband STARTBP ENDBP LENGTH START.PROBE END.PROBE symbol (N) N K08E 120353267 120435251 11 81985 1 exm-rs2469997 exm717390 K08T 120353267 120435251 11 81985 1 exm-rs2469997 exm717390 A01E 8q24.22 TG, SLA 133961157 134072363 27 111207 1 exm722083 exm722239 A01T 134024155 134145863 31 121709 1 exm722138 exm722321 A03E 133961157 134072363 27 111207 1 exm722083 exm722239 A03T 133961157 134072363 27 111207 1 exm722083 exm722239 K03E 133961157 134072363 27 111207 1 exm722083 exm722239 A02E 134024155 134072363 15 48209 1 exm722138 exm722239 A02T 134024155 134145863 31 121709 1 exm722138 exm722321 A08E 134024155 134072363 15 48209 1 exm722138 exm722239 A08T 134024155 134072363 15 48209 1 exm722138 exm722239 K01T 134024155 134072363 15 48209 1 exm722138 exm722239 K01E 134024155 134114798 22 90644 1 exm722138 exm722275 K03T 134024155 134072363 15 48209 1 exm722138 exm722239 K06E 134024155 134072363 15 48209 1 exm722138 exm722239 K06T 134024155 134072363 15 48209 1 exm722138 exm722239 K08E 134024155 134072363 15 48209 1 exm722138 exm722239 K08T 134024155 134072363 15 48209 1 exm722138 exm722239 AQP3, A04E 9p13.3 33442044 33472350 41 30307 1 exm745892 exm746131 NOL6 A04T 33442044 33472350 41 30307 1 exm745892 exm746131 UBAP1, A04E 9p13.3 34241267 34263155 33 21889 1 exm746636 exm746830 KIF24 A04T 34241267 34263155 33 21889 1 exm746636 exm746830 A01E 9p13.2 FRMPD1 37692711 37746756 45 54046 1 exm751472 exm751719 A01T 37692711 37761972 47 69262 1 exm751472 exm751725 A04T 37692711 37746756 45 54046 1 exm751472 exm751719 A04E 37692711 37761972 47 69262 1 exm751472 exm751725 SPATA31E A04E 9q22.1 90497810 90503734 41 5925 1 exm2248375 exm2259471 1 A04T 90497810 90502470 34 4661 1 exm2248375 exm759591 LOC286367 K03T 9q31.1 107266577 107367222 73 100646 1 exm768435 exm768736 , ABCA1 K03E 107266577 107664301 144 397725 1 exm768435 exm-rs1883025 K06E 107288540 107299051 32 10512 1 exm768492 exm768604 K06T 107288540 107664301 129 375762 1 exm768492 exm-rs1883025 LOC286367 A03E 9q31.1 107531159 107620889 46 89731 1 exm768944 exm769256 , ABCA1 A03T 107531159 107620889 46 89731 1 exm768944 exm769256 A08E 107531159 107664301 50 133143 1 exm768944 exm-rs1883025 A08T 107531159 107664301 50 133143 1 exm768944 exm-rs1883025 K01E 107531159 107664301 50 133143 1 exm768944 exm-rs1883025 K01T 107531159 107664301 50 133143 1 exm768944 exm-rs1883025 K08E 107531159 107664301 50 133143 1 exm768944 exm-rs1883025 K08T 107531159 107664301 50 133143 1 exm768944 exm-rs1883025 BSPRY, ALAD, K03E 9q32 POLE3, 116116523 116247960 51 131438 1 exm773598 exm773966 c9orf43, RGS3 K03T 116116523 116247960 51 131438 1 exm773598 exm773966 A01E 9q33.1 TLR4 120466796 120490389 25 23594 1 exm776725 exm2271221 A01T 120466796 120490389 25 23594 1 exm776725 exm2271221 A03E 120466796 120490389 25 23594 1 exm776725 exm2271221 A03T 120466796 120490389 25 23594 1 exm776725 exm2271221 A04E 120466796 120490389 25 23594 1 exm776725 exm2271221 A04T 120466796 120490389 25 23594 1 exm776725 exm2271221 K01E 120466796 120490389 25 23594 1 exm776725 exm2271221 K01T 120466796 120490389 25 23594 1 exm776725 exm2271221 K05E 120466796 120490389 25 23594 1 exm776725 exm2271221 K05T 120466796 120490389 25 23594 1 exm776725 exm2271221 K07E 120466796 120490389 25 23594 1 exm776725 exm2271221 K07T 120466796 120490389 25 23594 1 exm776725 exm2271221 K07E 120466796 120490389 25 23594 1 exm776725 exm2271221 K07T 120466796 120490389 25 23594 1 exm776725 exm2271221 K10E 120466796 120490389 25 23594 1 exm776725 exm2271221 K10T 120466796 120490389 25 23594 1 exm776725 exm2271221 K08E 9q33.2 OR1L1 125273361 125438220 106 164860 1 exm778989 exm779444 K08T 125390874 125438220 41 47347 1 exm779289 exm779444
８３
Gene SNP C ID Cytoband STARTBP ENDBP LENGTH START.PROBE END.PROBE symbol (N) N K03T 125424052 125552163 51 128112 1 exm779353 exm779643 K03E 125424052 125563347 64 139296 1 exm779353 exm779709 RASSF4, c10orf10, A04E 10q11.21 45407004 45499378 32 92375 1 exm821217 exm821439 c10orf25, ZNF22 A04T 45407004 45499378 32 92375 1 exm821217 exm821439 DNA2, K05T 10q21.3 SLC25A16, 70045105 70333803 61 288699 1 exm828746 exm829141 TET1 A01E 70209845 70333803 24 123959 1 exm828982 exm829141 A01T 70209845 70333803 24 123959 1 exm828982 exm829141 A02E 70209845 70333803 24 123959 1 exm828982 exm829141 A02T 70209845 70333803 24 123959 1 exm828982 exm829141 A03E 70209845 70333803 24 123959 1 exm828982 exm829141 A03T 70209845 70333803 24 123959 1 exm828982 exm829141 A04E 70209845 70333803 24 123959 1 exm828982 exm829141 A04T 70209845 70333803 24 123959 1 exm828982 exm829141 A08E 70209845 70333803 24 123959 1 exm828982 exm829141 A08T 70209845 70333803 24 123959 1 exm828982 exm829141 A10E 70209845 70333803 24 123959 1 exm828982 exm829141 A10T 70209845 70333803 24 123959 1 exm828982 exm829141 K01E 70209845 70333803 24 123959 1 exm828982 exm829141 K01T 70209845 70333803 24 123959 1 exm828982 exm829141 K03E 70209845 70333803 24 123959 1 exm828982 exm829141 K03T 70209845 70333803 24 123959 1 exm828982 exm829141 K05E 70209845 70333803 24 123959 1 exm828982 exm829141 K08E 70209845 70333803 24 123959 1 exm828982 exm829141 K08T 70229796 70333803 21 104008 1 exm1683069 exm829141 OR51D1, K05E 11p15.4 4661190 4674661 32 13472 1 exm881159 exm881261 OR51E1 K05T 4661190 4843595 88 182406 3 exm881159 exm881506 K08E 11p15.4 OR51B5 5322249 5475506 126 153258 1 exm1715435 exm882969 K08T 5322249 5530764 162 208516 1 exm1715435 exm883154 A04E 11p15.4 UBQLN3 5528864 5530764 23 1901 1 exm883051 exm883154 A04T 5528864 5530764 23 1901 1 exm883051 exm883154 TRIM6, TRIM34, K03E 11p15.4 5602135 5730854 74 128720 1 exm883308 exm2276151 TRIM5, TRIM22 K03T 5602135 5730854 74 128720 1 exm883308 exm2276151 A04E 11p15.4 OR52E6 5862238 5863100 16 863 1 exm883989 exm884056 A04T 5862238 5863100 16 863 1 exm883989 exm884056 PPFIBP2, K03E 11p15.4 CYB5R2m 7647063 7847458 77 200396 1 exm887862 exm888322 OVCH2 K03T 7647063 7847458 77 200396 1 exm887862 exm888322 STK33, TRIM66, A04T 11p15.4 8604593 8772187 31 167595 1 exm-rs4929949 exm889215 RPL27A, ST5 A04E 8604593 8947579 50 342987 1 exm-rs4929949 exm889294 A04E 11p15.3 MICALCL 12277214 12345596 24 68383 1 exm891526 exm2218155 A04T 12313734 12345596 16 31863 1 exm891564 exm2218155 A10E 12313734 12345596 16 31863 1 exm891564 exm2218155 A10T 12313734 12345596 16 31863 1 exm891564 exm2218155 ABCC8, A04T 11p15.1 17448641 17533463 32 84823 1 exm893416 exm893639 USM1C A04E 17448641 17554805 44 106165 1 exm893416 exm893747 K03E 57885990 57996312 58 110323 1 exm911875 exm912245 OR9Q1, OR0Q2, K03T 11q12.1 OR1S2, 57946921 57996312 47 49392 1 exm911929 exm912245 OR1S1, OR10Q1 CAPN5, K01E 11q13.5 OMP, 76795984 76853783 21 57800 1 exm942846 exm943011 MYO7A K01T 76795984 76853783 21 57800 1 exm942846 exm943011 A03E 11q21 HEPHL1, 93819142 93913409 23 94268 1 exm948625 exm948763
８４
Gene SNP C ID Cytoband STARTBP ENDBP LENGTH START.PROBE END.PROBE symbol (N) N PANX1 A03T 93819142 93913409 23 94268 1 exm948625 exm948763 AMOTL1, A01E 11q21 CWC15, 94528291 94620657 21 92367 1 exm949201 exm2250435 KDM4D A01T 94528291 94732025 29 203735 1 exm949201 exm949390 A04E 94528291 94732025 29 203735 1 exm949201 exm949390 A04T 94528291 94732025 29 203735 1 exm949201 exm949390 K03E 94528291 94732025 29 203735 1 exm949201 exm949390 K03T 94528291 94732025 29 203735 1 exm949201 exm949390 K10E 94528291 94620657 21 92367 1 exm949201 exm2250435 K10T 94528291 94732025 29 203735 1 exm949201 exm949390 GRIK4, K03E 11q23.3 TBCEL, 120673443 121058703 68 385261 1 exm963652 exm964180 TECTA K03T 120673443 121058703 68 385261 1 exm963652 exm964180 ARHGAP3 A01E 11q24.3 128838845 128856563 30 17719 1 exm2218272 exm969713 2 A01T 128838845 128856563 30 17719 1 exm2218272 exm969713 K03E 128838845 128856563 30 17719 1 exm2218272 exm969713 K03T 128838845 128856563 30 17719 1 exm2218272 exm969713 K10E 128838845 128856563 30 17719 1 exm2218272 exm969713 K10T 128838845 128856563 30 17719 1 exm2218272 exm969713 B4GALNT A04E 12p13.33 662392 675314 38 12923 1 exm973079 exm2221037 3, NINJ2 A04T 662392 675314 38 12923 1 exm973079 exm2221037 K03E 662392 675314 38 12923 1 exm973079 exm2221037 K03T 662392 675314 38 12923 1 exm973079 exm2221037 K10E 3782742 3931144 13 148403 1 exm975361 exm975409 exm- K10T 12p13.32 EFCAB4B 3782742 3868309 12 85568 1 exm975361 rs10774171 A01E 12p13.2 TAS2R42 11338603 11339378 12 776 1 exm984780 exm984817 A01T 11338603 11339378 12 776 1 exm984780 exm984817 K05E 11338603 11339378 12 776 1 exm984780 exm984817 K05T 11338603 11339378 12 776 1 exm984780 exm984817 PPFIBP1, MRPS35, 12p11.23- A03E KLHL42, 27788020 28515383 53 727364 1 exm991303 exm991631 p11.22 PTHLH, CCDC91 A03T 27788020 28515383 53 727364 1 exm991303 exm991631 PDE1B, PPP1R1A, GLYCAM1 , LACRT, A03E 12q13.2 54955390 55421073 50 465684 1 exm1010038 exm1010330 DCD, MUCL1, TESPA1, NEUROD4 A03T 54955390 55421073 50 465684 1 exm1010038 exm1010330 K03E 54955390 55039423 16 84034 1 exm1010038 exm1778443 K03T 54955390 55039423 16 84034 1 exm1010038 exm1778443 K08E 54955390 55421073 50 465684 1 exm1010038 exm1010330 K08T 54955390 55421073 50 465684 1 exm1010038 exm1010330 A02E 55346235 55421073 30 74839 1 exm-rs7962801 exm1010330 A02T 55346235 55421073 30 74839 1 exm-rs7962801 exm1010330 A04E 55346235 55421073 30 74839 1 exm-rs7962801 exm1010330 A04T 55346235 55421073 30 74839 1 exm-rs7962801 exm1010330 A08E 55346235 55421073 30 74839 1 exm-rs7962801 exm1010330 A08T 55346235 55421073 30 74839 1 exm-rs7962801 exm1010330 K01E 55346235 55421073 30 74839 1 exm-rs7962801 exm1010330 K01T 55346235 55421073 30 74839 1 exm-rs7962801 exm1010330 K03E 55346235 55421073 30 74839 1 exm-rs7962801 exm1010330 K03T 55346235 55421073 30 74839 1 exm-rs7962801 exm1010330 K03E 12q21.1 TMEM19 72091161 72179446 11 88286 1 exm2221102 exm1022117 K03T 72091161 72179446 11 88286 1 exm2221102 exm1022117 K08E 72091161 72179446 11 88286 1 exm2221102 exm1022117 K08T 72091161 72179446 11 88286 1 exm2221102 exm1022117 DCUN1D2, A03B 13q34 114134903 114152730 12 17828 3 exm1081948 exm1082019 TMCO3 ８５
Gene SNP C ID Cytoband STARTBP ENDBP LENGTH START.PROBE END.PROBE symbol (N) N A03E 114134903 114201633 17 66731 1 exm1081948 exm1082098 A03T 114149919 114201633 14 51715 1 exm1081979 exm1082098 RPGRIP1, SUPT16H, CHD8, A01E 14q11.2 RAB2B, 21811196 22005036 60 193841 1 exm1086466 exm1087139 TOX4, METTL3, SALL2 A01T 21811196 22005036 60 193841 1 exm1086466 exm1087139 A03E 21811196 22005036 60 193841 1 exm1086466 exm1087139 A03T 21811196 22005036 60 193841 1 exm1086466 exm1087139 K01E 21811196 22005036 60 193841 1 exm1086466 exm1087139 K01T 21811196 22005036 60 193841 1 exm1086466 exm1087139 K03E 21811196 22005036 60 193841 1 exm1086466 exm1087139 K03T 21811196 22005036 60 193841 1 exm1086466 exm1087139 K10E 21811196 22005036 60 193841 1 exm1086466 exm1087139 K10T 21811196 22005036 60 193841 1 exm1086466 exm1087139 NKx2-1, K03E 14q13.3 PAX9, 36945384 37344204 27 398821 1 exm2272162 exm1097531 SLC25A21 K03T 36945384 37344204 27 398821 1 exm2272162 exm1097531 A03E 14q21.2 FSCB 44973719 45081126 27 107408 1 exm1098483 exm2267651 A03T 44973719 45081126 27 107408 1 exm1098483 exm2267651 K01E 44973719 44975971 26 2253 1 exm1098483 exm1098611 K01T 44973719 44975971 26 2253 1 exm1098483 exm1098611 K07E 44973719 44975971 26 2253 1 exm1098483 exm1098611 K07T 44973719 44975971 26 2253 1 exm1098483 exm1098611 K08E 44973719 44975971 26 2253 1 exm1098483 exm1098611 K08T 44973719 44975971 26 2253 1 exm1098483 exm1098611 VCPLMT, A03E 14q21.3 50579332 50626745 21 47414 1 exm1100171 exm1100306 SOS2 A03T 50579332 50626745 21 47414 1 exm1100171 exm1100306 OR4M2, A03E 15q11.2 22368588 22383299 17 14712 1 exm1140790 exm1140966 OR4N4 A03T 22368588 22383299 17 14712 1 exm1140790 exm1140966 K01E 22368588 22383299 17 14712 1 exm1140790 exm1140966 K01T 22368588 22383299 17 14712 1 exm1140790 exm1140966 A01E 15q15.2 TGM5 43525791 43552700 27 26910 1 exm1155477 exm1155585 A01T 43525791 43574718 41 48928 1 exm1155477 exm1155649 K03E 43525791 43574718 41 48928 1 exm1155477 exm1155649 K03T 43525791 43574718 41 48928 1 exm1155477 exm1155649 A04E 43544969 43574718 27 29750 1 exm1155541 exm1155649 A04T 43544969 43574718 27 29750 1 exm1155541 exm1155649 c16orf45, A02E 16p13.11 15661871 15719356 17 57486 1 exm1219560 exm1219707 KIAA0430 A02T 15661871 15719356 17 57486 1 exm1219560 exm1219707 A03E 15661871 15719356 17 57486 1 exm1219560 exm1219707 A03T 15661871 15719356 17 57486 1 exm1219560 exm1219707 A08E 15661871 15719356 17 57486 1 exm1219560 exm1219707 A08T 15661871 15719356 17 57486 1 exm1219560 exm1219707 K01E 15661871 15719356 17 57486 1 exm1219560 exm1219707 K01T 15661871 15719356 17 57486 1 exm1219560 exm1219707 K03E 15661871 15719356 17 57486 1 exm1219560 exm1219707 K03T 15661871 15719356 17 57486 1 exm1219560 exm1219707 K06E 15661871 15719356 17 57486 1 exm1219560 exm1219707 K06T 15661871 15719356 17 57486 1 exm1219560 exm1219707 K07E 15661871 15719356 17 57486 1 exm1219560 exm1219707 K07T 15661871 15719356 17 57486 1 exm1219560 exm1219707 K08E 15661871 15719356 17 57486 1 exm1219560 exm1219707 K08T 15661871 15719356 17 57486 1 exm1219560 exm1219707 K09E 15661871 15719356 17 57486 1 exm1219560 exm1219707 K09T 15661871 15732969 23 71099 1 exm1219560 exm1219762 K10E 15661871 15719356 17 57486 1 exm1219560 exm1219707 K10T 15661871 15719356 17 57486 1 exm1219560 exm1219707 DHODH, HP, HPR, K03E 16q22.2 71748603 72218612 144 470010 1 exm1256195 exm2272448 TXNL4B, DHX38,
８６
Gene SNP C ID Cytoband STARTBP ENDBP LENGTH START.PROBE END.PROBE symbol (N) N PMFBP1 K03T 71748603 72218612 144 470010 1 exm1256195 exm2272448 K08T 72042682 72174397 84 131716 1 exm1256625 exm1257201 K08E 72042682 72218612 90 175931 1 exm1256625 exm2272448 A01E 17q22 KIF2B 51900500 51902333 26 1834 1 exm1337954 exm2226760 A01T 51900500 51902333 26 1834 1 exm1337954 exm2226760 A04E 51900500 51902333 26 1834 1 exm1337954 exm2226760 A04T 51900500 51902333 26 1834 1 exm1337954 exm2226760 K01E 51900500 51902333 26 1834 1 exm1337954 exm2226760 K01T 51900500 51902333 26 1834 1 exm1337954 exm2226760 K03E 51900500 51902333 26 1834 1 exm1337954 exm2226760 K03T 51900500 51902333 26 1834 1 exm1337954 exm2226760 K08E 51900500 51902333 26 1834 1 exm1337954 exm2226760 K08T 51900500 51902333 26 1834 1 exm1337954 exm2226760 K10E 51900500 51902333 26 1834 1 exm1337954 exm2226760 K10T 51900500 51902333 26 1834 1 exm1337954 exm2226760 TMEM100, K03E 17q22 53798140 53852206 12 54067 1 exm1338329 exm1893608 PCTP K03T 53798140 53852206 12 54067 1 exm1338329 exm1893608 CCDC47, A03E 17q23.3 61829370 61895604 18 66235 1 exm1344664 exm1344805 DDX42 A03T 61829370 61897716 23 68347 1 exm1344664 exm1896189 K03E 61829370 61895604 18 66235 1 exm1344664 exm1344805 K03T 61829370 61895604 18 66235 1 exm1344664 exm1344805 K03T 5395098 6301903 45 906806 1 exm1372975 exm1373311 K03E 18p11.31 EPB41L3 5395098 5441359 24 46262 1 exm1372975 exm2268071 K06E 18q12.1 CDH2 25496945 25727748 13 230804 1 exm-rs8084703 exm1380173 K06T 25496945 25727748 13 230804 1 exm-rs8084703 exm1380173 DSC3, A03E 18q12.1 28598091 28666679 35 68589 1 exm1380256 exm1380419 DSC2 A03T 28598091 28666679 35 68589 1 exm1380256 exm1380419 CDH20, LOC100996 A02E 18q21.33 59157933 59713206 22 555274 1 exm1389758 exm1389926 669, RNF152 A02T 59157933 59713206 22 555274 1 exm1389758 exm1389926 A03E 59157933 59854993 37 697061 1 exm1389758 exm2253495 A03T 59157933 59828420 35 670488 1 exm1389758 exm1390044 K08E 59157933 59713206 22 555274 1 exm1389758 exm1389926 K08T 59157933 59713206 22 555274 1 exm1389758 exm1389926 A10E 18q22.1 CDH19 64066170 64239301 21 173132 1 exm2253510 exm1391574 A10T 64066170 64239301 21 173132 1 exm2253510 exm1391574 K03E 64066170 64239301 21 173132 1 exm2253510 exm1391574 K03T 64066170 64239301 21 173132 1 exm2253510 exm1391574 K06E 64066170 64239301 21 173132 1 exm2253510 exm1391574 K06T 64066170 64239301 21 173132 1 exm2253510 exm1391574 K08E 64066170 64239301 21 173132 1 exm2253510 exm1391574 K08T 64066170 64239301 21 173132 1 exm2253510 exm1391574 A02E 64172074 64239301 20 67228 1 exm1391477 exm1391574 A02T 64172074 64239301 20 67228 1 exm1391477 exm1391574 A03E 64172074 64239301 20 67228 1 exm1391477 exm1391574 A03T 64172074 64239301 20 67228 1 exm1391477 exm1391574 A08E 64172074 64239301 20 67228 1 exm1391477 exm1391574 A08T 64172074 64239301 20 67228 1 exm1391477 exm1391574 K01E 64172074 64239301 20 67228 1 exm1391477 exm1391574 K01T 64172074 64239301 20 67228 1 exm1391477 exm1391574 K06T 18q22.3 ZNF407 72103739 72347444 55 243706 1 exm1392629 exm1393069 A02E 72343156 72347444 25 4289 1 exm1392895 exm1393069 A02T 72343156 72347444 25 4289 1 exm1392895 exm1393069 A03E 72343156 72347444 25 4289 1 exm1392895 exm1393069 A03T 72343156 72347444 25 4289 1 exm1392895 exm1393069 K06E 72343156 72347444 25 4289 1 exm1392895 exm1393069 K07E 72343156 72347444 25 4289 1 exm1392895 exm1393069 K07T 72343156 72347444 25 4289 1 exm1392895 exm1393069 PSG1, 19q13.2- PSG6, A04B 43344686 43528980 30 184295 1 exm2272793 exm2229393 q13.31 PSG7, PSG11 A04E 43344686 43528980 30 184295 1 exm2272793 exm2229393
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Gene SNP C ID Cytoband STARTBP ENDBP LENGTH START.PROBE END.PROBE symbol (N) N A04T 43344686 43528980 30 184295 1 exm2272793 exm2229393 VRK3, A03E 19q13.33 ZNF473, 50484256 50662504 50 178249 1 exm1946944 exm1493532 IZUMO2 A03T 50484256 50662504 50 178249 1 exm1946944 exm1493532 K03E 50484256 50662504 50 178249 1 exm1946944 exm1493532 K03T 50484256 50662504 50 178249 1 exm1946944 exm1493532 K06E 50484256 50662504 50 178249 1 exm1946944 exm1493532 K06T 50484256 50662504 50 178249 1 exm1946944 exm1493532 ZNF610, A03E 19q13.41 52819102 52888282 41 69181 1 exm1499128 exm2229952 ZNF880 A03B 52852469 52888282 33 35814 1 exm1499190 exm2229952 A03T 52852469 52888282 33 35814 1 exm1499190 exm2229952 K06E 19q13.41 ZNF83 53116331 53117817 13 1487 1 exm1499882 exm2229979 K06T 53116331 53117817 13 1487 1 exm1499882 exm2229979 TMC4, MBOAT7, K08E 19q13.42 TSEN34, 54668181 54722700 22 54520 1 exm1503211 exm1503499 RPS9, LIRB3 K08T 54668181 54722700 22 54520 1 exm1503211 exm1503499 DEFB126, A08E 20q13.42 DEFB127, 126085 210225 24 84141 1 exm1517581 exm1517675 DEFB129 A08T 126085 210225 24 84141 1 exm1517581 exm1517675 K06E 126085 210225 24 84141 1 exm1517581 exm1517675 K06T 126085 210225 24 84141 1 exm1517581 exm1517675 NSFL1C, SIRPB2, A03E 20p13 1424531 1559330 34 134800 1 exm1518937 exm2254162 SIRPD, SIRPB1 A03T 1424531 1559330 34 134800 1 exm1518937 exm2254162 K01T 1424531 1471984 17 47454 1 exm1518937 exm1519034 K01E 1424531 1559330 34 134800 1 exm1518937 exm2254162 K03E 1424531 1559330 34 134800 1 exm1518937 exm2254162 K03T 1424531 1559330 34 134800 1 exm1518937 exm2254162 K08E 1424531 1559330 34 134800 1 exm1518937 exm2254162 K08T 1424531 1559330 34 134800 1 exm1518937 exm2254162 A01E 20q13.13 KCNB1 47989527 47990618 10 1092 1 exm1548901 exm1548938 A01T 47989527 47990618 10 1092 1 exm1548901 exm1548938 A02E 47989527 47990618 10 1092 1 exm1548901 exm1548938 A02T 47989527 47990618 10 1092 1 exm1548901 exm1548938 A03E 47989527 47990618 10 1092 1 exm1548901 exm1548938 A03T 47989527 47990618 10 1092 1 exm1548901 exm1548938 K01E 47989527 47990618 10 1092 1 exm1548901 exm1548938 K01T 47989527 47990618 10 1092 1 exm1548901 exm1548938 K03E 47989527 47990618 10 1092 1 exm1548901 exm1548938 K03T 47989527 47990618 10 1092 1 exm1548901 exm1548938 K06E 47989527 47990618 10 1092 1 exm1548901 exm1548938 K06T 47989527 47990618 10 1092 1 exm1548901 exm1548938 K08E 47989527 47990618 10 1092 1 exm1548901 exm1548938 K08T 47989527 47990618 10 1092 1 exm1548901 exm1548938 K10E 47989527 47990618 10 1092 1 exm1548901 exm1548938 K10T 47989527 47990618 10 1092 1 exm1548901 exm1548938 K10E 18293533 18389548 44 96016 1 exm1583786 exm1584098 K10T 18293533 18389548 44 96016 1 exm1583786 exm1584098 ZNF280B, K08E 22q11.22 ZNF280A, 22843254 22989304 11 146051 1 exm1590587 exm1590868 PRAME K08T 22843254 22892362 10 49109 0 exm1590587 exm2001794 K07T 26181397 26351314 32 169918 1 exm1595835 exm1596024 K03E 22q12.1 MYO18B 26239784 26351314 23 111531 1 exm1595895 exm1596024 K07E 26239784 26351314 23 111531 1 exm1595895 exm1596024 K03T 26264290 26351314 19 87025 1 exm2235431 exm1596024
８８
Appendix Ⅱ. Functional annotation clusters of significant DEGs from gene expression data
Gene Term Genes % P-Value Bonferroni FDR Count AQP9, IFI44L, LY9, HLA-DMB, TLR7, SKAP1, IL10, CD96, CXCR4, SEMA7A, CCL3L3, IL1A, LTA, RAB27A, LAIR1, GBP5, NCF2, CMKLR1, NCF4, CCL4L1, GEM, TRAT1, PDCD1LG2, CCR8, CCR7, CCR6, LAX1, LILRB4, FAIM3, AICDA, GBP4, GBP2, GBP1, GPR183, CCL3, TNF, ENPP2, IFITM2, 2.77E- immune response IFITM3, CCR1, OAS3, ACP5, RSAD2, OAS1, OAS2, 81 11.02 1.04E-18 2.77E-15 15 IL7R, CCL5, CCL4, IFI35, CCL22, CCL20, XBP1, TAP2, TAP1, CD24, IGKC, CD27, FYB, PTPRC, CR1, IL2RA, CR2, TNFSF4, IGKV3D-11, IGJ, CD1C, SMAD3, MYO1F, SLAMF7, CD180, AIM2, PSMB9, BTLA, DDX58, CD55, TNFSF10, CYBB, APOL1, RGS1, TGFBR3, IFI6 CCL3, TNF, FUT8, ENPP2, VIM, CCL5, ITGB1, CCL4, EPHB1, IL10, VCAM1, NRCAM, CD9, CCL22, APP, PTK2, CXCR4, ROBO1, LHX2, ROBO2, CD24, SEMA3A, SELPLG, PPAP2B, VNN2, FN1, 8.04E- cell motion 48 6.53 6.03E-09 1.61E-05 SYK, PTPRK, EGR2, ARID5B, ANXA1, CCL4L1, 06 ITGA4, STAT3, ASCL1, CCR6, PARP9, FYN, ITGA5, FOXG1, LRP6, TGFBR3, SDCBP, EFNA5, JAK2, APBB2, FEZ1, MYH10 PTPRC, TNF, CCL4L1, RSAD2, IFI44, STAT1, CCL5, 4.16E- response to virus CCL4, TLR7, IFI35, STAT2, DDX58, IRAK3, PLSCR1, 20 2.72 4.68E-08 1.25E-04 05 CCL22, ISG15, CXCR4, EIF2AK2, MX1, MX2 TNF, ZAK, BLK, TLR7, IL10, TRIB1, STAT4, RASGRP3, CXCR4, PRKACB, RAPGEF2, INSR, CD27, MAP2K6, GHR, SYK, FYB, ZFP36, PTPRC, 4.60E- protein kinase cascade ARHGEF6, STRADB, SMAD1, STAT1, STAT3, 39 5.31 6.89E-08 1.84E-04 05 STAT2, DAPK1, MAP4K3, TNFRSF10A, MAP4K4, DUSP4, PRLR, FYN, LAX1, JAK1, TGFBR3, JAK2, ERC1, LRRK2, F2R GPR183, TNF, BLM, IL7R, ITGB1, TLR7, IL10, VCAM1, CD9, CXCR4, BCL11A, NDRG1, CD24, DPP4, LTA, KIF13B, SYK, RAB27A, EGR1, PTPRC, 6.32E- cell activation 33 4.49 1.18E-07 3.16E-04 TNFSF4, SMAD3, MYO1F, SLAMF7, ITGA4, 05 PLSCR1, PRLR, FYN, LAX1, LCK, RIPK2, AICDA, F2R SGMS1, TLR7, IL10, CXCR4, CCL3L3, MX1, MX2, IL1A, RAB27A, PLD1, NCF2, CCL4L1, TRAT1, CCR7, CCR6, MNDA, FAIM3, RIPK2, PRF1, CCL3, TNF, CCR1, RSAD2, PXK, CCL5, ITGB1, CCL4, 7.63E- defense response 53 7.21 1.72E-07 4.58E-04 CCL22, CCL20, TAP2, TAP1, CD24, FN1, PTPRC, 05 CR1, IL2RA, TNFSF4, CR2, HCK, RNASE6, ANXA1, MYO1F, SMAD1, SLAMF7, CD180, STAT3, EPHA3, DDX58, CD55, CYBB, APOL1, ALOX5, F2R HNF1B, AQP9, IL10, CREB3L2, PRKACB, CASP1, INSR, LTA, GHR, EGR1, PLD1, EGR2, GRIN2A, LEF1, CD38, BTG2, RIPK2, SORT1, GNB4, EIF2AK2, ME1, PRF1, TNF, CYP1B1, MCL1, ACP5, HSPA1A, response to organic 1.54E- CDH1, HSPA1B, CCL5, LIN28B, TRIB1, IRAK3, 58 7.89 4.04E-07 1.08E-03 substance 04 BCHE, DGKD, TAP2, PPP3CA, CD24, CD27, TXNIP, MAP1B, SMAD3, SMAD1, STAT1, STAT3, EPHA3, ABCB4, CYP7B1, DUSP4, PLA2G4A, EPS8, ID2, FYN, TGFBR3, PTCH1, JAK2, MGST1, F2R, VLDLR CCL3, TNF, F13A1, CCR1, ITGB3, PXK, SGMS1, CCL5, TLR7, CCL4, IL10, CD9, CCL22, CCL20, CXCR4, CCL3L3, CD24, IL1A, FN1, RAB27A, CR1, IL2RA, CR2, TNFSF4, MAP1B, ANXA1, GRIN2A, 1.45E- response to wounding 47 6.39 4.36E-07 1.16E-03 SMAD3, CCL4L1, SMAD1, STAT3, CD180, EPHA3, 04 PLSCR1, CD55, CCR7, CYBB, F5, GNAQ, ITGA5, SERPINB2, RIPK2, JAK2, CTSB, ALOX5, MYH10, F2R
８９
Gene Term Genes % P-Value Bonferroni FDR Count MEF2C, ZAK, SGMS1, IL10, PCGF2, APP, FOXO3B, CASP1, MX1, IL1A, LTA, MAP2K6, RAB27A, GHR, ARHGEF6, GRIN2A, PIM2, PRKCE, DAPK1, TNFRSF10A, SERPINB9, TNFRSF9, CD38, BTG2, TNFRSF10D, HIPK2, LCK, SERPINB2, RIPK2, regulation of 2.67E- SORT1, FAIM3, CTSB, LRRK2, TNF, SYVN1, MCL1, 62 8.44 9.02E-07 2.40E-03 programmed cell death 04 HSPA1A, CDH1, HSPA1B, ITM2B, VDR, HSPA5, CD24, CD27, TXNIP, PTPRC, IL2RA, ANXA1, SMAD3, MAL, STRADB, SLAMF7, STAT1, ATF5, PLA2G4A, TNFSF10, PRLR, JAK2, APBB2, PERP, IFI6, F2R, TP53INP1 MEF2C, ZAK, SGMS1, IL10, PCGF2, APP, FOXO3B, CASP1, MX1, IL1A, LTA, MAP2K6, RAB27A, GHR, ARHGEF6, GRIN2A, PIM2, PRKCE, DAPK1, TNFRSF10A, SERPINB9, TNFRSF9, CD38, BTG2, TNFRSF10D, HIPK2, LCK, SERPINB2, RIPK2, 2.66E- regulation of cell death SORT1, FAIM3, CTSB, LRRK2, TNF, SYVN1, MCL1, 62 8.44 9.99E-07 2.66E-03 04 HSPA1A, CDH1, HSPA1B, ITM2B, VDR, HSPA5, CD24, CD27, TXNIP, PTPRC, IL2RA, ANXA1, SMAD3, MAL, STRADB, SLAMF7, STAT1, ATF5, PLA2G4A, TNFSF10, PRLR, JAK2, APBB2, PERP, IFI6, F2R, TP53INP1 GPR183, BLM, IL7R, ITGB1, IL10, VCAM1, CXCR4, BCL11A, CD24, DPP4, SYK, RAB27A, KIF13B, 2.74E- lymphocyte activation 25 3.40 1.13E-06 3.01E-03 EGR1, PTPRC, TNFSF4, SMAD3, ITGA4, SLAMF7, 04 PRLR, LAX1, FYN, LCK, RIPK2, AICDA GPR183, BLM, IL7R, TLR7, ITGB1, IL10, VCAM1, CXCR4, BCL11A, NDRG1, CD24, DPP4, SYK, 2.56E- leukocyte activation RAB27A, KIF13B, EGR1, PTPRC, TNFSF4, SMAD3, 28 3.81 1.15E-06 3.07E-03 04 MYO1F, ITGA4, SLAMF7, PRLR, LAX1, FYN, LCK, RIPK2, AICDA MEF2C, ZAK, SGMS1, IL10, PCGF2, APP, FOXO3B, CASP1, MX1, IL1A, MAP2K6, LTA, RAB27A, GHR, ARHGEF6, GRIN2A, PIM2, PRKCE, DAPK1, TNFRSF10A, SERPINB9, TNFRSF9, CD38, BTG2, TNFRSF10D, HIPK2, LCK, SERPINB2, RIPK2, 2.84E- regulation of apoptosis SORT1, FAIM3, CTSB, TNF, SYVN1, MCL1, 61 8.30 1.38E-06 3.68E-03 04 HSPA1A, CDH1, HSPA1B, ITM2B, VDR, HSPA5, CD24, CD27, TXNIP, PTPRC, IL2RA, ANXA1, SMAD3, MAL, STRADB, SLAMF7, STAT1, ATF5, PLA2G4A, TNFSF10, PRLR, JAK2, APBB2, PERP, IFI6, F2R, TP53INP1 TNF, ZAK, ITM2B, IL10, VDR, APP, CD24, MX1, CASP1, FOXO3B, LTA, CD27, MAP2K6, RAB27A, TXNIP, PTPRC, IL2RA, ARHGEF6, GRIN2A, positive regulation of 6.73E- SMAD3, MAL, SLAMF7, STAT1, PRKCE, DAPK1, 39 5.31 3.53E-06 9.38E-03 programmed cell death 04 TNFRSF10A, TNFRSF9, CD38, PLA2G4A, TNFSF10, HIPK2, LCK, RIPK2, SORT1, JAK2, APBB2, PERP, LRRK2, TP53INP1 TNF, ZAK, ITM2B, IL10, VDR, APP, CD24, MX1, CASP1, FOXO3B, LTA, CD27, MAP2K6, RAB27A, TXNIP, PTPRC, IL2RA, ARHGEF6, GRIN2A, ~positive regulation of 7.02E- SMAD3, MAL, SLAMF7, STAT1, PRKCE, DAPK1, 39 5.31 3.95E-06 1.05E-02 cell death 04 TNFRSF10A, TNFRSF9, CD38, PLA2G4A, TNFSF10, HIPK2, LCK, RIPK2, SORT1, JAK2, APBB2, PERP, LRRK2, TP53INP1 CCL3, PLD1, ENPP2, CMKLR1, CCR1, CCL4L1, CCL5, CCL4, IL10, CCR8, CCL22, CCR7, CCR6, 8.48E- taxis 21 2.86 5.09E-06 1.35E-02 CCL20, CXCR4, ROBO1, CCL3L3, ROBO2, 04 SEMA3A, CMTM3, SYK CCL3, PLD1, ENPP2, CMKLR1, CCR1, CCL4L1, CCL5, CCL4, IL10, CCR8, CCL22, CCR7, CCR6, 8.48E- chemotaxis 21 2.86 5.09E-06 1.35E-02 CCL20, CXCR4, ROBO1, CCL3L3, ROBO2, 04 SEMA3A, CMTM3, SYK CCL3, TNF, CCR1, PXK, SGMS1, CCL5, CCL4, TLR7, IL10, CCL22, CCL20, CXCR4, CCL3L3, CD24, 8.45E- inflammatory response IL1A, FN1, CR1, IL2RA, TNFSF4, CR2, ANXA1, 32 4.35 5.39E-06 1.43E-02 04 CCL4L1, SMAD1, CD180, STAT3, EPHA3, CD55, CCR7, CYBB, RIPK2, ALOX5, F2R TNF, ZAK, ITM2B, IL10, VDR, APP, CD24, MX1, positive regulation of 1.11E- CASP1, FOXO3B, LTA, CD27, MAP2K6, RAB27A, 38 5.17 7.46E-06 1.97E-02 apoptosis 03 TXNIP, PTPRC, IL2RA, ARHGEF6, GRIN2A, ９０
Gene Term Genes % P-Value Bonferroni FDR Count SMAD3, MAL, SLAMF7, STAT1, PRKCE, DAPK1, TNFRSF10A, TNFRSF9, CD38, PLA2G4A, TNFSF10, HIPK2, LCK, RIPK2, SORT1, JAK2, APBB2, PERP, TP53INP1 FERMT2, LY9, DDR2, NRCAM, CD96, APP, ARHGAP5, ROBO1, ROBO2, FNDC3A, SYK, PTPRK, FLOT2, LEF1, CCL4L1, CCR8, F5, CLDN1, RAB13, JAM2, CD226, CHL1, CLDN16, PARD3, 1.18E- cell adhesion TNF, CCR1, NEDD9, CDH1, ITGB3, CCL5, ITGB1, 53 7.21 8.40E-06 2.22E-02 03 CCL4, VCAM1, CD9, ITGB8, SCARB2, CD24, SELPLG, FN1, FLRT3, PTPRC, ADAM23, CNKSR3, CELSR3, NID1, SLAMF7, ITGA4, MCAM, DSG2, ITGA5, PERP, FEZ1, CDH11 FERMT2, LY9, DDR2, NRCAM, CD96, APP, ARHGAP5, ROBO1, ROBO2, FNDC3A, SYK, PTPRK, FLOT2, LEF1, CCL4L1, CCR8, F5, CLDN1, RAB13, JAM2, CD226, CHL1, CLDN16, PARD3, 1.14E- biological adhesion TNF, CCR1, NEDD9, CDH1, ITGB3, CCL5, ITGB1, 53 7.21 8.56E-06 2.26E-02 03 CCL4, VCAM1, CD9, ITGB8, SCARB2, CD24, SELPLG, FN1, FLRT3, PTPRC, ADAM23, CNKSR3, CELSR3, NID1, SLAMF7, ITGA4, MCAM, DSG2, ITGA5, PERP, FEZ1, CDH11 VCAM1, PTPRC, TNF, ITGA5, ITGA4, CD24, ITGB1, 1.11E- leukocyte adhesion 9 1.22 8.76E-06 2.31E-02 SELPLG, SYK 03 GNA15, ZAK, IQGAP2, TLR7, IL10, ARHGAP5, MCTP2, CXCR4, RAPGEF5, GUCY1A3, PRKACB, RAPGEF2, INSR, LTA, MAP2K6, RAB27A, SYK, GHR, ZFP36, PLD1, ARHGEF6, PRKCH, GEM, PRKCE, DAPK1, NRIP1, MCTP1, TNFRSF10A, MAP4K3, MAP4K4, NCOA1, GNAQ, LAX1, HTR7, intracellular signaling HIPK2, SDCBP, GNB4, GUCY1B3, RAB13, UNC13C, 1.38E- 81 11.02 1.14E-05 3.00E-02 cascade LRRK2, GRAP2, ERC1, LRRK1, PRKD3, RALGPS2, 03 TNF, BLM, BLK, CCR1, TRIB1, VDR, STAT4, RASGRP3, DGKD, RASGRP1, FBXO6, CD27, FYB, PTPRC, GPR155, STRADB, SMAD1, RGNEF, STAT1, STAT3, STAT2, DUSP4, RAB31, RAB30, RGS1, PRLR, PDE7A, FYN, RGS6, JAK1, TGFBR3, JAK2, RAB38, APBB2, F2R TNF, FUT8, CCL5, ITGB1, IL10, NRCAM, VCAM1, CCL22, PTK2, CXCR4, ROBO1, CD24, PPAP2B, 1.60E- cell migration SELPLG, SYK, FN1, PTPRK, ARID5B, ITGA4, 28 3.81 1.38E-05 3.61E-02 03 ASCL1, PARP9, ITGA5, FYN, LRP6, SDCBP, TGFBR3, APBB2, MYH10 MEF2C, TNFRSF21, PRF1, TNF, MCL1, EGLN3, SGMS1, ITM2B, DNASE1L3, ASAH2, APP, PEG10, ECE1, CXCR4, TRIM69, XAF1, CD24, SEMA3A, CASP1, FOXO3B, IL1A, LTA, CD27, IL2RA, 3.27E- apoptosis 46 6.26 2.95E-05 7.57E-02 ARHGEF6, SMAD3, PIM2, STAT1, AHR, DDIT4, 03 DAPK1, NCKAP1, TNFRSF10A, TNFSF10, TNFRSF10D, HIPK2, SULF1, LCK, RIPK2, JAK2, EAF2, PERP, EIF2AK2, IFI6, TP53INP1, F2R CCL5, STAT1, IL10, EPHA3, TRIB1, IRAK3, response to molecule of 3.29E- PLA2G4A, TAP2, RIPK2, CD24, LTA, MGST1, 14 1.90 3.08E-05 7.90E-02 bacterial origin 03 VLDLR, F2R CCL3, ENPP2, CCR1, UCHL1, CCL5, CCL4, IL10, APLP2, APP, CCL22, CCL20, ROBO1, CXCR4, 3.44E- locomotory behavior CCL3L3, ROBO2, SEMA3A, SYK, PLD1, CMKLR1, 27 3.67 3.36E-05 8.57E-02 03 CCL4L1, ANKH, CCR8, CCR7, CCR6, EPS8, HIPK2, CMTM3
９１
Appendix Ⅲ. Functional annotation clusters of significant differentially expression genes from miRNA expression data
Term Genes Count % P-Value Bonferroni FDR BMI1, E2F3, CDX2, PPARG, FOXO1, ZEB1, NR2E1, PTEN, TGFB1, GLI1, BDNF, CASP3, CDKN2A, SERPINE1, FOSL1, MYC, TP53, CDK6, IL6R, CDK4, MYCN, SUZ12, SMO, CCND1, HIF1A, HNF4A, GRN, VEGFA, LAMC1, FGFR3, regulation of cell proliferation 58 31.69 4.40E-28 1.04E-24 1.04E-24 GNAI2, ERBB3, ERBB2, SOX2, BMPR2, SOX4, ITGB1, IGF1R, CD9, VDR, BCL2, PRKRA, ZAP70, BCL6, CEBPA, FLT1, BECN1, SMAD4, IGF2, SIRT1, NOTCH2, NOTCH1, CDKN1A, ID2, ETS1, NOTCH4, FABP4, MTOR FOXO1, NFKB1, FOXO3, PTEN, NR2E1, TGFB1, AKT1, BAK1, CASP3, BDNF, CDKN2A, CD44, FOSL1, MYC, TERT, ARHGEF3, GRIN2A, TP53, IL6R, PRKCE, SMO, IGF2R, VEGFA, LRRK2, TNFAIP3, regulation of programmed MCL1, ERBB3, ERBB2, SOX4, CDH1, SRC, 53 28.96 5.43E-23 1.29E-19 6.44E-20 cell death IGF1R, VDR, BCL2, PRKRA, BCL3, BCL6, BMF, ARHGDIA, TEX261, BECN1, CREB1, BIRC5, IGF2, SIRT1, TP73, ATM, NOTCH2, NOTCH1, CDKN1A, ETS1, BBC3, TP53INP1 FOXO1, NFKB1, FOXO3, PTEN, NR2E1, TGFB1, AKT1, BAK1, CASP3, BDNF, CDKN2A, CD44, FOSL1, MYC, TERT, ARHGEF3, GRIN2A, TP53, IL6R, PRKCE, SMO, IGF2R, VEGFA, LRRK2, TNFAIP3, regulation of cell death MCL1, ERBB3, ERBB2, SOX4, CDH1, SRC, 53 28.96 6.43E-23 1.52E-19 5.08E-20 IGF1R, VDR, BCL2, PRKRA, BCL3, BCL6, BMF, ARHGDIA, TEX261, BECN1, CREB1, BIRC5, IGF2, SIRT1, TP73, ATM, NOTCH2, NOTCH1, CDKN1A, ETS1, BBC3, TP53INP1 FOXO1, NFKB1, FOXO3, PTEN, NR2E1, TGFB1, AKT1, BAK1, CASP3, BDNF, CDKN2A, CD44, FOSL1, MYC, TERT, ARHGEF3, GRIN2A, TP53, IL6R, PRKCE, SMO, IGF2R, VEGFA, TNFAIP3, MCL1, regulation of apoptosis ERBB3, ERBB2, SOX4, CDH1, SRC, IGF1R, 52 28.42 2.42E-22 5.74E-19 1.43E-19 VDR, BCL2, PRKRA, BCL3, BCL6, BMF, ARHGDIA, TEX261, BECN1, CREB1, BIRC5, IGF2, SIRT1, TP73, ATM, NOTCH2, NOTCH1, CDKN1A, ETS1, BBC3, TP53INP1 E2F1, E2F3, CDX2, PPARG, FOXO1, NFKB1, FOXO3, ZEB1, CBFB, TGFB1, GLI1, AKT1, H2AFX, FOSL1, MYC, AKT2, EGR2, TP53, IL6R, CDK4, HMGA1, positive regulation of CCND1, HIF1A, CCND3, HNF4A, macromolecule metabolic VEGFA, PRDM1, LRRK2, MED1, SOX2, 53 28.96 6.34E-22 1.50E-18 3.00E-19 process ONECUT2, BMPR2, SOX4, EGLN2, SRF, IGF1R, BCL2, BCL3, CEBPA, KLF13, SMAD7, CREB1, SMAD4, IGF2, DDX5, TP73, NOTCH1, ETS1, PLK1, MAPK14, NOTCH4, MTOR, IRF4 BMI1, E2F3, FGFR3, CDX2, GNAI2, ERBB2, SOX2, SOX4, ITGB1, NR2E1, TGFB1, GLI1, IGF1R, BCL2, ZAP70, BCL6, positive regulation of cell MYC, FOSL1, FLT1, CDK6, IGF2, IL6R, 37 20.22 3.98E-20 9.44E-17 1.57E-17 proliferation CDK4, MYCN, SUZ12, SMO, CDKN1A, CCND1, NOTCH1, HIF1A, ID2, GRN, VEGFA, NOTCH4, FABP4, MTOR, LAMC1
９２
Term Genes Count % P-Value Bonferroni FDR CDX2, SOX2, PPARG, BMPR2, NFKB1, FOXO3, SRF, TGFB1, AKT1, BDNF, BCL2, positive regulation of cell MAPT, ZAP70, ARHGDIA, AP3B1, LPL, 28 15.30 1.33E-18 3.14E-15 4.49E-16 differentiation SMAD4, IGF2, SOCS5, IL6R, NTRK3, SMO, NOTCH1, HIF1A, ID2, ETS1, MAPK14, BMPR1B E2F1, E2F3, CDX2, SOX2, PPARG, ONECUT2, SOX4, FOXO1, NFKB1, FOXO3, ZEB1, SRF, CBFB, TGFB1, GLI1, AKT1, IGF1R, BCL3, FOSL1, MYC, AKT2, macromolecule biosynthetic CEBPA, EGR2, KLF13, CREB1, TP53, 42 22.95 1.08E-17 2.57E-14 3.21E-15 process SMAD4, IGF2, DDX5, CDK4, HMGA1, TP73, NOTCH1, HIF1A, HNF4A, ETS1, MAPK14, VEGFA, NOTCH4, MTOR, IRF4, MED1 E2F1, E2F2, CCNG1, ITGB1, PTEN, TGFB1, CCNE2, AKT1, CDC42, BAK1, CASP3, CDKN2A, BCL2, BCL6, H2AFX, regulation of cell cycle 31 16.94 2.38E-17 5.64E-14 6.27E-15 MYC, FOSL1, ROCK2, TP53, CDK6, IGF2, BIRC5, CDK4, ATM, CDKN1A, CCND1, ID2, HNF4A, CCND3, ETS1, MAPK14 E2F1, E2F3, CDX2, SOX2, PPARG, ONECUT2, SOX4, FOXO1, NFKB1, FOXO3, ZEB1, SRF, CBFB, TGFB1, GLI1, AKT1, IGF1R, BCL3, FOSL1, MYC, AKT2, positive regulation of cellular CEBPA, EGR2, KLF13, CREB1, TP53, 42 22.95 5.54E-17 1.31E-13 1.31E-14 biosynthetic process SMAD4, IGF2, DDX5, CDK4, HMGA1, TP73, NOTCH1, HIF1A, HNF4A, ETS1, MAPK14, VEGFA, NOTCH4, MTOR, IRF4, MED1 E2F1, EID1, CDX2, E2F6, SOX2, PPARG, ONECUT2, FOXO1, NFKB1, FOXO3, ZEB1, SRF, NR2E1, TGFB1, CBFB, GLI1, regulation of transcription VDR, BCL3, BCL6, FOSL1, MYC, CEBPA, from RNA polymerase II 43 23.50 7.59E-17 2.63E-13 2.39E-14 EGR2, SMAD7, KLF13, CREB1, SMAD4, promoter TP53, SNAI2, SIRT1, MYCN, SUZ12, NOTCH1, HIF1A, HNF4A, ID2, ID1, ETS1, MAPK14, VEGFA, PRDM1, IRF4, MED1 E2F1, E2F3, CDX2, SOX2, PPARG, ONECUT2, SOX4, FOXO1, NFKB1, FOXO3, ZEB1, SRF, CBFB, TGFB1, GLI1, AKT1, IGF1R, BCL3, FOSL1, MYC, AKT2, positive regulation of CEBPA, EGR2, KLF13, CREB1, TP53, 42 22.95 9.21E-17 2.63E-13 2.19E-14 biosynthetic process SMAD4, IGF2, DDX5, CDK4, HMGA1, TP73, NOTCH1, HIF1A, HNF4A, ETS1, MAPK14, VEGFA, NOTCH4, MTOR, IRF4, MED1 CDX2, SOX2, PPARG, BMPR2, NFKB1, FOXO3, SRF, TGFB1, AKT1, BDNF, BCL2, positive regulation of MAPT, ZAP70, ARHGDIA, AP3B1, LPL, 28 15.30 1.92E-16 5.26E-13 4.04E-14 developmental process SMAD4, IGF2, SOCS5, IL6R, NTRK3, SMO, NOTCH1, HIF1A, ID2, ETS1, MAPK14, BMPR1B E2F1, E2F3, CDX2, SOX2, PPARG, ONECUT2, SOX4, FOXO1, NFKB1, positive regulation of FOXO3, ZEB1, SRF, TGFB1, CBFB, GLI1, transcription, DNA- BCL3, FOSL1, MYC, CEBPA, EGR2, 35 19.13 2.24E-16 5.26E-13 3.75E-14 dependent KLF13, CREB1, SMAD4, TP53, HMGA1, TP73, NOTCH1, HIF1A, HNF4A, ETS1, MAPK14, VEGFA, NOTCH4, IRF4, MED1 E2F1, E2F3, CDX2, SOX2, PPARG, ONECUT2, SOX4, FOXO1, NFKB1, FOXO3, ZEB1, SRF, TGFB1, CBFB, GLI1, positive regulation of AKT1, IGF1R, BCL3, H2AFX, FOSL1, nitrogen compound metabolic 40 21.86 2.49E-16 5.26E-13 3.51E-14 MYC, CEBPA, EGR2, KLF13, CREB1, process SMAD4, TP53, IGF2, DDX5, HMGA1, TP73, NOTCH1, HIF1A, HNF4A, ETS1, MAPK14, VEGFA, NOTCH4, IRF4, MED1 E2F1, E2F3, CDX2, SOX2, PPARG, positive regulation of RNA ONECUT2, SOX4, FOXO1, NFKB1, 35 19.13 2.88E-16 7.89E-13 4.93E-14 metabolic process FOXO3, ZEB1, SRF, TGFB1, CBFB, GLI1, BCL3, FOSL1, MYC, CEBPA, EGR2,
９３
Term Genes Count % P-Value Bonferroni FDR KLF13, CREB1, SMAD4, TP53, HMGA1, TP73, NOTCH1, HIF1A, HNF4A, ETS1, MAPK14, VEGFA, NOTCH4, IRF4, MED1
E2F1, E2F3, CDX2, SOX2, PPARG, ONECUT2, SOX4, FOXO1, NFKB1, positive regulation of FOXO3, ZEB1, SRF, TGFB1, CBFB, GLI1, nucleobase, nucleoside, IGF1R, BCL3, H2AFX, FOSL1, MYC, 39 21.31 6.48E-16 1.58E-12 9.28E-14 nucleotide and nucleic acid CEBPA, EGR2, KLF13, CREB1, SMAD4, metabolic process TP53, IGF2, DDX5, HMGA1, TP73, NOTCH1, HIF1A, HNF4A, ETS1, MAPK14, VEGFA, NOTCH4, IRF4, MED1 MCL1, ERBB3, ERBB2, SOX4, FOXO1, NFKB1, PTEN, NR2E1, AKT1, IGF1R, negative regulation of CASP3, BDNF, BCL2, BCL3, BCL6, MYC, 30 16.39 1.47E-15 3.42E-12 1.90E-13 apoptosis TERT, ARHGDIA, BECN1, TP53, IGF2, BIRC5, ATM, TP73, NOTCH2, SMO, CDKN1A, NOTCH1, VEGFA, TNFAIP3 MCL1, ERBB3, ERBB2, SOX4, FOXO1, NFKB1, PTEN, NR2E1, AKT1, IGF1R, negative regulation of CASP3, BDNF, BCL2, BCL3, BCL6, MYC, 30 16.39 2.03E-15 4.73E-12 2.49E-13 programmed cell death TERT, ARHGDIA, BECN1, TP53, IGF2, BIRC5, ATM, TP73, NOTCH2, SMO, CDKN1A, NOTCH1, VEGFA, TNFAIP3 MCL1, ERBB3, ERBB2, SOX4, FOXO1, NFKB1, PTEN, NR2E1, AKT1, IGF1R, negative regulation of cell CASP3, BDNF, BCL2, BCL3, BCL6, MYC, 30 16.39 2.16E-15 5.00E-12 2.50E-13 death TERT, ARHGDIA, BECN1, TP53, IGF2, BIRC5, ATM, TP73, NOTCH2, SMO, CDKN1A, NOTCH1, VEGFA, TNFAIP3 E2F1, E2F3, CDX2, SOX2, PPARG, ONECUT2, SOX4, FOXO1, NFKB1, FOXO3, ZEB1, SRF, TGFB1, CBFB, GLI1, positive regulation of gene BCL3, FOSL1, MYC, CEBPA, EGR2, 37 20.22 2.54E-15 6.05E-12 2.88E-13 expression KLF13, CREB1, SMAD4, TP53, DDX5, HMGA1, TP73, NOTCH1, HIF1A, HNF4A, ETS1, MAPK14, VEGFA, NOTCH4, PRDM1, IRF4, MED1 E2F1, E2F3, CDX2, SOX2, PPARG, ONECUT2, SOX4, FOXO1, NFKB1, FOXO3, ZEB1, SRF, TGFB1, CBFB, GLI1, positive regulation of BCL3, FOSL1, MYC, CEBPA, EGR2, 36 19.67 6.20E-15 1.47E-11 6.69E-13 transcription KLF13, CREB1, SMAD4, TP53, DDX5, HMGA1, TP73, NOTCH1, HIF1A, HNF4A, ETS1, MAPK14, VEGFA, NOTCH4, IRF4, MED1 FGFR3, CREB1, PPARG, TP53, SMAD4, IGF2, SOCS5, CDK4, CCNG1, DDX5, regulation of cell size RPTOR, TGFB1, TP73, AKT1, NTRK3, 23 12.57 2.21E-14 5.23E-11 2.28E-12 NOTCH2, CDKN1A, CDKN2A, HNF4A, MAPT, BCL2, BCL6, MTOR E2F1, EID1, CDX2, E2F6, SOX2, PPARG, NFKB1, ZEB2, REST, ZEB1, LIN28A, LIN28B, NR2E1, TGFB1, VDR, BAK1, negative regulation of EIF4EBP1, CDKN2A, PRKRA, EED, BCL3, macromolecule metabolic 40 21.86 2.23E-14 5.29E-11 2.20E-12 BCL6, TNRC6A, MYC, CEBPA, MSH3, process SMAD7, SMAD4, GRIN2A, TP53, IGF2, IL6R, SNAI2, SIRT1, SUZ12, HNF4A, ID2, ID1, FABP4, PRDM1 E2F1, SOX2, PPARG, ONECUT2, FOXO1, NFKB1, ZEB1, FOXO3, SRF, TGFB1, CBFB, positive regulation of GLI1, BCL3, MYC, FOSL1, CEBPA, EGR2, transcription from RNA 29 15.85 3.68E-14 8.71E-11 3.48E-12 KLF13, CREB1, SMAD4, TP53, NOTCH1, polymerase II promoter HIF1A, HNF4A, ETS1, MAPK14, VEGFA, IRF4, MED1 SOX4, FOXO3, PTEN, TGFB1, SRC, AKT1, VDR, BAK1, CASP3, CDKN2A, CD44, positive regulation of BCL2, PRKRA, BCL3, BCL6, MYC, FOSL1, 31 16.94 3.93E-14 9.31E-11 3.58E-12 programmed cell death TEX261, ARHGEF3, GRIN2A, TP53, PRKCE, ATM, TP73, NOTCH2, CDKN1A, NOTCH1, ETS1, BBC3, LRRK2, TP53INP1
９４
Term Genes Count % P-Value Bonferroni FDR SOX4, FOXO3, PTEN, TGFB1, SRC, AKT1, VDR, BAK1, CASP3, CDKN2A, CD44, positive regulation of cell BCL2, PRKRA, BCL3, BCL6, MYC, FOSL1, 31 16.94 4.45E-14 1.05E-10 3.90E-12 death TEX261, ARHGEF3, GRIN2A, TP53, PRKCE, ATM, TP73, NOTCH2, CDKN1A, NOTCH1, ETS1, BBC3, LRRK2, TP53INP1 E2F1, E2F2, E2F3, CDX2, E2F5, E2F6, PPARG, FOXO1, NFKB1, ZEB2, FOXO3, REST, ZEB1, NR2E1, CBFB, TGFB1, GLI1, CDKN2A, FOSL1, MYC, NANOG, EGR2, TP53, FOXN2, HMGA2, HMGA1, MYCN, regulation of transcription, SUZ12, HIF1A, HNF4A, VEGFA, PRDM1, 62 33.88 1.22E-13 2.88E-10 1.03E-11 DNA-dependent MED1, EID1, SOX2, ONECUT2, SOX4, LIN28A, SRF, LIN28B, VDR, POU2F2, BCL3, BCL6, CEBPA, KLF13, SMAD7, CREB1, SMAD4, IGF2, SNAI2, SIRT1, TP73, NOTCH2, NOTCH1, ID2, ETS1, ID1, MAPK14, NOTCH4, ZNF763, IRF4 SOX4, FOXO3, PTEN, TGFB1, SRC, AKT1, VDR, BAK1, CASP3, CDKN2A, CD44, positive regulation of BCL2, PRKRA, BCL3, BCL6, MYC, FOSL1, 30 16.39 2.19E-13 5.19E-10 1.79E-11 apoptosis TEX261, ARHGEF3, GRIN2A, TP53, PRKCE, ATM, TP73, NOTCH2, CDKN1A, NOTCH1, ETS1, BBC3, TP53INP1 E2F1, E2F2, E2F3, CDX2, E2F5, E2F6, PPARG, FOXO1, NFKB1, ZEB2, FOXO3, REST, ZEB1, NR2E1, CBFB, TGFB1, GLI1, CDKN2A, FOSL1, MYC, NANOG, EGR2, TP53, FOXN2, HMGA2, HMGA1, MYCN, regulation of RNA metabolic SUZ12, HIF1A, HNF4A, VEGFA, PRDM1, 62 33.88 3.32E-13 7.86E-10 2.62E-11 process MED1, EID1, SOX2, ONECUT2, SOX4, LIN28A, SRF, LIN28B, VDR, POU2F2, BCL3, BCL6, CEBPA, KLF13, SMAD7, CREB1, SMAD4, IGF2, SNAI2, SIRT1, TP73, NOTCH2, NOTCH1, ID2, ETS1, ID1, MAPK14, NOTCH4, ZNF763, IRF4 MCL1, ERBB3, ERBB2, PPARG, FOXO1, CDH1, LIN28A, MMP3, SRF, PTEN, LIN28B, TGFB1, SRC, AKT1, IGF1R, EIF4EBP1, CASP3, CD44, BCL2, PRKRA, response to organic substance 38 20.77 3.41E-13 8.08E-10 2.61E-11 MYC, FOSL1, CYR61, AKT2, EGR2, CREB1, GRIN2A, IGF2, IL6R, MMP13, CDKN1A, CCND1, HNF4A, ID2, ID1, MAPK14, FABP4, MTOR E2F1, EID1, CDX2, E2F6, SOX2, PPARG, ZEB2, NFKB1, ZEB1, REST, LIN28A, negative regulation of gene LIN28B, NR2E1, TGFB1, VDR, PRKRA, 32 17.49 3.46E-13 8.20E-10 2.56E-11 expression EED, BCL3, BCL6, TNRC6A, MYC, CEBPA, SMAD7, SMAD4, TP53, SNAI2, SIRT1, SUZ12, ID2, ID1, FABP4, PRDM1 MUC1, CYP24A1, NES, GNAI2, BECN1, SOX2, PPARG, BMPR2, TP53, SIRT1, response to extracellular PTEN, RPTOR, TGFB1, AKT1, VDR, 22 12.02 8.25E-13 1.95E-09 5.92E-11 stimulus CCND1, CDKN1A, CD44, BCL2, MTOR, FOSL1, TNRC6A BMI1, CEBPA, SGPL1, MSH3, UNG, PPARG, TP53, SOX4, CDK6, ITGB1, CBFB, immune system development TGFB1, CDC42, BAK1, NOTCH2, ID2, 24 13.11 1.10E-12 2.61E-09 7.69E-11 BCL2, VEGFA, NOTCH4, ZAP70, BCL3, BCL6, IRF4, MED1 GNAI2, ERBB2, BMPR2, ZEB2, CCNG1, PTEN, TGFB1, CCNE2, AKT1, CDC42, BAK1, CASP3, CDKN2A, BCL2, FLT1, regulation of phosphorylation 30 16.39 1.65E-12 3.91E-09 1.12E-10 SMAD7, MET, SMAD4, IGF2, IL6R, PRKCE, TP73, CDKN1A, CCND1, LRP1, HNF4A, CCND3, FABP4, RELN, MTOR FGFR3, ERBB3, ERBB2, BMPR2, FOXO1, PTEN, TGFB1, SRC, AKT1, IGF1R, enzyme linked receptor EIF4EBP1, CTGF, AKT2, SGPL1, FLT1, 26 14.21 2.00E-12 4.74E-09 1.32E-10 protein signaling pathway SMAD7, CREB1, MET, SMAD4, RAF1, IGF2, SOCS5, NTRK3, ID1, VEGFA, BMPR1B
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Term Genes Count % P-Value Bonferroni FDR BMI1, CEBPA, SGPL1, PPARG, TP53, SOX4, CDK6, ITGB1, CBFB, TGFB1, hemopoiesis CDC42, BAK1, NOTCH2, ID2, BCL2, 22 12.02 3.24E-12 7.67E-09 2.07E-10 VEGFA, NOTCH4, ZAP70, BCL3, BCL6, IRF4, MED1 GNAI2, ERBB2, BMPR2, ZEB2, CCNG1, PTEN, TGFB1, CCNE2, AKT1, CDC42, regulation of phosphate BAK1, CASP3, CDKN2A, BCL2, FLT1, 30 16.39 4.44E-12 1.05E-08 2.77E-10 metabolic process SMAD7, MET, SMAD4, IGF2, IL6R, PRKCE, TP73, CDKN1A, CCND1, LRP1, HNF4A, CCND3, FABP4, RELN, MTOR GNAI2, ERBB2, BMPR2, ZEB2, CCNG1, PTEN, TGFB1, CCNE2, AKT1, CDC42, regulation of phosphorus BAK1, CASP3, CDKN2A, BCL2, FLT1, 30 16.39 4.44E-12 1.05E-08 2.77E-10 metabolic process SMAD7, MET, SMAD4, IGF2, IL6R, PRKCE, TP73, CDKN1A, CCND1, LRP1, HNF4A, CCND3, FABP4, RELN, MTOR CDX2, SMAD7, SOX2, PPARG, TP53, CDK6, SOCS5, ZEB1, REST, LIN28A, negative regulation of cell SIRT1, ITGB1, NR2E1, TGFB1, NOTCH2, 21 11.48 5.27E-12 1.25E-08 3.20E-10 differentiation NOTCH1, BDNF, CCND1, NOTCH4, BCL6, ARHGDIA FGFR3, CREB1, PPARG, TP53, SMAD4, IGF2, SOCS5, CDK4, CCNG1, DDX5, regulation of cellular RPTOR, TGFB1, TP73, AKT1, NTRK3, 23 12.57 5.99E-12 1.42E-08 3.55E-10 component size NOTCH2, CDKN1A, CDKN2A, HNF4A, MAPT, BCL2, BCL6, MTOR MUC1, CYP24A1, NES, GNAI2, BECN1, SOX2, PPARG, BMPR2, TP53, SIRT1, response to nutrient levels 20 10.93 8.99E-12 2.13E-08 5.20E-10 PTEN, RPTOR, TGFB1, AKT1, VDR, CCND1, CD44, BCL2, MTOR, TNRC6A SGPL1, FGFR3, FLT1, ERBB3, ERBB2, transmembrane receptor MET, BMPR2, FOXO1, RAF1, IGF2, protein tyrosine kinase SOCS5, PTEN, SRC, TGFB1, AKT1, 21 11.48 1.03E-11 2.44E-08 5.82E-10 signaling pathway NTRK3, IGF1R, EIF4EBP1, CTGF, VEGFA, AKT2 ERBB2, VIM, ZEB2, CDH2, SRF, PTEN, NR2E1, ITGB1, TGFB1, SRC, CD9, BDNF, CD44, CTGF, ARHGDIA, SGPL1, EGR2, cell motion 29 15.85 1.53E-11 3.61E-08 8.41E-10 FLT1, MET, IL6R, SMO, HIF1A, CD34, ID1, ETS1, MAPK14, RELN, LAMC1, BMPR1B BMI1, CEBPA, SGPL1, PPARG, TP53, SOX4, CDK6, ITGB1, CBFB, TGFB1, hemopoietic or lymphoid CDC42, BAK1, NOTCH2, ID2, BCL2, 22 12.02 2.07E-11 4.90E-08 1.11E-09 organ development VEGFA, NOTCH4, ZAP70, BCL3, BCL6, IRF4, MED1 E2F1, EID1, CDX2, E2F6, SOX2, PPARG, ZEB2, NFKB1, ZEB1, REST, NR2E1, negative regulation of TGFB1, VDR, EIF4EBP1, EED, BCL3, 31 16.94 5.04E-11 1.20E-07 2.66E-09 biosynthetic process BCL6, TNRC6A, CEBPA, SMAD7, SMAD4, TP53, IGF2, IL6R, SNAI2, SIRT1, SUZ12, ID2, ID1, FABP4, PRDM1 E2F1, EID1, CDX2, E2F6, SOX2, PPARG, ZEB2, NFKB1, ZEB1, REST, NR2E1, negative regulation of TGFB1, VDR, EIF4EBP1, EED, BCL3, macromolecule biosynthetic 30 16.39 8.21E-11 1.95E-07 4.23E-09 BCL6, TNRC6A, CEBPA, SMAD7, process SMAD4, TP53, IL6R, SNAI2, SIRT1, SUZ12, ID2, ID1, FABP4, PRDM1 FGFR3, GNAI2, ERBB3, ERBB2, BMPR2, MKNK2, TGFB1, SRC, AKT1, IGF1R, BCL2, PRKRA, ZAP70, AKT2, FLT1, protein amino acid SMAD7, ROCK2, CREB1, MET, RAF1, 33 18.03 1.00E-10 2.37E-07 5.05E-09 phosphorylation CDK6, PRKCE, CDK4, ATM, NTRK3, CCND1, RPS6KA1, PLK1, MAPK14, RELN, MTOR, BMPR1B, LRRK2 E2F1, EID1, CDX2, E2F6, SOX2, PPARG, ZEB2, NFKB1, ZEB1, REST, NR2E1, negative regulation of cellular TGFB1, VDR, EIF4EBP1, EED, BCL3, 30 16.39 1.50E-10 3.55E-07 7.39E-09 biosynthetic process BCL6, TNRC6A, CEBPA, SMAD7, TP53, SMAD4, IGF2, SNAI2, SIRT1, SUZ12, ID2, ID1, FABP4, PRDM1
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Term Genes Count % P-Value Bonferroni FDR E2F1, EID1, CDX2, E2F6, SOX2, PPARG, ZEB2, NFKB1, ZEB1, REST, NR2E1, negative regulation of TGFB1, VDR, EED, BCL3, BCL6, CEBPA, 27 14.75 2.11E-10 4.99E-07 1.02E-08 transcription SMAD7, TP53, SMAD4, SNAI2, SIRT1, SUZ12, ID2, ID1, FABP4, PRDM1 MCL1, SOX2, ONECUT2, PPARG, TP53, SMAD4, NR2E1, ITGB1, CDC42, cell fate commitment 16 8.74 3.15E-10 7.47E-07 1.49E-08 NOTCH2, SMO, NOTCH1, CASP3, BCL2, NOTCH4, PRDM1 SGPL1, CDX2, FLT1, SMAD7, FOXO1, CDH2, SRF, PTEN, AKT1, BAK1, SMO, blood vessel development 20 10.93 3.98E-10 9.42E-07 1.85E-08 NOTCH1, HIF1A, CD44, ID1, CTGF, MAPK14, VEGFA, NOTCH4, CYR61 E2F1, EID1, CDX2, E2F6, SOX2, PPARG, negative regulation of ZEB2, NFKB1, ZEB1, REST, NR2E1, nucleobase, nucleoside, TGFB1, VDR, EED, BCL3, BCL6, CEBPA, 28 15.30 4.49E-10 1.06E-06 2.05E-08 nucleotide and nucleic acid MSH3, SMAD7, TP53, SMAD4, SNAI2, metabolic process SIRT1, SUZ12, ID2, ID1, FABP4, PRDM1 SGPL1, CREB1, PPARG, TP53, SMAD4, EGLN2, IGF2, SOCS5, HMGA2, TP73, regulation of growth TGFB1, AKT1, NTRK3, CDKN1A, 23 12.57 5.21E-10 1.23E-06 2.33E-08 CDKN2A, CD44, HNF4A, CTGF, BBC3, MAPT, BCL2, BCL6, CYR61 PPARG, TP53, SMAD4, EGLN2, IGF2, TP73, TGFB1, AKT1, NTRK3, CDKN1A, regulation of cell growth 18 9.84 5.35E-10 1.27E-06 2.35E-08 CDKN2A, HNF4A, CD44, CTGF, MAPT, BCL2, BCL6, CYR61 SGPL1, CDX2, FLT1, SMAD7, FOXO1, CDH2, SRF, PTEN, AKT1, BAK1, SMO, vasculature development 20 10.93 6.00E-10 1.42E-06 2.58E-08 NOTCH1, HIF1A, CD44, ID1, CTGF, MAPK14, VEGFA, NOTCH4, CYR61 E2F1, EID1, CDX2, E2F6, SOX2, PPARG, negative regulation of ZEB2, NFKB1, ZEB1, REST, NR2E1, nitrogen compound metabolic TGFB1, VDR, EED, BCL3, BCL6, CEBPA, 28 15.30 6.06E-10 1.44E-06 2.56E-08 process MSH3, SMAD7, TP53, SMAD4, SNAI2, SIRT1, SUZ12, ID2, ID1, FABP4, PRDM1 E2F1, BMI1, E2F2, E2F3, CDX2, E2F5, E2F6, PPARG, FOXO1, NFKB1, ZEB2, FOXO3, REST, ZEB1, NR2E1, CBFB, TGFB1, GLI1, CDKN2A, EED, FOSL1, MYC, NANOG, EGR2, RCOR1, TP53, FOXN2, HMGA2, MXD1, HMGA1, MYCN, SUZ12, HIF1A, HNF4A, VEGFA, regulation of transcription 69 37.70 1.06E-09 2.51E-06 4.40E-08 PRDM1, MED1, EID1, SOX2, ONECUT2, SOX4, LIN28A, SRF, LIN28B, VDR, POU2F2, BCL3, BCL6, CEBPA, KLF13, SMAD7, CREB1, SMAD4, ARID3B, IGF2, SNAI2, DDX5, SIRT1, TP73, NOTCH2, NOTCH1, ID2, ETS1, ID1, MAPK14, NOTCH4, FABP4, ZNF763, IRF4 CEBPA, BECN1, ERBB2, PPARG, TP53, SMAD4, CDK6, ZEB1, PTEN, TGFB1, CD9, negative regulation of cell NOTCH2, VDR, CASP3, BDNF, CDKN1A, 23 12.57 1.52E-09 3.61E-06 6.22E-08 proliferation CDKN2A, HNF4A, ETS1, BCL2, PRKRA, BCL6, FOSL1 CEBPA, SMAD7, CREB1, PPARG, TP53, regulation of gene-specific NFKB1, IGF2, SRF, SIRT1, VDR, NOTCH1, 15 8.20 1.94E-09 4.58E-06 7.77E-08 transcription HIF1A, HNF4A, ETS1, IRF4 BMPR2, MKNK2, ZEB2, NFKB1, TGFB1, AKT1, BAK1, EIF4EBP1, CDKN2A, BCL2, regulation of cellular protein KRT7, BCL3, TNRC6A, SMAD7, SMAD4, 26 14.21 2.13E-09 5.04E-06 8.39E-08 metabolic process IGF2, IL6R, CDK4, PRKCE, TP73, CCND1, HNF4A, CCND3, PLK1, MTOR, LRRK2 FGFR3, GNAI2, ERBB3, ERBB2, BMPR2, HK2, MKNK2, TGFB1, SRC, AKT1, IGF1R, BCL2, PRKRA, ZAP70, AKT2, FLT1, phosphorylation SMAD7, ROCK2, CREB1, MET, RAF1, 34 18.58 2.38E-09 5.64E-06 9.25E-08 CDK6, PRKCE, CDK4, ATM, NTRK3, CCND1, RPS6KA1, PLK1, MAPK14, RELN, MTOR, BMPR1B, LRRK2
９７
Term Genes Count % P-Value Bonferroni FDR EGR2, ERBB3, ERBB2, PPARG, GRIN2A, FOXO1, IGF2, IL6R, MMP3, SRF, MMP13, Gresponse to endogenous PTEN, TGFB1, SRC, AKT1, IGF1R, 24 13.11 2.45E-09 5.80E-06 9.36E-08 stimulus EIF4EBP1, CCND1, CDKN1A, BCL2, FABP4, MTOR, FOSL1, AKT2 FLT1, GNAI2, ERBB2, PPARG, MET, IGF2, ZEB2, CCNG1, PTEN, TP73, TGFB1, regulation of transferase CCNE2, AKT1, CDC42, CASP3, CCND1, 23 12.57 2.66E-09 6.30E-06 1.00E-07 activity CDKN1A, CDKN2A, LRP1, CCND3, FABP4, RELN, MTOR SGPL1, FLT1, MET, ZEB2, IL6R, CDH2, SRF, ITGB1, PTEN, NR2E1, SRC, TGFB1, localization of cell 21 11.48 2.86E-09 6.77E-06 1.06E-07 SMO, HIF1A, CD44, CD34, ID1, CTGF, ETS1, RELN, LAMC1 SGPL1, FLT1, MET, ZEB2, IL6R, CDH2, SRF, ITGB1, PTEN, NR2E1, SRC, TGFB1, cell motility 21 11.48 2.86E-09 6.77E-06 1.06E-07 SMO, HIF1A, CD44, CD34, ID1, CTGF, ETS1, RELN, LAMC1 regulation of specific CEBPA, SMAD7, CREB1, PPARG, TP53, transcription from RNA NFKB1, SIRT1, SRF, VDR, NOTCH1, 13 7.10 2.86E-09 6.78E-06 1.04E-07 polymerase II promoter HNF4A, ETS1, IRF4 SGPL1, FLT1, MET, ZEB2, IL6R, CDH2, SRF, ITGB1, PTEN, NR2E1, SRC, TGFB1, cell migration 20 10.93 2.94E-09 6.97E-06 1.06E-07 SMO, HIF1A, CD44, CD34, ID1, CTGF, RELN, LAMC1 CEBPA, FLT1, SMAD4, BMPR2, ZEB2, SRF, GLI1, MYCN, PPP1CA, NOTCH1, tube development 18 9.84 3.71E-09 8.78E-06 1.31E-07 BDNF, CD44, CTGF, BCL2, VEGFA, NOTCH4, CYR61, MED1 apoptotic mitochondrial AKT1, BAK1, CASP3, CDKN2A, BBC3, 9 4.92 4.09E-09 9.69E-06 1.42E-07 changes BCL2, TP53, MYC, TP73 E2F1, BMI1, E2F2, E2F3, CDX2, E2F5, E2F6, PPARG, FOXO1, NFKB1, ZEB2, FOXO3, REST, ZEB1, NR2E1, CBFB, GLI1, CDKN2A, EED, FOSL1, MYC, NANOG, EGR2, RCOR1, TP53, FOXN2, HMGA2, MXD1, HMGA1, SUZ12, HIF1A, HNF4A, transcription 59 32.24 4.68E-09 1.11E-05 1.61E-07 PRDM1, MED1, EID1, SOX2, ONECUT2, BMPR2, SOX4, SRF, VDR, POU2F2, BCL3, BCL6, CEBPA, KLF13, SMAD7, CREB1, SMAD4, ARID3B, SNAI2, SIRT1, TP73, NOTCH2, NOTCH1, ETS1, NOTCH4, ZNF763, IRF4 E2F1, CEBPA, EID1, CDX2, SMAD7, E2F6, negative regulation of SOX2, PPARG, TP53, SMAD4, NFKB1, transcription, DNA- 22 12.02 6.58E-09 1.56E-05 2.23E-07 ZEB1, REST, SNAI2, SIRT1, NR2E1, dependent SUZ12, VDR, ID2, ID1, BCL6, PRDM1 FLT1, GNAI2, ERBB2, MET, IGF2, ZEB2, CCNG1, PTEN, TP73, TGFB1, CCNE2, regulation of kinase activity AKT1, CDC42, CASP3, CCND1, CDKN1A, 22 12.02 6.92E-09 1.64E-05 2.31E-07 CDKN2A, LRP1, CCND3, FABP4, RELN, MTOR FGFR3, GNAI2, ERBB3, ERBB2, MKNK2, BMPR2, HK2, PTEN, TGFB1, SRC, AKT1, IGF1R, BCL2, PRKRA, ZAP70, AKT2, FLT1, ROCK2, SMAD7, INPPL1, CREB1, phosphate metabolic process 37 20.22 7.16E-09 1.70E-05 2.36E-07 MET, RAF1, CDK6, PRKCE, CDK4, ATM, NTRK3, CCND1, PPP1CA, RPS6KA1, PLK1, MAPK14, RELN, MTOR, BMPR1B, LRRK2 FGFR3, GNAI2, ERBB3, ERBB2, MKNK2, BMPR2, HK2, PTEN, TGFB1, SRC, AKT1, IGF1R, BCL2, PRKRA, ZAP70, AKT2, FLT1, ROCK2, SMAD7, INPPL1, CREB1, phosphorus metabolic process 37 20.22 7.16E-09 1.70E-05 2.36E-07 MET, RAF1, CDK6, PRKCE, CDK4, ATM, NTRK3, CCND1, PPP1CA, RPS6KA1, PLK1, MAPK14, RELN, MTOR, BMPR1B, LRRK2 E2F1, CEBPA, EID1, CDX2, SMAD7, E2F6, negative regulation of RNA SOX2, PPARG, TP53, SMAD4, NFKB1, 22 12.02 8.84E-09 2.09E-05 2.87E-07 metabolic process ZEB1, REST, SNAI2, SIRT1, NR2E1, SUZ12, VDR, ID2, ID1, BCL6, PRDM1
９８
Term Genes Count % P-Value Bonferroni FDR SMAD7, SOX2, PPARG, TP53, SMAD4, regulation of cell IGF2, CDH2, REST, NR2E1, TGFB1, 17 9.29 9.46E-09 2.24E-05 3.03E-07 development NTRK3, SMO, NOTCH1, BDNF, MAPT, BCL2, ARHGDIA E2F1, CEBPA, EID1, CDX2, SMAD7, E2F6, negative regulation of SOX2, PPARG, TP53, NFKB1, ZEB1, transcription from RNA 19 10.38 1.03E-08 2.44E-05 3.25E-07 SNAI2, NR2E1, SUZ12, VDR, ID2, ID1, polymerase II promoter BCL6, PRDM1 EGR2, ERBB3, ERBB2, PPARG, FOXO1, IGF2, IL6R, SRF, MMP13, PTEN, SRC, response to hormone stimulus TGFB1, AKT1, IGF1R, EIF4EBP1, CCND1, 22 12.02 1.12E-08 2.66E-05 3.51E-07 CDKN1A, BCL2, FABP4, MTOR, FOSL1, AKT2 CEBPA, PPARG, TP53, SOX4, ITGB1, leukocyte differentiation CBFB, TGFB1, CDC42, BAK1, BCL2, 14 7.65 1.40E-08 3.32E-05 4.31E-07 ZAP70, BCL3, BCL6, IRF4 SMAD7, MKNK2, SOX4, CDK4, LIN28A, posttranscriptional regulation PTEN, LIN28B, AKT1, EIF4EBP1, 17 9.29 1.43E-08 3.38E-05 4.34E-07 of gene expression CDKN2A, BCL2, KRT7, VEGFA, PRKRA, BCL3, MTOR, TNRC6A CYP24A1, FGFR3, GNAI2, PLEK2, ERBB3, ERBB2, MKNK2, EGLN2, SRC, AKT1, CDC42, IGF1R, VDR, CTGF, ZAP70, BCL3, H2AFX, RHOC, ARHGDIA, ARHGEF3, intracellular signaling cascade FLT1, ROCK2, SMAD7, MET, TP53, RAF1, 42 22.95 1.93E-08 4.58E-05 5.80E-07 IGF2, SOCS5, PRKCE, ATM, TP73, CCND1, RPS6KA1, BBC3, MAPK14, RAB34, NOTCH4, MTOR, STMN1, LRRK2, NKIRAS2, MED1 FLT1, GNAI2, ERBB2, MET, IGF2, ZEB2, CCNG1, PTEN, TP73, TGFB1, CCNE2, regulation of protein kinase AKT1, CASP3, CCND1, CDKN1A, 21 11.48 2.07E-08 4.91E-05 6.14E-07 activity CDKN2A, LRP1, CCND3, FABP4, RELN, MTOR SMAD7, CDK6, CDH2, FOXO3, TGFB1, regulation of homeostatic BAK1, HIF1A, CD44, ETS1, BCL2, 13 7.10 2.65E-08 6.27E-05 7.74E-07 process MAPK14, VEGFA, MYC ARHGEF3, TP53, FOXO3, PRKCE, PTEN, TP73, ATM, TGFB1, BAK1, NOTCH2, induction of apoptosis 20 10.93 3.27E-08 7.76E-05 9.46E-07 VDR, CASP3, CDKN1A, CDKN2A, BBC3, ETS1, PRKRA, BCL3, MYC, TP53INP1 ARHGEF3, TP53, FOXO3, PRKCE, PTEN, induction of programmed cell TP73, ATM, TGFB1, BAK1, NOTCH2, 20 10.93 3.44E-08 8.15E-05 9.82E-07 death VDR, CASP3, CDKN1A, CDKN2A, BBC3, ETS1, PRKRA, BCL3, MYC, TP53INP1 PPP1CA, NOTCH1, FLT1, CD44, BCL2, morphogenesis of a branching VEGFA, NOTCH4, SMAD4, TGFB1, 11 6.01 3.57E-08 8.45E-05 1.01E-06 structure CYR61, MYCN EGR2, ERBB3, CREB1, ERBB2, ONECUT2, ITGB1, NR2E1, TGFB1, CD9, CDC42, cellular component BAK1, SMO, IGF1R, NOTCH1, BDNF, 22 12.02 4.39E-08 1.04E-04 1.22E-06 morphogenesis HIF1A, BCL2, NOTCH4, RELN, BCL6, LAMC1, BMPR1B NES, GRIN2A, TP53, IL6R, SNAI2, ATM, response to radiation TGFB1, AKT1, BAK1, CASP3, CCND1, 16 8.74 4.77E-08 1.13E-04 1.31E-06 CDKN1A, BCL2, BCL3, H2AFX, MYC FLT1, ERBB3, ERBB2, SOX2, SMAD4, positive regulation of signal SOX4, ZEB2, IGF2, IL6R, RPTOR, SRC, 19 10.38 5.09E-08 1.21E-04 1.39E-06 transduction TGFB1, NOTCH2, HIF1A, VEGFA, ZAP70, RHOC, RELN, MTOR FLT1, ERBB3, BECN1, ERBB2, SOX2, positive regulation of cell SMAD4, SOX4, ZEB2, IGF2, IL6R, RPTOR, 20 10.93 5.09E-08 1.21E-04 1.37E-06 communication SRC, TGFB1, NOTCH2, HIF1A, VEGFA, ZAP70, RHOC, RELN, MTOR EGR2, ERBB3, CREB1, ERBB2, SOX2, ONECUT2, SMAD4, CDH1, SRF, PTEN, neuron differentiation NR2E1, TP73, NTRK3, CDC42, SMO, 23 12.57 5.13E-08 1.21E-04 1.36E-06 IGF1R, NOTCH1, BDNF, CD44, BCL2, VEGFA, RELN, BMPR1B
９９
Term Genes Count % P-Value Bonferroni FDR
SMAD7, SMAD4, BMPR2, ZEB2, IGF2, regulation of protein amino IL6R, PRKCE, TP73, TGFB1, BAK1, 15 8.20 5.26E-08 1.25E-04 1.38E-06 acid phosphorylation CCND1, CCND3, HNF4A, BCL2, MTOR AKT1, CDKN1A, CDKN2A, HNF4A, negative regulation of cell BCL2, PPARG, SMAD4, TP53, BCL6, 12 6.56 5.83E-08 1.38E-04 1.52E-06 size MTOR, TP73, TGFB1 E2F1, E2F2, MCL1, ERBB3, NFKB1, FOXO3, PTEN, AKT1, BAK1, CASP3, CDKN2A, BCL2, MYC, BMF, SGPL1, apoptosis 27 14.75 6.02E-08 1.43E-04 1.55E-06 ARHGEF3, TP53, RAF1, BIRC5, IL24, SIRT1, ATM, TP73, BBC3, TNFAIP3, TP53INP1, BLCAP BMI1, EGR2, CDX2, FLT1, SMAD4, BMPR2, ZEB2, ZEB1, ATM, GLI1, pattern specification process 18 9.84 6.60E-08 1.56E-04 1.68E-06 NOTCH2, SMO, NOTCH1, VEGFA, NOTCH4, RELN, BMPR1B, CYR61 E2F1, E2F2, MCL1, ERBB3, NFKB1, FOXO3, PTEN, AKT1, BAK1, CASP3, CDKN2A, BCL2, MYC, BMF, SGPL1, programmed cell death 27 14.75 8.09E-08 1.92E-04 2.04E-06 ARHGEF3, TP53, RAF1, BIRC5, IL24, SIRT1, ATM, TP73, BBC3, TNFAIP3, TP53INP1, BLCAP CDKN1A, CASP3, CDKN2A, HNF4A, negative regulation of cell ETS1, BCL2, TP53, CDK6, BCL6, ATM, 11 6.01 8.63E-08 2.04E-04 2.15E-06 cycle TGFB1 SGPL1, FLT1, SMAD7, CDH2, SRF, PTEN, blood vessel morphogenesis SMO, BAK1, NOTCH1, HIF1A, CTGF, 16 8.74 9.70E-08 2.30E-04 2.39E-06 ID1, MAPK14, NOTCH4, VEGFA, CYR61 E2F1, AKT1, CDKN1A, CCND1, interphase CDKN2A, E2F6, KRT7, BCL2, CDK6, 12 6.56 1.19E-07 2.82E-04 2.90E-06 BIRC5, CDK4, ITGB1 VDR, CYP24A1, CDKN1A, BECN1, cellular response to BMPR2, TP53, SIRT1, FOSL1, TNRC6A, 10 5.46 1.23E-07 2.92E-04 2.98E-06 extracellular stimulus RPTOR NES, ERBB3, CREB1, ERBB2, PPARG, GRIN2A, TP53, CDH1, PTEN, TGFB1, GO:0042493~response to drug 16 8.74 1.32E-07 3.12E-04 3.16E-06 BDNF, CCND1, CDKN1A, BCL2, FABP4, FOSL1 PPP1CA, NOTCH1, FLT1, CD44, BCL2, branching morphogenesis of a VEGFA, NOTCH4, SMAD4, CYR61, 10 5.46 1.42E-07 3.36E-04 3.36E-06 tube MYCN E2F1, E2F2, MCL1, ERBB3, NFKB1, FOXO3, PTEN, TGFB1, AKT1, BAK1, CASP3, CDKN2A, BCL2, BMF, MYC, cell death 29 15.85 1.55E-07 3.66E-04 3.63E-06 SGPL1, ARHGEF3, TP53, RAF1, BIRC5, IGF2, IL24, SIRT1, ATM, TP73, BBC3, TNFAIP3, TP53INP1, BLCAP E2F1, E2F2, MCL1, ERBB3, NFKB1, FOXO3, PTEN, TGFB1, AKT1, BAK1, CASP3, CDKN2A, BCL2, BMF, MYC, death 29 15.85 1.78E-07 4.22E-04 4.14E-06 SGPL1, ARHGEF3, TP53, RAF1, BIRC5, IGF2, IL24, SIRT1, ATM, TP73, BBC3, TNFAIP3, TP53INP1, BLCAP SOX2, PPARG, TP53, CDH2, REST, regulation of nervous system NR2E1, TGFB1, GLI1, NTRK3, SMO, 15 8.20 1.93E-07 4.58E-04 4.45E-06 development NOTCH1, BDNF, MAPT, BCL2, ARHGDIA release of cytochrome c from BAK1, CASP3, BBC3, BCL2, TP53, MYC, 7 3.83 1.99E-07 4.71E-04 4.53E-06 mitochondria TP73 SMAD7, ERBB3, ERBB2, ONECUT2, regulation of cell adhesion CDK6, PTEN, SRC, TGFB1, CDKN2A, 13 7.10 2.06E-07 4.88E-04 4.65E-06 BCL2, BCL6, ARHGDIA, CYR61 E2F1, NANOG, GNAI2, ERBB2, MET, TP53, RAF1, ZEB2, ZEB1, MXD1, PTEN, cell proliferation 22 12.02 2.14E-07 5.06E-04 4.77E-06 SRC, TGFB1, BAK1, LRP1, CCND3, PLK1, BCL2, VEGFA, MPL, MYC, CYR61 E2F1, E2F2, EID1, E2F3, E2F6, CCNG1, ITGB1, TGFB1, CCNE2, AKT1, CDKN2A, cell cycle BCL2, KRT7, H2AFX, MYC, TP53, CDK6, 30 16.39 2.15E-07 5.10E-04 4.77E-06 BIRC5, HMGA2, CDK4, ATM, TP73, NOTCH2, CDKN1A, CCND1, PPP1CA,
１００
Term Genes Count % P-Value Bonferroni FDR CCND3, PLK1, STMN1, TP53INP1 SOX2, PPARG, TP53, CDH2, REST, regulation of neurogenesis NR2E1, TGFB1, NTRK3, SMO, NOTCH1, 14 7.65 2.35E-07 5.57E-04 5.16E-06 BDNF, MAPT, BCL2, ARHGDIA NTRK3, SMO, NOTCH1, BCL2, MAPT, positive regulation of cell SOX2, PPARG, SMAD4, ARHGDIA, 10 5.46 2.40E-07 5.69E-04 5.22E-06 development TGFB1 SMAD7, SMAD4, BMPR2, ZEB2, IGF2, regulation of protein IL6R, PRKCE, TP73, TGFB1, BAK1, 18 9.84 2.76E-07 6.55E-04 5.95E-06 modification process CCND1, CDKN2A, CCND3, HNF4A, PLK1, BCL2, MTOR, LRRK2 NES, SOX2, PPARG, GRIN2A, TP53, IL6R, SNAI2, MMP13, ATM, TGFB1, AKT1, response to abiotic stimulus 20 10.93 2.93E-07 6.94E-04 6.26E-06 BAK1, CASP3, CCND1, CDKN1A, BCL2, BCL3, H2AFX, FOSL1, MYC EGR2, ERBB3, CREB1, ERBB2, ONECUT2, CDH1, SRF, PTEN, NR2E1, TP73, SMO, neuron development 19 10.38 4.07E-07 9.65E-04 8.62E-06 IGF1R, NOTCH1, BDNF, CD44, BCL2, VEGFA, RELN, BMPR1B regulation of cyclin- CCNE2, AKT1, CDKN1A, CCND1, dependent protein kinase CASP3, CDKN2A, CCND3, CCNG1, 9 4.92 4.19E-07 9.91E-04 8.78E-06 activity PTEN MCL1, BECN1, FOXO1, BIRC5, NFKB1, AKT1, IGF1R, NOTCH2, BDNF, BCL2, anti-apoptosis 15 8.20 4.60E-07 1.09E-03 9.57E-06 VEGFA, TNFAIP3, MYC, ARHGDIA, TERT positive regulation of cell IGF1R, FLT1, HIF1A, ETS1, BCL2, VEGFA, 11 6.01 5.32E-07 1.26E-03 1.10E-05 motion ONECUT2, BCL6, IGF2, IL6R, TGFB1 SMAD7, SMAD4, BMPR2, EGLN2, IGF2, positive regulation of protein IL6R, CDK4, TGFB1, AKT1, CCND1, 16 8.74 6.03E-07 1.43E-03 1.23E-05 metabolic process CCND3, PLK1, BCL2, BCL3, MTOR, LRRK2 positive regulation of specific CEBPA, NOTCH1, HNF4A, ETS1, CREB1, transcription from RNA 9 4.92 6.43E-07 1.52E-03 1.30E-05 PPARG, TP53, IRF4, SRF polymerase II promoter SMAD7, SMAD4, SIRT1, TGFB1, SMO, regulation of binding BAK1, CDKN2A, HNF4A, ID2, ID1, BCL2, 13 7.10 6.83E-07 1.62E-03 1.37E-05 BCL3, IRF4 FGFR3, FOXO3, SOCS5, CCNG1, DDX5, growth TGFB1, AKT1, SMO, NOTCH2, NOTCH1, 14 7.65 7.22E-07 1.71E-03 1.44E-05 BCL2, SERPINE1, MTOR, BMPR1B PPP1CA, NOTCH1, FLT1, CD44, BCL2, tube morphogenesis VEGFA, NOTCH4, SMAD4, ZEB2, SRF, 12 6.56 7.53E-07 1.78E-03 1.49E-05 CYR61, MYCN EGR2, ERBB3, CREB1, ERBB2, ONECUT2, NR2E1, TGFB1, CDC42, SMO, IGF1R, cell morphogenesis 19 10.38 8.31E-07 1.97E-03 1.63E-05 NOTCH1, BDNF, HIF1A, BCL2, NOTCH4, RELN, BCL6, LAMC1, BMPR1B E2F1, AKT1, CDKN1A, CCND1, interphase of mitotic cell CDKN2A, E2F6, BCL2, CDK6, BIRC5, 11 6.01 8.48E-07 2.01E-03 1.65E-05 cycle CDK4, ITGB1 FLT1, MSH3, GNAI2, ERBB2, MET, TP53, positive regulation of catalytic IGF2, ZEB2, TGFB1, AKT1, CDC42, BAK1, 23 12.57 9.79E-07 2.32E-03 1.88E-05 activity VDR, CCND1, CDKN2A, LRP1, HIF1A, CCND3, PLK1, BBC3, BCL2, RELN, MYC E2F1, E2F6, TP53, CDK6, BIRC5, CDK4, HMGA2, CCNG1, ITGB1, TP73, ATM, cell cycle process TGFB1, AKT1, NOTCH2, CCND1, 24 13.11 1.06E-06 2.50E-03 2.02E-05 CDKN1A, CDKN2A, PLK1, BCL2, KRT7, H2AFX, STMN1, MYC, TP53INP1 CEBPA, E2F2, E2F3, CDX2, KLF13, CREB1, transcription, DNA- TP53, BMPR2, NFKB1, CBFB, CDKN2A, 17 9.29 1.23E-06 2.91E-03 2.33E-05 dependent HIF1A, ETS1, POU2F2, FOSL1, MYC, MED1 MCL1, ERBB2, PPARG, EGLN2, FOXO3, SRF, TGFB1, AKT1, VDR, BAK1, CD9, GO:0042592~homeostatic CASP3, BCL2, SERPINE1, BCL6, MYC, 28 15.30 1.26E-06 2.99E-03 2.38E-05 process TERT, LPL, EGR2, SMAD7, GRIN2A, TP53, IGF2, HIF1A, ID2, HNF4A, VEGFA, FABP4 FLT1, SMAD7, ONECUT2, IGF2, IL6R, regulation of cell motion 14 7.65 1.32E-06 3.12E-03 2.46E-05 PTEN, TGFB1, AKT1, IGF1R, HIF1A, １０１
Term Genes Count % P-Value Bonferroni FDR ETS1, BCL2, VEGFA, BCL6 EGR2, ERBB3, CREB1, ERBB2, ONECUT2, CDH1, PTEN, NR2E1, AKT1, CDC42, cell projection organization 19 10.38 1.34E-06 3.17E-03 2.48E-05 SMO, IGF1R, NOTCH1, BDNF, CD44, BCL2, RELN, MTOR, BMPR1B ERBB3, ERBB2, GRIN2A, IGF2, NFKB1, IL6R, SRF, TP73, TGFB1, AKT1, CD9, response to wounding NOTCH2, SMO, CASP3, NOTCH1, 23 12.57 1.34E-06 3.18E-03 2.47E-05 HIF1A, HNF4A, CD44, CTGF, BCL2, SERPINE1, BMPR1B, AP3B1 cellular response to nutrient VDR, CYP24A1, BECN1, BMPR2, TP53, 8 4.37 1.38E-06 3.25E-03 2.51E-05 levels SIRT1, TNRC6A, RPTOR IGF1R, ERBB3, BCL2, ERBB2, CREB1, gland development MET, SOX2, NOTCH4, HK2, CDH1, 12 6.56 1.38E-06 3.28E-03 2.50E-05 TGFB1, GLI1 CEBPA, E2F2, E2F3, CDX2, KLF13, CREB1, TP53, BMPR2, NFKB1, CBFB, CDKN2A, RNA biosynthetic process 17 9.29 1.47E-06 3.48E-03 2.64E-05 HIF1A, ETS1, POU2F2, FOSL1, MYC, MED1 GNAI2, SMAD7, PPARG, TP53, IGF2, negative regulation of BIRC5, NFKB1, SIRT1, TP73, AKT1, SMO, 18 9.84 1.56E-06 3.69E-03 2.78E-05 molecular function CDKN1A, CASP3, CDKN2A, ID2, HNF4A, ID1, FABP4 CDKN2A, LRP1, BCL2, NOTCH4, aging SERPINE1, TP53, SRF, SIRT1, PTEN, 11 6.01 1.56E-06 3.69E-03 2.76E-05 TERT, TGFB1 CDKN1A, CDKN2A, HNF4A, BBC3, negative regulation of growth BCL2, PPARG, SMAD4, TP53, BCL6, TP73, 11 6.01 1.56E-06 3.69E-03 2.76E-05 TGFB1 AKT1, SMO, HNF4A, BCL2, SMAD4, regulation of protein BCL3, CDH1, IGF2, CDH2, SIRT1, 12 6.56 1.72E-06 4.07E-03 3.02E-05 localization ARHGDIA, TGFB1 positive regulation of gene- CEBPA, NOTCH1, HIF1A, HNF4A, ETS1, 10 5.46 1.78E-06 4.21E-03 3.10E-05 specific transcription CREB1, PPARG, TP53, IRF4, SRF TP53, SOX4, IGF2, ITGB1, CBFB, TGFB1, lymphocyte activation BAK1, CCND3, BCL2, ULBP2, ZAP70, 14 7.65 1.86E-06 4.40E-03 3.22E-05 BCL3, BCL6, IRF4 FLT1, MSH3, GNAI2, ERBB2, MET, TP53, IGF2, ZEB2, TGFB1, AKT1, CDC42, BAK1, positive regulation of VDR, CCND1, CDKN2A, LRP1, HIF1A, 24 13.11 1.97E-06 4.65E-03 3.38E-05 molecular function CCND3, PLK1, BBC3, BCL2, RELN, IRF4, MYC MUC1, VDR, CYP24A1, CCND1, GNAI2, response to nutrient CD44, BCL2, SOX2, PPARG, MTOR, 12 6.56 1.98E-06 4.69E-03 3.38E-05 PTEN, TGFB1 SMAD7, SMAD4, BMPR2, IGF2, IL6R, positive regulation of cellular CDK4, TGFB1, AKT1, CCND1, CCND3, 15 8.20 2.00E-06 4.72E-03 3.38E-05 protein metabolic process PLK1, BCL2, BCL3, MTOR, LRRK2 MUC1, VDR, CYP24A1, CCND1, CD44, response to vitamin 9 4.92 2.03E-06 4.79E-03 3.40E-05 BCL2, SOX2, PPARG, TGFB1 NOTCH2, SMO, CDKN1A, CCND1, regeneration NOTCH1, BCL2, PPARG, SERPINE1, 9 4.92 2.85E-06 6.74E-03 4.76E-05 TGFB1 CDKN1A, CDKN2A, HNF4A, BCL2, GO:0030308~negative PPARG, SMAD4, TP53, BCL6, TP73, 10 5.46 2.86E-06 6.74E-03 4.73E-05 regulation of cell growth TGFB1 EGR2, ERBB3, CREB1, ERBB2, NR2E1, cell morphogenesis involved TGFB1, IGF1R, NOTCH1, BDNF, HIF1A, 15 8.20 3.42E-06 8.06E-03 5.62E-05 in differentiation BCL2, NOTCH4, RELN, LAMC1, BMPR1B regulation of T cell CDKN2A, ERBB2, ZAP70, BCL6, IRF4, 8 4.37 3.85E-06 9.09E-03 6.29E-05 differentiation SOCS5, ZEB1, AP3B1 SGPL1, CYP24A1, FGFR3, IGF2, ZEB1, MMP13, CBFB, TGFB1, GLI1, VDR, SMO, skeletal system development 17 9.29 3.88E-06 9.14E-03 6.29E-05 CTGF, MAPK14, BCL2, PRKRA, BMPR1B, MYC GNAI2, SMAD7, ERBB3, ONECUT2, negative regulation of cell SOX2, SOCS5, PTEN, SIRT1, AKT1, 15 8.20 4.15E-06 9.78E-03 6.68E-05 communication CCND1, LRP1, HNF4A, BCL6, MTOR, TNFAIP3 SMAD7, ERBB3, ERBB2, SOX4, SRF, heart development 14 7.65 4.39E-06 1.03E-02 7.03E-05 PTEN, ITGB1, ATM, SMO, NOTCH1,
１０２
Term Genes Count % P-Value Bonferroni FDR CASP3, ID2, ID1, MED1 CDC42, CCND1, CDKN2A, HNF4A, regulation of mitotic cell cycle BCL2, TP53, BIRC5, BCL6, IGF2, MYC, 12 6.56 4.43E-06 1.04E-02 7.04E-05 ATM, TGFB1 AKT1, IGF1R, EIF4EBP1, EGR2, ERBB3, response to peptide hormone BCL2, PPARG, FOXO1, IGF2, IL6R, 12 6.56 5.03E-06 1.18E-02 7.94E-05 stimulus MTOR, AKT2 induction of apoptosis by CDKN1A, CASP3, BBC3, TP53, BCL3, 8 4.37 5.70E-06 1.34E-02 8.95E-05 intracellular signals MYC, ATM, TP73 AKT1, IGF1R, EIF4EBP1, EGR2, ERBB3, response to insulin stimulus 10 5.46 5.72E-06 1.35E-02 8.92E-05 PPARG, FOXO1, IGF2, MTOR, AKT2 EGR2, ERBB3, CREB1, ERBB2, CDH1, neuron projection PTEN, NR2E1, IGF1R, SMO, NOTCH1, 15 8.20 5.99E-06 1.41E-02 9.27E-05 development BDNF, CD44, BCL2, RELN, BMPR1B FGFR3, FLT1, GNAI2, ERBB3, ERBB2, MET, MKNK2, IGF2, SRC, AKT1, IGF1R, protein kinase cascade 18 9.84 6.18E-06 1.45E-02 9.51E-05 RPS6KA1, MAPK14, NOTCH4, ZAP70, BCL3, LRRK2, NKIRAS2 ERBB3, ERBB2, IGF2, SRF, TGFB1, wound healing NOTCH2, CD9, NOTCH1, HIF1A, 13 7.10 6.99E-06 1.64E-02 1.07E-04 HNF4A, CD44, SERPINE1, AP3B1 BAK1, BCL2, ZAP70, TP53, SOX4, BCL3, lymphocyte differentiation 10 5.46 7.31E-06 1.72E-02 1.11E-04 BCL6, ITGB1, CBFB, TGFB1 G1/S transition of mitotic cell AKT1, CDKN1A, CCND1, CDKN2A, 8 4.37 7.31E-06 1.72E-02 1.10E-04 cycle E2F6, BCL2, CDK4, ITGB1 ERBB3, ERBB2, SOX2, ZEB1, NR2E1, sensory organ development TGFB1, BAK1, BDNF, BCL2, VEGFA, 14 7.65 8.71E-06 2.04E-02 1.31E-04 PRKRA, BMPR1B, MYC, MED1 regulation of SMO, CDKN2A, HNF4A, SMAD4, BCL3, 8 4.37 9.27E-06 2.17E-02 1.38E-04 nucleocytoplasmic transport CDH1, SIRT1, TGFB1 CEBPA, E2F2, E2F3, CDX2, KLF13, transcription from RNA BMPR2, NFKB1, CBFB, HIF1A, ETS1, 14 7.65 1.10E-05 2.57E-02 1.63E-04 polymerase II promoter POU2F2, FOSL1, MYC, MED1 BAK1, CCND1, NES, BCL2, TP53, H2AFX, response to ionizing radiation 8 4.37 1.17E-05 2.72E-02 1.71E-04 IL6R, ATM CEBPA, AKT1, VDR, HIF1A, CDX2, placenta development 8 4.37 1.17E-05 2.72E-02 1.71E-04 PPARG, PRDM1, MED1 AKT1, IGF1R, FLT1, HIF1A, SMAD7, regulation of cell migration BCL2, VEGFA, ONECUT2, IGF2, IL6R, 12 6.56 1.22E-05 2.85E-02 1.79E-04 PTEN, TGFB1 NOTCH2, FGFR3, BCL2, MTOR, SOCS5, cell growth 8 4.37 1.30E-05 3.04E-02 1.89E-04 CCNG1, DDX5, TGFB1 TP53, SOX4, IGF2, ITGB1, CBFB, TGFB1, leukocyte activation BAK1, CCND3, BCL2, ULBP2, ZAP70, 14 7.65 1.57E-05 3.66E-02 2.27E-04 BCL3, BCL6, IRF4 IGF1R, ERBB3, ERBB2, CREB1, MET, mammary gland development 8 4.37 1.62E-05 3.76E-02 2.32E-04 NOTCH4, HK2, TGFB1 regulation of lymphocyte CDKN2A, ERBB2, ZAP70, BCL6, IRF4, 8 4.37 1.62E-05 3.76E-02 2.32E-04 differentiation SOCS5, ZEB1, AP3B1 positive regulation of cell IGF1R, FLT1, HIF1A, BCL2, VEGFA, 9 4.92 1.93E-05 4.48E-02 2.76E-04 migration ONECUT2, IGF2, IL6R, TGFB1 positive regulation of protein CCND1, CCND3, BCL2, SMAD4, BMPR2, 9 4.92 1.93E-05 4.48E-02 2.76E-04 amino acid phosphorylation IGF2, IL6R, MTOR, TGFB1 regulation of protein import SMO, HNF4A, SMAD4, BCL3, CDH1, 7 3.83 2.02E-05 4.67E-02 2.86E-04 into nucleus SIRT1, TGFB1 CASP3, CDKN2A, ERBB2, ZAP70, BCL6, regulation of T cell activation 10 5.46 2.06E-05 4.76E-02 2.90E-04 IRF4, SOCS5, ZEB1, TGFB1, AP3B1 ERBB3, ERBB2, ZEB2, IGF2, IL6R, PTEN, regulation of protein kinase TP73, TGFB1, AKT1, HNF4A, RHOC, 14 7.65 2.13E-05 4.93E-02 2.99E-04 cascade MTOR, TNFAIP3, AKT2 TP53, SOX4, IGF2, ITGB1, CBFB, TGFB1, cell activation CD9, BAK1, CCND3, BCL2, ULBP2, 15 8.20 2.18E-05 5.03E-02 3.04E-04 ZAP70, BCL3, BCL6, IRF4 regulation of cell-matrix CDKN2A, BCL2, ONECUT2, CDK6, BCL6, 6 3.28 2.19E-05 5.06E-02 3.04E-04 adhesion PTEN CDKN1A, CASP3, CDKN2A, ERBB2, regulation of lymphocyte ZAP70, BCL6, IRF4, SOCS5, ZEB1, TGFB1, 11 6.01 2.22E-05 5.12E-02 3.06E-04 activation AP3B1 NOTCH1, FLT1, HIF1A, ID1, CTGF, GO:0001525~angiogenesis MAPK14, VEGFA, NOTCH4, SRF, PTEN, 11 6.01 2.22E-05 5.12E-02 3.06E-04 CYR61
１０３
Term Genes Count % P-Value Bonferroni FDR CCNE2, CCND1, CDKN2A, MAPK14, cell cycle checkpoint 9 4.92 2.28E-05 5.25E-02 3.12E-04 TP53, BIRC5, H2AFX, ATM, TGFB1 regulation of cell-substrate CDKN2A, BCL2, ONECUT2, CDK6, BCL6, 7 3.83 2.62E-05 6.02E-02 3.57E-04 adhesion PTEN, CYR61 positive regulation of lipid AKT1, CDC42, HNF4A, PPARG, IGF2, 7 3.83 2.62E-05 6.02E-02 3.57E-04 metabolic process TGFB1, AKT2 E2F1, E2F6, CDK6, BIRC5, CDK4, CCNG1, HMGA2, ITGB1, ATM, AKT1, CCND1, cell cycle phase 18 9.84 2.65E-05 6.09E-02 3.59E-04 CDKN1A, CDKN2A, PLK1, BCL2, KRT7, H2AFX, STMN1 CEBPA, CDC42, ID2, VEGFA, PPARG, myeloid cell differentiation 9 4.92 2.67E-05 6.13E-02 3.59E-04 BCL6, IRF4, CBFB, TGFB1 cellular response to insulin AKT1, IGF1R, EIF4EBP1, ERBB3, PPARG, 8 4.37 2.68E-05 6.16E-02 3.59E-04 stimulus FOXO1, IGF2, AKT2 SMO, CDKN2A, HNF4A, ID2, ID1, regulation of DNA binding 10 5.46 2.70E-05 6.19E-02 3.59E-04 SMAD7, BCL3, IRF4, SIRT1, TGFB1 E2F1, NOTCH1, CREB1, SOX2, CDH1, forebrain development 11 6.01 2.80E-05 6.41E-02 3.70E-04 ZEB2, RELN, NR2E1, SRC, TP73, GLI1 EGR2, ERBB3, ERBB2, CREB1, ONECUT2, cell part morphogenesis NR2E1, BAK1, IGF1R, SMO, NOTCH1, 14 7.65 2.85E-05 6.52E-02 3.75E-04 BDNF, BCL2, RELN, BMPR1B SMAD7, ERBB3, ONECUT2, SOX2, negative regulation of signal SOCS5, PTEN, SIRT1, AKT1, CCND1, 13 7.10 3.03E-05 6.92E-02 3.96E-04 transduction LRP1, HNF4A, BCL6, TNFAIP3 CCND1, CCND3, PLK1, SMAD7, BCL2, positive regulation of protein SMAD4, BMPR2, IGF2, IL6R, MTOR, 12 6.56 3.14E-05 7.16E-02 4.08E-04 modification process LRRK2, TGFB1 AKT1, HIF1A, BECN1, SMAD7, GRIN2A, regulation of catabolic process 9 4.92 3.36E-05 7.66E-02 4.35E-04 EGLN2, IGF2, MTOR, AKT2 LPL, EGR2, SMAD7, ERBB2, PPARG, GRIN2A, TP53, IGF2, FOXO3, TGFB1, chemical homeostasis 20 10.93 3.55E-05 8.07E-02 4.57E-04 CD9, BAK1, VDR, HIF1A, HNF4A, BCL2, VEGFA, SERPINE1, FABP4, MYC regulation of intracellular SMO, CDKN2A, HNF4A, SMAD4, BCL3, 8 4.37 3.56E-05 8.09E-02 4.56E-04 transport CDH1, SIRT1, TGFB1 positive regulation of CCND1, CCND3, BCL2, SMAD4, BMPR2, 9 4.92 3.63E-05 8.23E-02 4.62E-04 phosphorylation IGF2, IL6R, MTOR, TGFB1 positive regulation of AKT1, HIF1A, BECN1, SMAD7, EGLN2, 7 3.83 3.79E-05 8.59E-02 4.80E-04 catabolic process IGF2, AKT2 positive regulation of IGF1R, FLT1, HIF1A, BCL2, VEGFA, 9 4.92 3.91E-05 8.84E-02 4.92E-04 locomotion ONECUT2, IGF2, IL6R, TGFB1 CDKN1A, CCND1, BCL2, ERBB2, PPARG, response to steroid hormone FABP4, IL6R, MMP13, FOSL1, PTEN, SRC, 12 6.56 4.01E-05 9.07E-02 5.03E-04 stimulus TGFB1 AKT1, IGF1R, FLT1, HIF1A, SMAD7, regulation of locomotion BCL2, VEGFA, ONECUT2, IGF2, IL6R, 12 6.56 4.01E-05 9.07E-02 5.03E-04 PTEN, TGFB1 NTRK3, BECN1, VEGFA, PPARG, regulation of response to SERPINE1, FABP4, BCL6, IGF2, IL6R, 11 6.01 4.11E-05 9.29E-02 5.13E-04 external stimulus MTOR, TGFB1 EGR2, ERBB3, BCL2, ERBB2, VEGFA, rhythmic process 10 5.46 4.21E-05 9.49E-02 5.22E-04 GRIN2A, FOXO3, CDK4, BMPR1B, SIRT1 MSH3, BECN1, UNG, BMPR2, TP53, FOXO3, SIRT1, TP73, ATM, SMO, CASP3, cellular response to stress CCND1, CDKN1A, HIF1A, BBC3, 21 11.48 4.37E-05 9.84E-02 5.39E-04 MAPK14, BCL2, BCL3, BCL6, H2AFX, TNRC6A
１０４
Appendix Ⅳ. Functional annotation clusters of significant DEGs with CNVs from miRNA expression data
Term Genes Count % P-Value Bonferroni FDR
SEC31A, CHMP5, C16ORF70, LHCGR, APP, GBF1, ABRA, STAM, TLK1, KIF13B, RAB27A, KIF5B, VPS45, MYH4, OPTN, AP4M1, MYH9, VTI1A, MAPK1, KRT18, ATP2C1, JUN, TXNDC5, TBRG1, F2, TRAPPC4, MRPL45, TRAPPC3, KIF4B, RIMS2, RIMS1, STX12, KIAA1012, TRAM1, SEC23IP, HAP1, RANBP17, OSBPL5, RGPD2, RGPD1, RGPD4, RGPD3, NXF2, TINAGL1, HNRNPA1, CBLB, ATP2A2, MLX, PCNA, SYTL4, BET1L, HGS, NUTF2, GOSR2, SMURF1, RERE, ARSB, SPG7, HTATIP2, PDIA3, FGF9, MYO7A, WASF2, BNIP3, AP3S1, AP1S3, AP1S2, LONP2, GOLGA5, FGF2, DNAJC19, AP3B1, KDELR2, STX1A, ARHGEF2, STX2, MYRIP, PSEN1, NUP205, TOMM20, MGEA5, SORT1, GNAS, BID, YWHAZ, BET1, MUDENG, SET, BCL2, EXOC4, PPP3CB, CHM, RAB11A, BCL6, PEX13, CD24, RAB2A, FYB, ACTC1, UPF1, IPO11, YWHAB, NLGN1, EXPH5, PPP1R10, STRADB, COG3, COG4, COG5, intracellular ERBB2IP, GSK3B, YWHAQ, AP4B1, COG1, DNM2, 214 4.45 1.08E-07 5.64E-04 5.64E-04 transport SSR3, NCBP2, XPO1, GRPEL2, SRP14, NCBP1, GRPEL1, AP4E1, AP1G1, EIF5A, CNO, CSPG5, SRP19, AGXT, KLHL2, TGFB1, PUM1, SLC25A27, SCAMP1, NUP133, ARNTL, TNNT2, COPG2, ARRB1, LYST, VAMP7, USO1, SLC25A37, AKAP6, ERC1, VPS26A, LRPPRC, BAT1, DRD1, ARFGAP3, NAPG, STAM2, ABCA1, NAPB, LMAN1, NPM1, DOPEY1, AP2M1, RHOBTB3, SEC61A2, RAB8A, SMG1, ICMT, PPIF, SLC25A12, TRNT1, UCP3, TSC1, AKTIP, VCP, TOMM70A, NEDD4, RHOT1, SEC13, XPO7, HDAC6, MYH10, COPA, CLTA, ATL2, PEX5, PEX7, NDE1, SLC1A3, ZFYVE16, GOPC, RANBP2, KPNB1, CLINT1, SEC23A, ARL1, SYNRG, HSP90AA1, PRKCI, TIMM23, M6PR, KIF1C, ATG4D, KIF1B, IPO7, ATG4A, IPO4, COPG, STON1, MUTED, TPM1, AP3M2, CEP57, TAP2, BCAP29, PAFAH1B1, EHD1, NEFL, SRP14P1, NXF2B, SFRS13A, MON2, SFRS13B, JAK2 OXA1L, SEC31B, SEC31A, CHMP5, SLC9A2, LHCGR, C16ORF70, GRIN3B, RAB1A, CTNNB1, FAM125A, APOB, VPS13D, KIFAP3, AAGAB, ABRA, STAM, TLK1, NUP35, RAB27A, KIF13B, PTPRK, CD3G, VPS45, GRIN2A, OPTN, AP4M1, MYH9, VTI1A, MAPK1, KRT18, CD36, LCA5, RAB19, JUN, BACE2, F2, RAB12, MRPL45, RAB10, RTP1, RAB40C, CCDC91, ARF6, ARF5, RIMS2, RIMS1, RAB40B, STX12, DMD, TNKS, TRAM1, SEC23IP, RANBP17, RGPD4, RGPD3, RAB7L1, DVL1, CBLB, ARF4, PCNA, SYTL4, BET1L, HGS, GOSR2, NUTF2, SMURF1, RERE, MSR1, PDIA3, FGF9, AP1AR, PPARG, AP3S1, AP1S3, BLZF1, AP1S2, LONP2, DNAJC14, RAB6A, COX18, AGAP1, FGF2, DNAJC19, DHCR24, AP3B1, KDELR2, STX1A, ARHGEF2, STX2, RAB4A, SENP2, ZDHHC15, protein localization 274 5.70 1.95E-07 1.01E-03 5.08E-04 ZDHHC17, MYRIP, RAB11FIP2, PSEN1, LAX1, NUP205, MGEA5, RAB5A, TOMM20, SORT1, GNAS, EIF5A2, SERP1, BID, RAB3A, SHROOM2, YWHAZ, BET1, MUDENG, UEVLD, MORC3, EXOC4, PPP3CB, CHM, RAB11A, APBA2, BCL6, PEX13, CD24, PCSK5, RAB2A, FYB, IPO11, YWHAB, NLGN1, EXPH5, PPP1R10, STRADB, COG3, COG4, COG5, TEX15, RAB30, COG6, RAB37, GRIA2, ERBB2IP, GSK3B, MCFD2, RAB34, YWHAQ, RAB39, AP4B1, COG1, SSR3, XPO1, SRP14, GRPEL2, GRPEL1, AP4E1, AP1G1, XPO4, EIF5A, SRP19, AGXT, TGFB1, KLHL2, CXCL10, ANK3, RABGEF1, EGFR, SCAMP1, NUP133, ACTN4, SGOL2, LRP1B, ARNTL, TNS4, COPG2, VAMP7, LYST, FGFR1OP, USO1, AKAP6, AKAP7, COL1A1, PDCD6IP, ERC1, VPS26A, CAV1, ARFGAP3, DRD1, AFTPH, １０５
Term Genes Count % P-Value Bonferroni FDR
NAPG, DRD2, STAM2, SNX7, SNX4, NAPB, ABCA1, SNX3, LMAN1, CHMP2B, KATNA1, NPM1, DOPEY1, SRGN, SEC61A2, AP2M1, PRAF2, RAB8A, MYO1C, LIN7C, ITGA2, ICMT, ATG3, RAB33A, RAB33B, TRNT1, PLEKHA8, VCP, AKTIP, NEDD4, TOMM70A, SEC13, YIPF5, ATG16L1, XPO7, ATG16L2, HDAC6, COPA, CLTA, TLN1, PAX6, PEX5, OS9, PEX7, CDC42, ZFYVE16, GOPC, NECAP1, RANBP2, KPNB1, NSF, SEC23A, SYNRG, PRKCI, STXBP2, STXBP3, TOPORS, TIMM23, BBS2, ATG4D, IPO7, IPO4, ATG4A, COPG, SNX13, SNX10, LCP2, SNX18, STON1, SNX16, RDX, EFCAB4B, CEP57, AP3M2, SH3GLB1, TAP2, BCAP29, SNX24, SNX20, SCG2, NUP153, SRP14P1, SNX25, CENPF, CENPE, CBY1, MON2, ARL17A, VPS24, JAK2 JUB, CTHRC1, PDGFB, RPS6KB1, ENPEP, NR2E1, CXCL12, TGFB1, NRCAM, CD44, GAB2, SYK, TWIST1, PTPRK, SATB2, RET, ROCK1, MDGA1, EMX2, SCYL3, SIX4, MYH9, CTNNA2, ASCL1, HIF1A, CD34, LYST, PDGFRB, OPHN1, RELN, CAV2, CDK5R1, DRD1, CCL2, DRD2, ITGB1, SCRIB, ITGAM, ARX, OVOL2, KATNA1, RAC1, SBDSP1, NKX2-3, FN1, VAV3, TGFBR1, MET, ITGA1, NR4A2, ITGA4, ITGA6, cell migration 103 2.14 4.07E-07 2.12E-03 7.06E-04 LAMA5, PTENP1, MYH10, NRP2, CCKAR, NRP1, WASF2, PAX6, PEX5, ZEB2, PEX7, EDNRB, NDE1, CXCR4, SEMA3C, CAP1, FGF2, ICAM1, CCDC88A, ARHGEF7, ARID5B, NCK2, PSEN1, IL12A, VCAN, ACVR1, CER1, DCC, SHROOM2, FUT8, ABI2, KITLG, PRKDC, CDH2, PEX13, POU3F2, PAFAH1B1, CD24, SCG2, THBS4, APC, SELP, IL6, FLT1, ISL1, COL5A1, LRP6, NEUROD4, APBB2, SELE, LRP5 GRPEL2, SRP14, XPO1, OXA1L, GRPEL1, AP4E1, AP1G1, C16ORF70, LHCGR, EIF5A, GRIN3B, SRP19, AGXT, KLHL2, TGFB1, CTNNB1, ABRA, TLK1, STAM, KIF13B, RAB27A, EGFR, PTPRK, VPS45, OPTN, ARNTL, AP4M1, VTI1A, MAPK1, COPG2, KRT18, JUN, F2, USO1, AKAP6, MRPL45, DRD1, ARFGAP3, NAPG, STAM2, RTP1, NAPB, RIMS2, RIMS1, STX12, NPM1, TNKS, SEC23IP, TRAM1, SRGN, AP2M1, SEC61A2, RANBP17, ICMT, DVL1, TRNT1, CBLB, VCP, TOMM70A, NEDD4, SYTL4, PCNA, HGS, SEC13, cellular NUTF2, GOSR2, SMURF1, XPO7, RERE, HDAC6, macromolecule COPA, CLTA, PDIA3, FGF9, PAX6, AP3S1, PEX5, PEX7, 142 2.95 7.94E-07 4.12E-03 1.03E-03 localization AP1S3, CDC42, AP1S2, LONP2, ZFYVE16, RANBP2, COX18, KPNB1, FGF2, DNAJC19, AP3B1, SEC23A, KDELR2, STX1A, ARHGEF2, SYNRG, STX2, PRKCI, TOPORS, TIMM23, BBS2, MYRIP, ATG4D, IPO7, ATG4A, NUP205, IPO4, MGEA5, TOMM20, SORT1, COPG, BID, YWHAZ, STON1, STAU1, MUDENG, AP3M2, CEP57, SH3GLB1, MORC3, TAP2, BCAP29, PPP3CB, EXOC4, CHM, RAB11A, BCL6, PEX13, CD24, FYB, SRP14P1, IPO11, NLGN1, YWHAB, EXPH5, PPP1R10, STRADB, COG3, TEX15, ERBB2IP, GSK3B, YWHAQ, JAK2, AP4B1, SSR3 SEC31B, SEC31A, CHMP5, C16ORF70, LHCGR, RAB1A, FAM125A, APOB, AAGAB, ABRA, STAM, TLK1, NUP35, RAB27A, KIF13B, CD3G, VPS45, OPTN, AP4M1, MYH9, VTI1A, MAPK1, KRT18, CD36, LCA5, RAB19, JUN, BACE2, F2, RAB12, MRPL45, RAB10, RAB40C, CCDC91, ARF6, ARF5, RIMS2, RIMS1, RAB40B, STX12, TNKS, TRAM1, SEC23IP, RANBP17, RGPD4, RGPD3, RAB7L1, CBLB, ARF4, PCNA, SYTL4, BET1L, HGS, GOSR2, NUTF2, SMURF1, RERE, MSR1, establishment of PDIA3, FGF9, AP1AR, PPARG, AP3S1, AP1S3, BLZF1, 240 4.99 8.22E-07 4.27E-03 8.55E-04 protein localization AP1S2, LONP2, DNAJC14, RAB6A, AGAP1, FGF2, DNAJC19, AP3B1, KDELR2, STX1A, ARHGEF2, STX2, RAB4A, SENP2, ZDHHC15, ZDHHC17, MYRIP, RAB11FIP2, PSEN1, LAX1, NUP205, MGEA5, RAB5A, TOMM20, SORT1, GNAS, EIF5A2, SERP1, BID, RAB3A, YWHAZ, BET1, MUDENG, UEVLD, EXOC4, PPP3CB, CHM, RAB11A, APBA2, BCL6, PEX13, CD24, PCSK5, RAB2A, FYB, IPO11, YWHAB, NLGN1, EXPH5, PPP1R10, STRADB, COG3, COG4, COG5, RAB30, COG6, RAB37, ERBB2IP, GRIA2, GSK3B, MCFD2, １０６
Term Genes Count % P-Value Bonferroni FDR
RAB34, YWHAQ, RAB39, AP4B1, COG1, SSR3, XPO1, SRP14, GRPEL2, GRPEL1, AP4E1, AP1G1, XPO4, EIF5A, SRP19, AGXT, KLHL2, TGFB1, CXCL10, ANK3, RABGEF1, SCAMP1, NUP133, ACTN4, LRP1B, ARNTL, COPG2, LYST, VAMP7, USO1, AKAP6, COL1A1, PDCD6IP, ERC1, VPS26A, ARFGAP3, DRD1, AFTPH, NAPG, STAM2, SNX7, SNX4, ABCA1, NAPB, SNX3, LMAN1, CHMP2B, NPM1, DOPEY1, SEC61A2, AP2M1, RAB8A, PRAF2, MYO1C, ITGA2, LIN7C, ICMT, ATG3, RAB33A, RAB33B, TRNT1, PLEKHA8, AKTIP, VCP, NEDD4, TOMM70A, SEC13, YIPF5, ATG16L1, XPO7, ATG16L2, HDAC6, COPA, CLTA, PEX5, PEX7, ZFYVE16, GOPC, NECAP1, RANBP2, KPNB1, NSF, SEC23A, SYNRG, PRKCI, STXBP2, STXBP3, TIMM23, ATG4D, IPO7, ATG4A, IPO4, COPG, SNX13, SNX10, LCP2, SNX18, STON1, SNX16, EFCAB4B, CEP57, AP3M2, TAP2, BCAP29, SNX24, SCG2, SNX20, NUP153, SRP14P1, SNX25, CENPF, CENPE, MON2, ARL17A, VPS24, JAK2 GRPEL2, SRP14, XPO1, OXA1L, GRPEL1, AP4E1, AP1G1, C16ORF70, LHCGR, EIF5A, GRIN3B, SRP19, AGXT, KLHL2, TGFB1, CTNNB1, ABRA, TLK1, STAM, KIF13B, RAB27A, EGFR, PTPRK, VPS45, OPTN, ARNTL, AP4M1, VTI1A, MAPK1, COPG2, KRT18, JUN, F2, USO1, AKAP6, MRPL45, DRD1, ARFGAP3, NAPG, STAM2, RTP1, NAPB, RIMS2, RIMS1, STX12, NPM1, TNKS, SEC23IP, TRAM1, SRGN, AP2M1, SEC61A2, RANBP17, ICMT, DVL1, TRNT1, CBLB, VCP, TOMM70A, NEDD4, SYTL4, PCNA, HGS, SEC13, NUTF2, GOSR2, SMURF1, XPO7, RERE, HDAC6, cellular protein COPA, CLTA, PDIA3, FGF9, PAX6, AP3S1, PEX5, PEX7, 141 2.93 8.60E-07 4.46E-03 7.46E-04 localization AP1S3, CDC42, AP1S2, LONP2, ZFYVE16, RANBP2, COX18, KPNB1, FGF2, DNAJC19, AP3B1, SEC23A, KDELR2, STX1A, ARHGEF2, SYNRG, STX2, PRKCI, TOPORS, TIMM23, BBS2, MYRIP, ATG4D, IPO7, ATG4A, NUP205, IPO4, MGEA5, TOMM20, SORT1, COPG, BID, YWHAZ, STON1, MUDENG, AP3M2, CEP57, MORC3, SH3GLB1, TAP2, BCAP29, PPP3CB, EXOC4, CHM, RAB11A, BCL6, PEX13, CD24, FYB, SRP14P1, IPO11, NLGN1, YWHAB, EXPH5, PPP1R10, STRADB, COG3, TEX15, ERBB2IP, GSK3B, YWHAQ, JAK2, AP4B1, SSR3 CTHRC1, SLC22A16, JUB, PDGFB, PTGS2, CAPZA2, CAPZA1, RPS6KB1, ENPEP, MYLIP, CXCL12, NR2E1, TGFB1, VCL, NRCAM, APP, APOB, CD44, GAB2, ANK3, RPS27A, TWIST1, SYK, PTPRK, RET, SATB2, EFNB3, ROCK1, MDGA1, KIF5C, EMX2, CCL4L1, CCL4L2, SCYL3, SIX4, MYH9, CTNNA2, ASCL1, HIF1A, CD34, LYST, FOXG1, PDGFRB, OPHN1, RELN, EFNA5, CAV2, ITGAL, DRD1, CCL3, CDK5R1, CCL2, ENPP2, DRD2, ARF6, CCL4, ITGB1, EPHB1, ITGAM, SCRIB, ARX, ALCAM, HOXA2, OVOL2, KATNA1, RAC1, SBDSP1, B3GNT2, FN1, NKX2-3, VAV3, NTF3, TGFBR1, MET, NR4A2, ITGA1, ITGA2, ITGA4, EPHA7, cell motion LYVE1, ITGA6, LAMA5, PTENP1, MYH10, NRP2, 159 3.31 9.01E-07 4.67E-03 6.69E-04 CCKAR, TLN1, NRP1, WASF2, PAX6, PEX5, ZEB2, GLI2, PEX7, ACTR3, EDNRB, NDE1, CXCR4, SEMA3C, CAP1, FGF2, ICAM1, EGR2, CCDC88A, NRXN3, ARHGEF7, ARID5B, OTX2, CHST4, NCK2, PSEN1, SERPINB5, IL12A, VCAN, SIAH1, CNTN4, WASL, ACVR1, CER1, DCC, SHROOM2, FUT8, CALD1, PRKDC, KITLG, ABI2, CDH2, TPM1, CDH4, TPM4, MYCBP2, TPM3, DNALI1, TNR, PAFAH1B1, POU3F2, PEX13, CD24, APC, SCG2, THBS4, SELP, IL6, FLT1, MSH2, DPYSL5, IGF1, ATP1A4, LMX1A, ISL1, COL5A1, TNP2, MAPK14, LRP6, JAK2, NEUROD4, APBB2, SELE, FEZ2, LRP5 OXA1L, SEC31A, AP1G1, SNCA, GRIN3B, CNO, MEGF10, NRCAM, DAB2, APP, PICALM, GBF1, membrane ADAM2, PUM1, RABGEF1, SH3GL3, SCAMP1, EGFR, 132 2.74 1.10E-06 5.69E-03 7.12E-04 organization DBNL, CRISP1, LRP1B, COLEC12, CD36, GAPVD1, FNBP1L, ARRB1, TXNDC5, LRP12, VAMP7, USO1, OPHN1, VAMP3, CAV2, ABCA7, CAV1, NAPG, RTP1, １０７
Term Genes Count % P-Value Bonferroni FDR
HFE, SNX4, SNX3, ABCA1, ABCA4, RIMS1, AHSG, ITGAV, MTCH1, RAC1, DULLARD, ZMPSTE24, EMD, RAB8A, VAV3, TGFBR2, DENND1A, PPIF, NEDD4, SEC13, GOSR2, CLEC7A, MYH10, COPA, CLTA, MSR1, MYO7A, SYNJ1, WASF2, BNIP3, PEX5, AP1S3, AP1S2, NECAP1, CAP1, COX18, CLINT1, GHR, AP3B1, VCPIP1, DHCR24, SEC23A, SYNRG, HSP90AA1, CCDC88A, STX2, PRKCI, M6PR, LDLRAP1, ELMO2, ZDHHC15, MFN1, RAB5A, SORT1, COPG, EPN1, SERP1, BID, MBL2, RAB3A, STON1, GULP1, MUTED, SCARF1, AMPH, ELMOD3, SH3GLB1, BCL2, PAFAH1B1, CD24, PLA2R1, EHD1, PTX3, ELMOD2, EHD4, LY75, DNM3, SCLT1, DNM1L, HCK, LRRN3, LMNA, COL5A1, LMBR1L, PLSCR1, GRIA2, PLSCR4, GRIA1, JMJD6, RAB34, PLSCR3, LRP6, CD302, LRP4, LRP5, DNM2, VLDLR SEC31B, SEC31A, AP4E1, CHMP5, AP1G1, C16ORF70, SNCA, CNO, MEGF10, RAB1A, CTNNB1, DAB2, APP, PICALM, GBF1, RABGEF1, PUM1, RAB27A, SH3GL3, SCAMP1, DBNL, VPS45, LRP1B, COLEC12, OPTN, AP4M1, PCLO, VTI1A, COPG2, KRT18, TRIM36, CD36, GAPVD1, ARRB1, FNBP1L, TXNDC5, LRP12, VAMP7, LYST, PI4K2A, USO1, OPHN1, TRAPPC4, VAMP3, UNC13C, VAMP1, ERC1, VPS26A, TRAPPC3, KALRN, CAV2, ABCA7, CAV1, CCL3, ARFGAP3, CNIH, NAPG, HFE, SNX4, ARF6, ARF5, ABCA1, NAPB, SNX3, LMAN1, ARFGEF2, RIMS1, ARFGEF1, AHSG, LLGL2, STX12, KIAA1012, ITGAV, RAC1, DOPEY1, AP2M1, RHOBTB3, OSBPL5, RAB8A, VAV3, TGFBR2, DENND1A, LIN7C, TINAGL1, AKTIP, VCP, NEDD4, vesicle-mediated ARF4, SYTL4, CPNE1, HGS, SEC13, BET1L, YIPF5, 185 3.85 2.38E-06 1.23E-02 1.37E-03 transport GOSR2, CLEC7A, MYH10, COPA, CLTA, MSR1, GLRA1, ATL2, MYO7A, WASF2, SYNJ1, AP3S1, CRCP, AP1S3, BLZF1, AP1S2, ZFYVE16, TRAPPC6B, GOPC, NECAP1, RAB6A, CAP1, GOLGA5, CLINT1, GOLGA4, GHR, AP3B1, SEC23A, KDELR2, ARL1, STX1A, SYNRG, STX2, PRKCI, STXBP2, STXBP3, M6PR, LDLRAP1, ELMO2, ZDHHC15, KIF1C, PSEN1, RAB5A, SORT1, COPG, EPN1, MBL2, RAB3A, YWHAZ, STON1, GULP1, BET1, MUTED, SCARF1, AMPH, MUDENG, ELMOD3, AP3M2, BCAP29, EXOC4, CD24, PLA2R1, EHD1, PTX3, ELMOD2, EHD4, LY75, RAB2A, DNM3, HCK, LRRN3, NLGN1, SCRN1, MON2, TNP2, COG3, LMBR1L, COG4, COG5, ARL17A, GRIA2, GRIA1, JMJD6, MCFD2, RAB34, LRP6, AP4B1, CD302, LRP4, COG1, LRP5, DNM2, VLDLR SEC31B, SEC31A, CHMP5, C16ORF70, LHCGR, RAB1A, FAM125A, APOB, AAGAB, ABRA, STAM, TLK1, NUP35, RAB27A, KIF13B, CD3G, VPS45, OPTN, AP4M1, MYH9, VTI1A, MAPK1, KRT18, CD36, LCA5, RAB19, JUN, BACE2, F2, RAB12, MRPL45, RAB10, RAB40C, CCDC91, ARF6, ARF5, RIMS2, RIMS1, RAB40B, STX12, TNKS, TRAM1, SEC23IP, RANBP17, RGPD4, RGPD3, RAB7L1, CBLB, ARF4, PCNA, SYTL4, BET1L, HGS, GOSR2, NUTF2, SMURF1, RERE, MSR1, PDIA3, FGF9, AP1AR, PPARG, AP3S1, AP1S3, BLZF1, AP1S2, LONP2, DNAJC14, RAB6A, AGAP1, FGF2, DNAJC19, AP3B1, KDELR2, STX1A, ARHGEF2, STX2, RAB4A, SENP2, ZDHHC17, MYRIP, RAB11FIP2, protein transport PSEN1, LAX1, NUP205, MGEA5, TOMM20, RAB5A, 235 4.89 2.90E-06 1.50E-02 1.51E-03 SORT1, GNAS, EIF5A2, SERP1, BID, RAB3A, YWHAZ, BET1, MUDENG, UEVLD, EXOC4, PPP3CB, CHM, RAB11A, APBA2, BCL6, PEX13, CD24, PCSK5, RAB2A, FYB, IPO11, YWHAB, NLGN1, EXPH5, PPP1R10, STRADB, COG3, COG4, COG5, RAB30, COG6, RAB37, ERBB2IP, GSK3B, MCFD2, RAB34, YWHAQ, RAB39, AP4B1, COG1, SSR3, XPO1, SRP14, GRPEL2, GRPEL1, AP4E1, AP1G1, XPO4, EIF5A, SRP19, AGXT, KLHL2, TGFB1, CXCL10, RABGEF1, SCAMP1, NUP133, ACTN4, LRP1B, ARNTL, COPG2, LYST, VAMP7, USO1, AKAP6, COL1A1, PDCD6IP, ERC1, VPS26A, DRD1, ARFGAP3, AFTPH, NAPG, STAM2, SNX7, SNX4, ABCA1, NAPB, SNX3, LMAN1, CHMP2B, １０８
Term Genes Count % P-Value Bonferroni FDR
NPM1, DOPEY1, SEC61A2, AP2M1, RAB8A, PRAF2, MYO1C, LIN7C, ICMT, ATG3, RAB33A, RAB33B, TRNT1, PLEKHA8, AKTIP, VCP, NEDD4, TOMM70A, SEC13, YIPF5, XPO7, ATG16L1, ATG16L2, HDAC6, COPA, CLTA, PEX5, PEX7, ZFYVE16, GOPC, NECAP1, RANBP2, KPNB1, NSF, SEC23A, SYNRG, PRKCI, STXBP2, STXBP3, TIMM23, ATG4D, IPO7, ATG4A, IPO4, COPG, SNX13, SNX10, LCP2, SNX18, STON1, SNX16, EFCAB4B, CEP57, AP3M2, TAP2, BCAP29, SNX24, SCG2, SNX20, NUP153, SRP14P1, SNX25, CENPF, MON2, ARL17A, VPS24, JAK2 SEPT2, RPE65, CXCL12, NR2E1, KLHL1, NRCAM, ZFP91, APP, CD44, ANK3, SS18L1, RPS27A, CDH23, EGFR, RET, EFNB3, KIF5C, LRTOMT, FARP2, CTNNA2, SLITRK2, HES1, ASCL1, NCAM2, SLITRK4, VEGFA, FOXG1, OPHN1, TRAPPC4, RELN, EFNA5, KALRN, FGFR1, DRD1, CDK5R1, PKHD1, DRD2, EPHB1, ARX, LIF, ALCAM, HOXA2, DMD, MTCH1, RAC1, NUMB, B3GNT2, OLFM3, LHX8, LAMB1, neuron PARD6B, NTF3, NR4A2, ITGA1, NTN4, EN1, DOCK7, 118 2.45 3.31E-06 1.71E-02 1.56E-03 development EN2, DVL1, EPHA7, S100B, NEDD4, NTRK2, MAP2, PTENP1, MYH10, NRP2, CCKAR, NRP1, MYO7A, PAX6, GJA1, GLI2, SLC1A3, DYNLL2, CXCR4, NR2F6, EGR2, NRXN3, OTX2, PRKCI, TBCE, PSEN1, GNAQ, NRL, SIAH1, VCAN, CNTN4, DCC, RAB3A, RTN4RL1, CTF1, ABI2, HPRT1, CDH4, SCARF1, MYCBP2, TNR, BCL2, PAFAH1B1, CD24, NEFL, APC, SCLT1, IL6, PTPRZ1, MAP1B, NTNG1, DPYSL5, LMX1A, ISL1, TP73, LEP, NEUROD2, NEUROD4, JAK2, APBB2, FEZ2 MAEL, TTN, CXCL12, NR2E1, TGFB1, CTNNB1, CUL3, NRCAM, DAB2, APP, ANK3, COL4A3BP, TBPL1, RPS27A, CDH23, EGFR, CD3G, EFNB3, KIF5C, CCL4L1, CCL4L2, MYH9, STK4, MARK2, CTNNA2, SLITRK2, HES1, TNNT2, NCAM2, SLITRK4, HIF1A, FOXG1, OPHN1, RELN, EFNA5, PMP22, KALRN, CDK5R1, BBS7, ONECUT1, PKHD1, DRD2, CCL4, ITGB1, EPHB1, SCRIB, ARX, ALCAM, HOXA2, DMD, RAC1, NUMB, OBSL1, B3GNT2, LAMB1, FN1, HNRNPAB, COL18A1, PARD6B, RAB8A, NTF3, cellular component ESRRB, EPB42, NR4A2, ITGA1, CASC5, MUL1, 134 2.79 4.32E-06 2.22E-02 1.87E-03 morphogenesis DOCK7, HGF, DVL1, SFRP5, EPHA7, S100B, LAMA5, MYH11, MAP7, ANTXR1, MYH10, NRP2, CCKAR, NRP1, MYO7A, PAX6, GJA1, GLI2, TTLL3, CDC42, NDE1, SLC1A3, CXCR4, RHOA, CAP1, ARHGEF2, EGR2, NRXN3, OTX2, TBCE, PRKCI, ECT2, BBS2, SS18, MFN1, CNTN4, SIAH1, VCAN, DCC, RAB3A, SHROOM2, SHROOM4, RTN4RL1, HPRT1, TPM1, CDH4, MYCBP2, TNR, BCL2, PAFAH1B1, BCL6, NEFL, APC, NOX4, ACTC1, DNM1L, PTPRZ1, MAP1B, DPYSL5, NTNG1, STRADB, LMX1A, WWTR1, ISL1, ERBB2IP, JAK2, APBB2, FEZ2 MAEL, CXCL12, NR2E1, TGFB1, CTNNB1, NRCAM, CUL3, DAB2, APP, ANK3, COL4A3BP, RPS27A, CDH23, EGFR, CD3G, EFNB3, KIF5C, CCL4L1, CCL4L2, MYH9, STK4, CTNNA2, MARK2, SLITRK2, HES1, NCAM2, SLITRK4, HIF1A, FOXG1, OPHN1, RELN, EFNA5, KALRN, CDK5R1, BBS7, ONECUT1, PKHD1, DRD2, CCL4, EPHB1, SCRIB, ARX, ALCAM, HOXA2, DMD, RAC1, NUMB, B3GNT2, LAMB1, FN1, HNRNPAB, COL18A1, PARD6B, RAB8A, NTF3, ESRRB, EPB42, NR4A2, ITGA1, DOCK7, HGF, DVL1, cell morphogenesis 121 2.52 9.05E-06 4.60E-02 3.62E-03 SFRP5, EPHA7, S100B, LAMA5, MAP7, ANTXR1, MYH10, NRP2, CCKAR, NRP1, MYO7A, PAX6, GJA1, GLI2, TTLL3, CDC42, NDE1, SLC1A3, CXCR4, RHOA, CAP1, ARHGEF2, EGR2, NRXN3, OTX2, PRKCI, TBCE, ECT2, SS18, BBS2, CNTN4, SIAH1, VCAN, DCC, RAB3A, SHROOM2, SHROOM4, RTN4RL1, HPRT1, CDH4, MYCBP2, TNR, BCL2, PAFAH1B1, BCL6, NEFL, APC, NOX4, PTPRZ1, MAP1B, DPYSL5, NTNG1, STRADB, LMX1A, WWTR1, ISL1, ERBB2IP, JAK2, APBB2, FEZ2
１０９
Term Genes Count % P-Value Bonferroni FDR
SEPT2, JAG2, RPE65, CXCL12, NR2E1, KLHL1, NRCAM, ZFP91, APP, HOXC8, CD44, ANK3, SS18L1, RPS27A, CDH23, EGFR, RET, EFNB3, STMN2, MDGA1, MDGA2, KIF5C, EMX2, LRTOMT, FGF20, FARP2, CTNNA2, SLITRK2, HES1, ASCL1, NCAM2, SLITRK4, VEGFA, FOXG1, OPHN1, TRAPPC4, RELN, EFNA5, KALRN, FGFR1, DRD1, CDK5R1, DRD2, PKHD1, SOX5, EPHB1, ARX, LIF, ALCAM, HOXA2, MTPN, DMD, MTCH1, RAC1, NUMB, LHX5, B3GNT2, OLFM3, LHX8, LAMB1, BMP4, PARD6B, NTF3, TGFBR1, NR4A2, ITGA1, NTN4, EN1, DOCK7, EN2, neuron DVL1, DLX2, EPHA7, S100B, NEDD4, NTRK2, MAP2, 144 2.99 9.06E-06 4.60E-02 3.36E-03 differentiation PTENP1, MYH10, NRP2, CCKAR, NRP1, AGTPBP1, MYO7A, PAX6, GJA1, PEX5, GLI2, CDC42, GPC2, SLC1A3, CXCR4, DYNLL2, NR2F6, KCNMA1, EGR2, NRXN3, OTX2, TBCE, PRKCI, PIGT, BTG2, PSEN1, GNAQ, NRL, VCAN, SIAH1, CNTN4, DCC, RAB3A, RTN4RL1, CTF1, ABI2, HPRT1, CDH4, SCARF1, MYCBP2, ALDH1A2, TNR, BCL2, POU3F4, PAFAH1B1, POU3F2, GFI1, CD24, NEFL, TLX1, APC, SCLT1, IL6, PTPRZ1, MAP1B, DPYSL5, NTNG1, LMX1A, ISL1, TP73, LEP, NEUROD2, JAK2, NEUROD4, ID4, APBB2, FEZ2 SLC22A16, JUB, CTHRC1, PDGFB, RPS6KB1, ENPEP, NR2E1, CXCL12, TGFB1, NRCAM, APOB, CD44, GAB2, SYK, TWIST1, PTPRK, SATB2, RET, ROCK1, MDGA1, EMX2, SCYL3, SIX4, MYH9, CTNNA2, ASCL1, HIF1A, CD34, LYST, PDGFRB, OPHN1, RELN, CAV2, CDK5R1, DRD1, CCL2, DRD2, ITGB1, SCRIB, ITGAM, ARX, OVOL2, KATNA1, RAC1, SBDSP1, NKX2-3, FN1, VAV3, TGFBR1, MET, NR4A2, ITGA1, ITGA4, ITGA6, localization of cell 107 2.22 9.23E-06 4.69E-02 3.20E-03 LAMA5, PTENP1, MYH10, NRP2, CCKAR, NRP1, WASF2, PAX6, PEX5, ZEB2, PEX7, EDNRB, NDE1, CXCR4, SEMA3C, CAP1, FGF2, ICAM1, CCDC88A, ARHGEF7, ARID5B, NCK2, PSEN1, IL12A, VCAN, ACVR1, CER1, DCC, SHROOM2, FUT8, ABI2, KITLG, PRKDC, CDH2, PAFAH1B1, PEX13, POU3F2, CD24, SCG2, THBS4, APC, SELP, IL6, FLT1, ATP1A4, ISL1, COL5A1, TNP2, LRP6, NEUROD4, APBB2, SELE, LRP5 SLC22A16, JUB, CTHRC1, PDGFB, RPS6KB1, ENPEP, NR2E1, CXCL12, TGFB1, NRCAM, APOB, CD44, GAB2, SYK, TWIST1, PTPRK, SATB2, RET, ROCK1, MDGA1, EMX2, SCYL3, SIX4, MYH9, CTNNA2, ASCL1, HIF1A, CD34, LYST, PDGFRB, OPHN1, RELN, CAV2, CDK5R1, DRD1, CCL2, DRD2, ITGB1, SCRIB, ITGAM, ARX, OVOL2, KATNA1, RAC1, SBDSP1, NKX2-3, FN1, VAV3, TGFBR1, MET, NR4A2, ITGA1, ITGA4, ITGA6, cell motility 107 2.22 9.23E-06 4.69E-02 3.20E-03 LAMA5, PTENP1, MYH10, NRP2, CCKAR, NRP1, WASF2, PAX6, PEX5, ZEB2, PEX7, EDNRB, NDE1, CXCR4, SEMA3C, CAP1, FGF2, ICAM1, CCDC88A, ARHGEF7, ARID5B, NCK2, PSEN1, IL12A, VCAN, ACVR1, CER1, DCC, SHROOM2, FUT8, ABI2, KITLG, PRKDC, CDH2, PAFAH1B1, PEX13, POU3F2, CD24, SCG2, THBS4, APC, SELP, IL6, FLT1, ATP1A4, ISL1, COL5A1, TNP2, LRP6, NEUROD4, APBB2, SELE, LRP5 JUB, NELL2, MEGF10, CTNNB1, CD47, APP, CD44, ADAM2, COL12A1, CDH26, SYK, CDH23, TYRO3, PTPRK, CLCA2, ROCK1, MAGI1, CDHR3, CTNNA1, MYH9, SSPN, SSPO, BCL2L11, CTNNA3, CTNNA2, HES1, JUP, RND3, PGM5, CD36, CD34, ATP2C1, LAMC2, DCBLD2, DCBLD1, CDK5R1, PCDH20, ARF6, OTOR, SCRIB, ITGBL1, ALCAM, RAC1, EMB, LAMB1, COL18A1, CNKSR3, PCDH10, PCDH15, PMF1, ECM2, COL16A1, PCDH17, PCDH18, LAMA4, COL14A1, cell adhesion 215 4.47 1.08E-05 5.46E-02 3.50E-03 NLGN4Y, HSPB11, ATP2A2, LAMA5, PKP4, CD58, NLGN4X, CLEC7A, NRP2, NRP1, COL21A1, FERMT1, CDSN, PDPK1, FGF4, ICAM1, PCDH11Y, PCDH11X, FBLIM1, CD164, AMBN, PSEN1, SGCE, VCAN, SEMA4D, CHL1, PARVA, PPFIA2, CLDN18, PPFIA1, COL3A1, CLDN10, CBLL1, CLDN12, CLDN14, IGSF11, FAT3, BCL2, PKD2, COL6A1, CD24, MLLT4, THBS4, FLRT3, HAPLN1, SELP, SELL, NLGN1, COL15A1, NID1, NID2, CLDN20, RAPH1, ERBB2IP, CDH19, １１０
Term Genes Count % P-Value Bonferroni FDR
PERP, SELE, CDH10, MPZL3, MAEA, MPZL2, CASK, CXCL12, VCL, PNN, NRCAM, TGFBI, FNDC3A, SPON1, EGFR, RET, ACTN1, CCL4L1, CCL4L2, ACTN2, NCAM1, NCAM2, TESK2, RELN, CXADRP2, COL24A1, ITGAL, CCL2, PKHD1, ITGB4, ITGB5, NEDD9, CCL4, ITGB1, ITGAM, PCDHAC1, AZGP1P1, ITGB8, ITGB7, ITGAV, SSX2IP, ANGPTL3, FN1, LPP, ITGA1, ITGA2, EFS, ITGA4, TINAG, LYVE1, OMD, DSG4, TSC1, DSG2, ITGA6, FREM2, TMEM8A, ITGA8, DSG1, ADAM22, ANTXR1, TRIP6, HABP2, CLDN7, FER, CXADR, ARHGAP6, PCDH1, CNTNAP3, RHOA, DLG5, BOC, TRPM7, NRXN3, PCDH9, PCDH8, CHST4, STXBP3, PCDH7, SIGLEC16, CD84, DDR1, SIGLEC6, CLDN1, CLDN2, CNTN4, CNTN3, NCAN, JAM2, TNC, KITLG, CTNND1, CNTNAP3B, CDH2, CDH4, SCARF1, CDH5, CDH8, COL9A1, TNR, COL27A1, COL8A1, DPT, APC, COL4A3, COL5A1, COL4A6, DSC2 JUB, NELL2, MEGF10, CTNNB1, CD47, APP, CD44, ADAM2, COL12A1, CDH26, SYK, CDH23, TYRO3, PTPRK, CLCA2, ROCK1, MAGI1, CDHR3, CTNNA1, MYH9, SSPN, SSPO, BCL2L11, CTNNA3, CTNNA2, HES1, JUP, RND3, PGM5, CD36, CD34, ATP2C1, LAMC2, DCBLD2, DCBLD1, CDK5R1, PCDH20, ARF6, OTOR, SCRIB, ITGBL1, ALCAM, RAC1, EMB, LAMB1, COL18A1, CNKSR3, PCDH10, PCDH15, PMF1, ECM2, COL16A1, PCDH17, PCDH18, LAMA4, COL14A1, NLGN4Y, HSPB11, ATP2A2, LAMA5, PKP4, CD58, NLGN4X, CLEC7A, NRP2, NRP1, COL21A1, FERMT1, CDSN, PDPK1, FGF4, ICAM1, PCDH11Y, PCDH11X, FBLIM1, CD164, AMBN, PSEN1, SGCE, VCAN, SEMA4D, CHL1, PARVA, PPFIA2, CLDN18, PPFIA1, COL3A1, CLDN10, CBLL1, CLDN12, CLDN14, IGSF11, FAT3, BCL2, PKD2, COL6A1, CD24, MLLT4, THBS4, FLRT3, HAPLN1, SELP, SELL, NLGN1, COL15A1, biological adhesion NID1, NID2, CLDN20, RAPH1, ERBB2IP, CDH19, 215 4.47 1.20E-05 6.04E-02 3.66E-03 PERP, SELE, CDH10, MPZL3, MAEA, MPZL2, CASK, CXCL12, VCL, PNN, NRCAM, TGFBI, FNDC3A, SPON1, EGFR, RET, ACTN1, CCL4L1, CCL4L2, ACTN2, NCAM1, NCAM2, TESK2, RELN, CXADRP2, COL24A1, ITGAL, CCL2, PKHD1, ITGB4, ITGB5, NEDD9, CCL4, ITGB1, ITGAM, PCDHAC1, AZGP1P1, ITGB8, ITGB7, ITGAV, SSX2IP, ANGPTL3, FN1, LPP, ITGA1, ITGA2, EFS, ITGA4, TINAG, LYVE1, OMD, DSG4, TSC1, DSG2, ITGA6, FREM2, TMEM8A, ITGA8, DSG1, ADAM22, ANTXR1, TRIP6, HABP2, CLDN7, FER, CXADR, ARHGAP6, PCDH1, CNTNAP3, RHOA, DLG5, BOC, TRPM7, NRXN3, PCDH9, PCDH8, CHST4, STXBP3, PCDH7, SIGLEC16, CD84, DDR1, SIGLEC6, CLDN1, CLDN2, CNTN4, CNTN3, NCAN, JAM2, TNC, KITLG, CTNND1, CNTNAP3B, CDH2, CDH4, SCARF1, CDH5, CDH8, COL9A1, TNR, COL27A1, COL8A1, DPT, APC, COL4A3, COL5A1, COL4A6, DSC2 NRP2, FGF18, CDX2, NRP1, HTATIP2, LMO2, FGF9, PGF, DICER1, WASF2, PRRX1, PRRX2, ENPEP, CXCL12, MMP2, CTNNB1, AGTR2, APOB, CUL7, MYOCD, CD44, ATG5, CXCR4, CASP8, HEY2, ROBO4, SEMA3C, ERAP1, QKI, MKL2, LOX, FGF2, PTPRJ, RECK, MMP19, MYH9, ARHGAP24, HIF1A, BGN, blood vessel PSEN1, EREG, NUS1, JUN, VEGFA, COL1A2, COL1A1, 88 1.83 1.73E-05 8.59E-02 4.98E-03 development SMARCA4, ACVR1, CAV1, TIPARP, COL3A1, WARS2, CDH2, CDH5, T, ANGPTL6, ITGAV, CHM, TGM2, ZC3H12A, ANGPTL3, RASA1, SCG2, KLF5, BMP4, COL18A1, SELP, FLT1, TGFBR1, TBX4, NF1, TGFBR2, COL15A1, ITGA4, ESX1, TMPRSS6, COL5A1, ANXA2, DLX3, GPI, LAMA4, PKNOX1, MEOX2, JMJD6, LAMA5, MAPK14, NTRK2, PTENP1 NCBP2, NCBP1, SRP14, EIF2C2, CPEB2, DICER1, EIF5B, EIF5A, EIF2A, CPEB1, YBX1, YBX2, APP, posttranscriptional CDKN2A, DGCR8, RBM8A, PIWIL1, PUM1, QKI, regulation of gene SAMD4A, EIF2B4, NLRP5, GTPBP4, ZCCHC11, ACO1, 78 1.62 1.74E-05 8.65E-02 4.75E-03 expression CCDC88C, CDK4, BOLL, HNRNPU, MAPK1, NCK2, EIF4G3, EIF2AK1, MTRF1, TBRG1, VEGFA, MDM4, EIF5A2, EIF2AK4, EIF2C3, EIF2C4, EIF4E3, NAPG, １１１
Term Genes Count % P-Value Bonferroni FDR
PRKDC, IGF2BP2, MAPKAPK2, IGF2BP3, LIN28A, GCN1L1, LIN28B, ZFP36L2, TNRC6C, STX12, MORC3, BCL2, MTPN, SEPSECS, PABPC1, TNRC6B, TNRC6A, FBXO7, IL6, UPF1, PAIP2, PAIP1, SRP14P1, IREB2, ELAVL1, ITGA2, ETF1, COG3, EIF4B, ATXN2, EIF4E, DIO2, TSC1, CDKN2AIP, MIF4GD, PTENP1 JUB, SEPT2, PDGFB, LPAR1, CXCL12, NR2E1, VCL, KLHL1, NRCAM, APP, CD44, ANK3, SS18L1, RPS27A, CDH23, EGFR, ROCK1, EFNB3, KIF5C, ACTN2, MYH9, CTNNA2, SLITRK2, NCAM2, SLITRK4, CC2D2A, FOXG1, OPHN1, TRAPPC4, RELN, EFNA5, KALRN, FGFR1, CDK5R1, BBS7, ONECUT1, PKHD1, DRD2, ITGB4, ARF6, EPHB1, ARX, ALCAM, HOXA2, DMD, RAC1, NUMB, B3GNT2, LAMB1, FGD4, KLF5, PARD6B, RAB8A, VAV3, NTF3, NR4A2, ITGA1, cell projection DOCK7, DVL1, EPHA7, TSC1, S100B, ITGA6, LAMA5, 123 2.56 1.85E-05 9.17E-02 4.80E-03 organization NEDD4, ITGA8, MAP2, PTENP1, MYH10, NRP2, CCKAR, NRP1, MYO7A, WASF2, PAX6, GJA1, GLI2, TTLL3, SPAG16, CDC42, CXCR4, EGR2, CCDC88A, STX2, NRXN3, OTX2, TBCE, LPIN1, NCK2, BBS2, CNTN4, SIAH1, VCAN, DCC, RAB3A, RTN4RL1, ABI2, RDX, HPRT1, TPM1, CDH4, SCARF1, MYCBP2, TNR, BCL2, PAFAH1B1, CD24, NEFL, THBS4, APC, DNM3, IL6, BAIAP2L2, PTPRZ1, MAP1B, NTNG1, DPYSL5, LMX1A, WWTR1, ISL1, JAK2, APBB2, FEZ2 DZIP3, IDE, PPP2R5C, RNF217, VPRBP, MYLIP, KLHL3, LNX1, CUL3, G2E3, CUL5, USP53, USP54, CUL7, WWP2, RABGEF1, ERAP1, FBXO21, FBXO22, RPS27A, PAN2, SOCS2, SOCS3, ENC1, UBR4, SOCS6, SOCS4, UBR2, UBR1, SOCS5, SKP1, MYH9, PSMA2, PSMA1, UHRF1, DCUN1D1, UHRF2, TRIM33, BACE2, UBR5, TRIM32, BACE1, RNF138, FBXL7, KBTBD10, ASB7, FBXO10, FBXL3, FBXL2, FBXO11, WDR5B, SUMO1P3, RAB40C, ANAPC10, RAB40B, PSMB5, CACYBP, OTUD7B, STAMBPL1, HECTD2, ZMPSTE24, FBXO3, PPIL5, FBXO45, FBXO8, RNF14, HECTD1, FBXO7, SHPRH, UBE2CBP, CDC23, MUL1, PCNP, MARCH10, ATG3, UBE2E3, RNF6, CBLB, TULP4, RNF7, VCP, NEDD4, UBA2, UBA3, SMURF2, SMURF1, proteolysis FBXO36, UBE2E2, HDAC6, HECW2, UBE2G1, NFKB1, involved in cellular SENP5, OS9, ZYG11B, CASP8, MTBP, PSMD3, YOD1, 186 3.87 2.46E-05 1.20E-01 6.08E-03 protein catabolic RANBP2, FBXL14, FBXL16, USP15, KLHL20, USP14, process VCPIP1, PSMD9, NFX1, FBXL18, DCAF15, ADAM10, BRCC3, FBXL21, FBXL20, UFD1L, DDB1, HERC6, RING1, ERLIN2, HERC4, ERLIN1, TOPORS, UBE2H, HLTF, SENP2, WDR48, UBE2O, USP28, ATG4D, SENP1, PSEN1, MED8, ATG4A, KLHL13, UCHL5, UBE2W, MDM2, BUB1B, UCHL3, SIAH1, USP26, USP7, USP30, UBE2Z, USP3, USP9Y, UBE3A, USP9X, EDEM3, CBLL1, UBE3C, EDEM1, MYCBP2, SUMO2, UEVLD, UFM1, MAP3K1, RNF128, USP38, USP37, USP36, USP34, FBXW11, USP33, USP32, RNF144A, USP40, RNF19A, LRRC41, UBE4B, BIRC6, MARCH7, PARK2, MARCH6, UBE2Q1, MARCH5, CISH, WSB1, CUL4A, USP47, SH3RF2, USP48, RNF19B, CUL4B, TBL1X, RNF111 GRPEL2, SRP14, XPO1, GRPEL1, AP4E1, AP1G1, C16ORF70, LHCGR, EIF5A, SRP19, AGXT, TGFB1, KLHL2, ABRA, TLK1, STAM, KIF13B, RAB27A, VPS45, OPTN, ARNTL, AP4M1, VTI1A, MAPK1, COPG2, KRT18, JUN, F2, USO1, AKAP6, MRPL45, DRD1, ARFGAP3, NAPG, STAM2, NAPB, RIMS2, RIMS1, STX12, NPM1, SEC23IP, TRAM1, AP2M1, SEC61A2, RANBP17, ICMT, TRNT1, CBLB, VCP, TOMM70A, intracellular NEDD4, SYTL4, PCNA, HGS, SEC13, GOSR2, NUTF2, 124 2.58 2.59E-05 1.26E-01 6.11E-03 protein transport SMURF1, XPO7, RERE, HDAC6, COPA, CLTA, PDIA3, FGF9, AP3S1, PEX5, PEX7, AP1S3, AP1S2, LONP2, ZFYVE16, RANBP2, KPNB1, FGF2, DNAJC19, AP3B1, SEC23A, KDELR2, STX1A, ARHGEF2, SYNRG, STX2, PRKCI, TIMM23, MYRIP, ATG4D, IPO7, ATG4A, NUP205, IPO4, TOMM20, MGEA5, SORT1, COPG, BID, YWHAZ, STON1, MUDENG, AP3M2, CEP57, TAP2, BCAP29, CHM, PPP3CB, EXOC4, RAB11A, BCL6, １１２
Term Genes Count % P-Value Bonferroni FDR
PEX13, CD24, FYB, SRP14P1, IPO11, NLGN1, YWHAB, EXPH5, PPP1R10, STRADB, COG3, ERBB2IP, GSK3B, YWHAQ, JAK2, AP4B1, SSR3 NRP2, FGF18, CDX2, NRP1, HTATIP2, LMO2, FGF9, PGF, DICER1, WASF2, PRRX1, PRRX2, ENPEP, CXCL12, MMP2, CTNNB1, AGTR2, APOB, CUL7, MYOCD, CD44, ATG5, CXCR4, CASP8, HEY2, ROBO4, SEMA3C, ERAP1, QKI, MKL2, LOX, FGF2, PTPRJ, RECK, MMP19, MYH9, ARHGAP24, HIF1A, BGN, vasculature PSEN1, EREG, NUS1, JUN, VEGFA, COL1A2, COL1A1, 89 1.85 2.70E-05 1.31E-01 6.08E-03 development SMARCA4, ACVR1, CAV1, TIPARP, COL3A1, WARS2, CDH2, CDH5, T, TCF21, ANGPTL6, ITGAV, CHM, TGM2, ZC3H12A, ANGPTL3, RASA1, SCG2, KLF5, BMP4, COL18A1, SELP, FLT1, TGFBR1, TBX4, NF1, TGFBR2, COL15A1, ITGA4, ESX1, TMPRSS6, COL5A1, ANXA2, DLX3, GPI, LAMA4, PKNOX1, MEOX2, JMJD6, LAMA5, MAPK14, NTRK2, PTENP1 DZIP3, IDE, PPP2R5C, RNF217, VPRBP, MYLIP, KLHL3, LNX1, CUL3, G2E3, CUL5, USP53, USP54, CUL7, WWP2, RABGEF1, ERAP1, FBXO21, FBXO22, RPS27A, PAN2, SOCS2, SOCS3, ENC1, UBR4, SOCS6, SOCS4, UBR2, UBR1, SOCS5, SKP1, MYH9, PSMA2, PSMA1, UHRF1, DCUN1D1, UHRF2, TRIM33, BACE2, UBR5, TRIM32, BACE1, RNF138, FBXL7, KBTBD10, ASB7, FBXO10, FBXL3, FBXL2, FBXO11, WDR5B, SUMO1P3, RAB40C, ANAPC10, RAB40B, PSMB5, CACYBP, OTUD7B, STAMBPL1, HECTD2, ZMPSTE24, FBXO3, PPIL5, FBXO45, FBXO8, RNF14, HECTD1, FBXO7, SHPRH, UBE2CBP, CDC23, MUL1, PCNP, MARCH10, ATG3, UBE2E3, RNF6, CBLB, TULP4, RNF7, VCP, NEDD4, UBA2, UBA3, SMURF2, SMURF1, FBXO36, UBE2E2, HDAC6, HECW2, UBE2G1, NFKB1, cellular protein SENP5, OS9, ZYG11B, CASP8, MTBP, PSMD3, YOD1, 186 3.87 3.37E-05 1.61E-01 7.28E-03 catabolic process RANBP2, FBXL14, FBXL16, USP15, KLHL20, USP14, VCPIP1, PSMD9, NFX1, FBXL18, DCAF15, ADAM10, BRCC3, FBXL21, FBXL20, UFD1L, DDB1, HERC6, RING1, ERLIN2, HERC4, ERLIN1, TOPORS, UBE2H, HLTF, SENP2, WDR48, UBE2O, USP28, ATG4D, SENP1, PSEN1, MED8, ATG4A, KLHL13, UCHL5, UBE2W, MDM2, BUB1B, UCHL3, SIAH1, USP26, USP7, USP30, UBE2Z, USP3, USP9Y, UBE3A, USP9X, EDEM3, CBLL1, UBE3C, EDEM1, MYCBP2, SUMO2, UEVLD, UFM1, MAP3K1, RNF128, USP38, USP37, USP36, USP34, FBXW11, USP33, USP32, RNF144A, USP40, RNF19A, LRRC41, UBE4B, BIRC6, MARCH7, PARK2, MARCH6, UBE2Q1, MARCH5, CISH, WSB1, CUL4A, USP47, SH3RF2, USP48, RNF19B, CUL4B, TBL1X, RNF111 RET, STX2, CYP1A1, BBS7, FGF9, TGFBR1, COL3A1, OXTR, GLI2, FOXP4, TINAG, TGFB1, CTNNB1, gut development 21 0.44 3.76E-05 1.78E-01 7.79E-03 EDNRB, ALDH1A2, OVOL2, BCL2, FOXF2, PCSK5, NR1H4, NKX2-3 ADAMTS18, ITGAL, FUT8, COL3A1, ITGB4, ITGB5, NEDD9, ITGB1, ITGAM, ITGBL1, CD47, GAB2, ITGB8, integrin-mediated ITGB7, ITGAV, ADAM33, ANGPTL3, SYK, PLP1, 33 0.69 4.20E-05 1.96E-01 8.37E-03 signaling pathway ADAM11, ADAM10, VAV3, ITGA1, ITGA2, ITGA4, MYH9, COL16A1, ADAMTS7, ERBB2IP, ITGA6, LAMA5, ITGA8, ADAM22 NRP2, CCKAR, NRP1, MYO7A, PAX6, GLI2, NR2E1, CXCL12, TGFB1, CTNNB1, NRCAM, CUL3, DAB2, APP, SLC1A3, ANK3, CXCR4, RPS27A, CDH23, EGR2, EFNB3, NRXN3, OTX2, KIF5C, TBCE, MYH9, CTNNA2, SLITRK2, HES1, NCAM2, SLITRK4, HIF1A, FOXG1, OPHN1, CNTN4, SIAH1, EFNA5, VCAN, cell morphogenesis RELN, KALRN, DCC, RAB3A, CDK5R1, RTN4RL1, involved in 86 1.79 4.77E-05 2.20E-01 9.15E-03 PKHD1, DRD2, HPRT1, CDH4, EPHB1, MYCBP2, ARX, differentiation ALCAM, HOXA2, TNR, BCL2, RAC1, NUMB, PAFAH1B1, B3GNT2, LAMB1, NEFL, FN1, APC, HNRNPAB, COL18A1, PARD6B, NTF3, PTPRZ1, ESRRB, MAP1B, NR4A2, NTNG1, DPYSL5, DOCK7, LMX1A, HGF, ISL1, DVL1, EPHA7, S100B, LAMA5, JAK2, ANTXR1, APBB2, FEZ2, MYH10
１１３
Term Genes Count % P-Value Bonferroni FDR
JUB, NRP1, PDGFB, IL6ST, TACR1, PAX6, JAG2, RPS6KB1, CXCL12, TGFB1, CXCL10, VCL, AGTR2, CXCR4, GAB1, ROBO4, FGF2, EGFR, ICAM1, PTPRK, GTPBP4, SP100, ADAM10, ACTN4, ACTN1, VASH1, MAPK1, SPAG9, BBS2, HIF1A, CLIC4, VEGFA, PRR5- regulation of cell ARHGAP8, PDGFRB, DRD1, ONECUT1, DRD2, 71 1.48 5.15E-05 2.35E-01 9.53E-03 motion PKHD1, ENPP2, CSF1, ABHD2, CBLL1, TPM1, BCL2, MAP3K1, RAC1, BCL6, ANGPTL3, LAMB1, PIK3R1, APC, COL18A1, SELP, PARD6B, IL6, FLT1, TGFBR1, NF1, IGF1, ITGA2, FURIN, HDAC5, LAMA4, CDKN1B, LAMA5, PTP4A1, JAK2, TRIP6, IGFBP3, PTENP1, HDAC6 PPFIA2, JUB, PPFIA1, COL3A1, ITGB4, ITGB5, ITGB1, CTNNB1, ITGBL1, ARHGAP6, PDPK1, CD44, ITGB8, cell-matrix BCL2, ITGB7, ITGAV, PKD2, RHOA, ANGPTL3, FN1, 39 0.81 5.51E-05 2.49E-01 9.83E-03 adhesion PTPRK, TRPM7, ITGA1, ITGA2, ACTN1, NID1, ACTN2, NID2, ECM2, RAPH1, BCL2L11, LYVE1, ITGA6, TSC1, LAMA5, ITGA8, TESK2, SGCE, TRIP6 JUB, SHROOM2, TLN1, GJA1, CXADR, TGFB1, VCL, CDC42, ARHGAP6, PDPK1, BCL2, NUMB, APC, FN1, cell junction PTPRK, PARD6B, MPZ, PRKCI, ACTN1, ACTN2, 28 0.58 7.70E-05 3.30E-01 1.33E-02 organization CTNNA1, TJP1, ITGA6, LAMA5, NLGN4X, DSG1, TESK2, CXADRP2, TRIP6 DZIP3, PPP2R5C, RNF217, VPRBP, MYLIP, KLHL3, LNX1, CUL3, G2E3, CUL5, USP53, USP54, CUL7, WWP2, RABGEF1, FBXO21, FBXO22, RPS27A, PAN2, SOCS2, SOCS3, ENC1, UBR4, SOCS6, SOCS4, UBR2, UBR1, SOCS5, SKP1, PSMA2, PSMA1, UHRF1, DCUN1D1, UHRF2, TRIM33, UBR5, TRIM32, RNF138, FBXL7, KBTBD10, ASB7, FBXO10, FBXL3, FBXL2, FBXO11, WDR5B, SUMO1P3, RAB40C, ANAPC10, RAB40B, PSMB5, CACYBP, HECTD2, STAMBPL1, OTUD7B, ZMPSTE24, FBXO3, PPIL5, FBXO45, FBXO8, RNF14, HECTD1, FBXO7, SHPRH, UBE2CBP, CDC23, MUL1, PCNP, MARCH10, ATG3, UBE2E3, RNF6, CBLB, TULP4, RNF7, VCP, NEDD4, UBA2, UBA3, modification- SMURF2, SMURF1, FBXO36, UBE2E2, HECW2, dependent protein UBE2G1, SENP5, OS9, ZYG11B, MTBP, PSMD3, YOD1, 176 3.66 8.01E-05 3.41E-01 1.34E-02 catabolic process RANBP2, FBXL14, FBXL16, USP15, KLHL20, USP14, PSMD9, FBXL18, DCAF15, NFX1, VCPIP1, BRCC3, FBXL21, FBXL20, UFD1L, DDB1, HERC6, RING1, ERLIN2, HERC4, ERLIN1, TOPORS, UBE2H, HLTF, SENP2, WDR48, UBE2O, USP28, ATG4D, SENP1, ATG4A, MED8, KLHL13, UCHL5, UBE2W, MDM2, BUB1B, UCHL3, SIAH1, USP26, USP7, USP30, UBE2Z, USP3, USP9Y, UBE3A, USP9X, EDEM3, CBLL1, UBE3C, EDEM1, MYCBP2, SUMO2, UEVLD, UFM1, MAP3K1, RNF128, USP38, USP37, USP36, USP34, FBXW11, USP33, USP32, RNF144A, USP40, RNF19A, LRRC41, UBE4B, BIRC6, MARCH7, PARK2, MARCH6, UBE2Q1, MARCH5, CISH, WSB1, CUL4A, USP47, SH3RF2, USP48, RNF19B, CUL4B, TBL1X, RNF111 DZIP3, PPP2R5C, RNF217, VPRBP, MYLIP, KLHL3, LNX1, CUL3, G2E3, CUL5, USP53, USP54, CUL7, WWP2, RABGEF1, FBXO21, FBXO22, RPS27A, PAN2, SOCS2, SOCS3, ENC1, UBR4, SOCS6, SOCS4, UBR2, UBR1, SOCS5, SKP1, PSMA2, PSMA1, UHRF1, DCUN1D1, UHRF2, TRIM33, UBR5, TRIM32, RNF138, FBXL7, KBTBD10, ASB7, FBXO10, FBXL3, FBXL2, FBXO11, WDR5B, SUMO1P3, RAB40C, ANAPC10, modification- RAB40B, PSMB5, CACYBP, HECTD2, STAMBPL1, dependent OTUD7B, ZMPSTE24, FBXO3, PPIL5, FBXO45, FBXO8, 176 3.66 8.01E-05 3.41E-01 1.34E-02 macromolecule RNF14, HECTD1, FBXO7, SHPRH, UBE2CBP, CDC23, catabolic process MUL1, PCNP, MARCH10, ATG3, UBE2E3, RNF6, CBLB, TULP4, RNF7, VCP, NEDD4, UBA2, UBA3, SMURF2, SMURF1, FBXO36, UBE2E2, HECW2, UBE2G1, SENP5, OS9, ZYG11B, MTBP, PSMD3, YOD1, RANBP2, FBXL14, FBXL16, USP15, KLHL20, USP14, PSMD9, FBXL18, DCAF15, NFX1, VCPIP1, BRCC3, FBXL21, FBXL20, UFD1L, DDB1, HERC6, RING1, ERLIN2, HERC4, ERLIN1, TOPORS, UBE2H, HLTF, SENP2, WDR48, UBE2O, USP28, ATG4D, SENP1,
１１４
Term Genes Count % P-Value Bonferroni FDR
ATG4A, MED8, KLHL13, UCHL5, UBE2W, MDM2, BUB1B, UCHL3, SIAH1, USP26, USP7, USP30, UBE2Z, USP3, USP9Y, UBE3A, USP9X, EDEM3, CBLL1, UBE3C, EDEM1, MYCBP2, SUMO2, UEVLD, UFM1, MAP3K1, RNF128, USP38, USP37, USP36, USP34, FBXW11, USP33, USP32, RNF144A, USP40, RNF19A, LRRC41, UBE4B, BIRC6, MARCH7, PARK2, MARCH6, UBE2Q1, MARCH5, CISH, WSB1, CUL4A, USP47, SH3RF2, USP48, RNF19B, CUL4B, TBL1X, RNF111 DRD1, NF1, EMX2, PAX6, PEX5, ZEB2, LMX1A, pallium NR2E1, TP73, TACC2, AHSG, ARX, ASCL1, DLX2, 24 0.50 9.14E-05 3.79E-01 1.48E-02 development BBS2, NDE1, PSEN1, TSC1, RAC1, POU3F2, ID4, RELN, PEX13, PAFAH1B1 RAB3A, TAPT1, MYO7A, TIPARP, APOB, MORC3, BCL2, CHST11, SEMA3C, CDH23, NKX2-3, BMP4, post-embryonic GABRG2, PNLIPRP1, ACADM, ACO1, ARID5B, 33 0.69 1.14E-04 4.48E-01 1.78E-02 development TGFBR1, TBCE, IREB2, NR4A2, CCDC47, TP73, BCL2L11, FOXP2, PSEN1, GNAQ, SLC18A2, PYGO2, GNAS, KLF4, PLEKHA1, SERP1 FGF18, PDGFB, IL6ST, GDF6, RPE65, FSTL1, FOXO4, TGFB1, FNTA, TIAM1, GAB1, PDGFC, CHRNA3, SYK, PTPRJ, EGFR, PTPRK, RET, EFNB3, SOCS2, PTPRG, FGF23, SOCS5, FGF20, JUN, VEGFA, COL1A2, ROR1, PDGFRB, FGFR1, TWSG1, EID2, CCL2, FGFR3, GRB2, EPHB4, EPHB1, LIF, ANGPTL1, BMP4, CNKSR1, NIN, TGFBR1, TGFBR2, MET, SMAD5, DUSP22, MSTN, enzyme linked HGF, DVL1, EPHA7, NTRK2, ARF4, SMURF2, AREG, receptor protein SMURF1, PTENP1, PLEKHA1, NRP1, FGF9, AP3S1, 112 2.33 1.15E-04 4.51E-01 1.75E-02 signaling pathway SHOC2, RHOQ, ZFYVE16, SHC1, FGF2, SIK2, FGF4, GHR, IRAK1, ARID5B, ECSIT, DDR1, NCK2, SS18, ACVR2A, CHRDL1, EREG, SORT1, ACVR1, LCP2, CER1, FUT8, USP9Y, CTF1, USP9X, TIPARP, COL3A1, TFG, ABI1, FKBP1A, PHIP, CEP57, DGKD, SOS1, MAP3K1, PIK3R3, PIK3R1, GIGYF1, GUCA1B, PTPRE, FLT1, FLT3, KL, NLK, FLT4, PTPRA, AXL, ERBB2IP, JAK1, JAK2, HPGD PPFIA2, JUB, PPFIA1, COL3A1, ITGB4, ITGB5, ITGB1, CTNNB1, ITGBL1, ARHGAP6, PDPK1, CD44, ITGB8, BCL2, ITGB7, ITGAV, PKD2, RHOA, LAMB1, cell-substrate ANGPTL3, FN1, PTPRK, TRPM7, ITGA1, ITGA2, 41 0.85 1.19E-04 4.61E-01 1.75E-02 adhesion ACTN1, NID1, ACTN2, NID2, ECM2, RAPH1, BCL2L11, LYVE1, ITGA6, TSC1, LAMA5, ITGA8, TESK2, SGCE, ANTXR1, TRIP6 DZIP3, IDE, PPP2R5C, RNF217, VPRBP, MYLIP, KLHL3, LNX1, CUL3, G2E3, CUL5, USP53, USP54, CUL7, WWP2, RABGEF1, ERAP1, FBXO21, FBXO22, RPS27A, PAN2, SOCS2, SOCS3, ENC1, UBR4, SOCS6, SOCS4, UBR2, UBR1, SOCS5, SKP1, MYH9, PSMA2, PSMA1, UHRF1, DCUN1D1, UHRF2, TRIM33, BACE2, UBR5, TRIM32, BACE1, RNF138, FBXL7, KBTBD10, ASB7, FBXO10, FBXL3, FBXL2, FBXO11, WDR5B, SUMO1P3, RAB40C, ANAPC10, RAB40B, PSMB5, CACYBP, OTUD7B, STAMBPL1, HECTD2, ZMPSTE24, PPIL5, FBXO3, FBXO45, FBXO8, RNF14, HECTD1, FBXO7, SHPRH, UBE2CBP, CDC23, MUL1, PCNP, MARCH10, ATG3, UBE2E3, RNF6, CBLB, TULP4, RNF7, VCP, NEDD4, UBA2, UBA3, SMURF2, SMURF1, protein catabolic FBXO36, UBE2E2, HDAC6, SPG7, HECW2, UBE2G1, 187 3.89 1.53E-04 5.49E-01 2.19E-02 process NFKB1, SENP5, OS9, ZYG11B, CASP8, MTBP, PSMD3, YOD1, RANBP2, FBXL14, FBXL16, USP15, KLHL20, USP14, VCPIP1, PSMD9, NFX1, FBXL18, DCAF15, ADAM10, BRCC3, FBXL21, FBXL20, UFD1L, DDB1, HERC6, RING1, ERLIN2, HERC4, ERLIN1, TOPORS, UBE2H, HLTF, SENP2, WDR48, UBE2O, USP28, ATG4D, SENP1, PSEN1, MED8, ATG4A, KLHL13, UCHL5, UBE2W, MDM2, BUB1B, UCHL3, SIAH1, USP26, USP7, USP30, UBE2Z, USP3, USP9Y, UBE3A, USP9X, EDEM3, CBLL1, UBE3C, EDEM1, MYCBP2, SUMO2, UEVLD, UFM1, MAP3K1, RNF128, USP38, USP37, USP36, USP34, FBXW11, USP33, USP32, RNF144A, USP40, RNF19A, LRRC41, UBE4B, BIRC6, MARCH7, PARK2, MARCH6, UBE2Q1, MARCH5,
１１５
Term Genes Count % P-Value Bonferroni FDR
CISH, WSB1, CUL4A, USP47, SH3RF2, USP48, RNF19B, CUL4B, TBL1X, RNF111 MSR1, AP1G1, MYO7A, SYNJ1, SNCA, WASF2, MEGF10, AP1S3, DAB2, APP, PICALM, AP1S2, RABGEF1, NECAP1, CAP1, CLINT1, GHR, AP3B1, SCAMP1, SH3GL3, DBNL, SYNRG, LRP1B, COLEC12, LDLRAP1, M6PR, ELMO2, ZDHHC15, GAPVD1, CD36, FNBP1L, VAMP7, LRP12, RAB5A, SORT1, OPHN1, membrane EPN1, RAB3A, MBL2, ABCA7, CAV1, STON1, GULP1, 77 1.60 1.59E-04 5.62E-01 2.21E-02 invagination HFE, SNX4, ABCA1, SNX3, SCARF1, AMPH, AHSG, ELMOD3, ITGAV, RAC1, CD24, PLA2R1, PTX3, EHD1, ELMOD2, EHD4, LY75, DNM3, HCK, TGFBR2, LRRN3, DENND1A, LMBR1L, GRIA2, GRIA1, JMJD6, NEDD4, RAB34, LRP6, CLEC7A, CD302, LRP4, LRP5, VLDLR, DNM2 MSR1, AP1G1, MYO7A, SYNJ1, SNCA, WASF2, MEGF10, AP1S3, DAB2, APP, PICALM, AP1S2, RABGEF1, NECAP1, CAP1, CLINT1, GHR, AP3B1, SCAMP1, SH3GL3, DBNL, SYNRG, LRP1B, COLEC12, LDLRAP1, M6PR, ELMO2, ZDHHC15, GAPVD1, CD36, FNBP1L, VAMP7, LRP12, RAB5A, SORT1, OPHN1, endocytosis EPN1, RAB3A, MBL2, ABCA7, CAV1, STON1, GULP1, 77 1.60 1.59E-04 5.62E-01 2.21E-02 HFE, SNX4, ABCA1, SNX3, SCARF1, AMPH, AHSG, ELMOD3, ITGAV, RAC1, CD24, PLA2R1, PTX3, EHD1, ELMOD2, EHD4, LY75, DNM3, HCK, TGFBR2, LRRN3, DENND1A, LMBR1L, GRIA2, GRIA1, JMJD6, NEDD4, RAB34, LRP6, CLEC7A, CD302, LRP4, LRP5, VLDLR, DNM2 DRD1, DRD2, PAX6, OXTR, PEX5, ZEB2, HPRT1, NR2E1, AHSG, ARX, NDE1, RAC1, POU3F2, PEX13, telencephalon PAFAH1B1, BMP4, NF1, EMX2, LMX1A, TP73, TACC2, 30 0.62 1.62E-04 5.69E-01 2.19E-02 development FOXP2, DLX2, ASCL1, BBS2, PSEN1, TSC1, ID4, RELN, MYH10 DZIP3, PPP2R5C, RNF217, VPRBP, MYLIP, DNASE1L1, CUL3, G2E3, CUL5, APOB, USP53, USP54, CUL7, WWP2, RBM8A, ERAP1, PAN2, UBR4, UBR2, UBR1, SKP1, MYH9, UHRF1, CD36, UHRF2, UBR5, BACE2, BACE1, FBXL7, EIF2C3, FBXL3, FBXL2, EIF2C4, WDR5B, SUMO1P3, RAB40C, HSPA1B, OAS2, RAB40B, CACYBP, ZMPSTE24, FBXO3, FBXO8, FBXO7, UBE2CBP, CDC23, PCNP, MARCH10, TULP4, CBLB, RNF6, RNF7, UBA2, UBA3, SMURF2, SMURF1, UBE2G1, BNIP3, NFKB1, SENP5, AUH, ZYG11B, MTBP, FBXL14, FBXL16, USP15, DEDD2, USP14, FBXL18, ADAM10, ZCCHC11, FBXL21, UFD1L, FBXL20, HERC6, HERC4, ERLIN2, MBD4, ERLIN1, WDR48, SENP2, USP28, SENP1, PSEN1, MED8, SIAH1, USP26, USP7, USP30, USP3, CBLL1, EDEM3, EDEM1, MYCBP2, ZFP36L2, SUMO2, UEVLD, USP38, USP37, USP36, USP34, FBXW11, USP33, USP32, USP40, UPF1, cellular RNF19A, LRRC41, BIRC6, MARCH7, MARCH6, macromolecule 214 4.45 1.67E-04 5.80E-01 2.20E-02 MARCH5, CISH, MNAT1, PPP1R8, USP47, SH3RF2, catabolic process USP48, RNF19B, NCBP2, NCBP1, IDE, KLHL3, LNX1, CDKN2A, RABGEF1, FBXO21, FBXO22, RPS27A, SOCS2, SOCS3, ENC1, SOCS6, SOCS4, SOCS5, PSMA2, PSMA1, DCUN1D1, TRIM33, TRIM32, RNF138, KBTBD10, ASB7, FBXO10, XRN2, FBXO11, PNPT1, ANAPC10, LIN28A, LIN28B, PSMB5, HECTD2, STAMBPL1, OTUD7B, PPIL5, FBXO45, RNF14, HECTD1, SHPRH, MUL1, SMG1, ATG3, UBE2E3, VCP, NEDD4, UBE2E2, FBXO36, HDAC6, HECW2, OS9, CASP8, PSMD3, YOD1, RANBP2, KLHL20, PSMD9, DCAF15, VCPIP1, NFX1, BRCC3, DDB1, RING1, TOPORS, UBE2H, HLTF, UBE2O, XPC, ATG4D, ATG4A, KLHL13, UCHL5, UBE2W, BUB1B, MDM2, UCHL3, UBE2Z, USP9Y, UBE3A, USP9X, UBE3C, SMUG1, ERCC5, UFM1, MAP3K1, RNF128, RNF144A, UBE4B, PARK2, UBE2Q1, WSB1, CUL4A, CUL4B, TBL1X, RNF111 JUB, PDGFB, IL6ST, TACR1, PAX6, JAG2, RPS6KB1, regulation of cell CXCL12, TGFB1, CXCL10, VCL, AGTR2, CXCR4, GAB1, 62 1.29 1.77E-04 6.02E-01 2.28E-02 migration ROBO4, FGF2, EGFR, ICAM1, PTPRK, GTPBP4,
１１６
Term Genes Count % P-Value Bonferroni FDR
ADAM10, VASH1, MAPK1, SPAG9, HIF1A, CLIC4, VEGFA, PRR5-ARHGAP8, PDGFRB, DRD1, ONECUT1, DRD2, ENPP2, CSF1, ABHD2, CBLL1, TPM1, BCL2, MAP3K1, RAC1, LAMB1, ANGPTL3, PIK3R1, APC, COL18A1, SELP, PARD6B, IL6, FLT1, NF1, IGF1, ITGA2, FURIN, HDAC5, LAMA4, LAMA5, PTP4A1, JAK2, TRIP6, IGFBP3, PTENP1, HDAC6 RAD51C, JUB, DBF4B, WTAP, SART1, CTNNB1, CUL3, MEI1, CUL5, CDCA8, APP, MAP3K8, CDCA2, TLK1, MAP2K6, CCAR1, STAG1, POLE, UBR2, SKP1, MYH9, DCTN1, BOLL, ESCO2, VASH1, RAD1, PRDM7, MAPK1, UHRF1, KRT18, UHRF2, PRDM5, TBRG1, NEK9, TMPRSS11A, PELO, NEK1, MRE11A, CEP164, UHMK1, KIAA1009, SBDSP1, PBRM1, TNKS, TDRD1, MLL, NUF2, CDC23, PCNP, PMF1, ATR, HGF, SEPT10, NOTCH2, DMTF1, UBA3, CCNT2, STEAP3, SPIN1, LZTS2, KIAA0174, SENP5, LATS1, CCNE2, CCNE1, EVI5, MTBP, TUBB1, SIK1, DHCR24, FGF4, ARHGEF2, PAPD7, PAPD5, RAD51, FMN2, CCND1, EREG, FANCD2, IL12A, USH1C, SIAH1, CYTSA, G0S2, GADD45A, MAP3K11, RABGAP1, CETN3, POLA1, NCAPG, RB1CC1, BCL2, PKD2, PPP3CB, HBP1, PDS5B, UPF1, ILF3, STRADB, APPL2, TP73, MNAT1, TEX15, ERBB2IP, DUSP1, GSK3B, PTP4A1, KIF20B, CALM3, C21ORF45, APBB2, CALM2, DNM2, CALM1, SEPT4, cell cycle MAEA, SEPT2, ZAK, JAG2, MAEL, FOXO4, TTN, 227 4.72 1.87E-04 6.22E-01 2.35E-02 TGFB1, RCBTB1, MLL5, CDKN2A, CASP8AP2, OIP5, TARDBP, RPS27A, EGFR, KILLIN, SGOL2, PLK1S1, PPP1CC, AHR, WEE1, DDIT3, WEE2, TACC2, PSMA2, PSMA1, STMN1, PDCD6IP, SEPT6, PKHD1, LRRCC1, NEDD9, ANLN, ANAPC10, CCNG1, ITGB1, SYCP1, SESN1, SESN3, LLGL2, PSMB5, PRUNE2, NIPBL, RAD51L1, KATNA1, NPM1, MNS1, HELLS, TAF2, PARD6B, WDR6, BRCA2, TET2, PYHIN1, CDKN1B, PLK2, PARD6G, SMC1A, CCNDBP1, MYH10, E2F3, CDC14A, E2F6, E2F7, RHOU, FAM83D, NDE1, PIWIL1, PSMD3, CABLES2, VCPIP1, PSMD9, ARL2, RB1, HMGA2, CDK4, NEK11, EML4, SASS6, PRR5- ARHGAP8, MDM2, BUB1B, MDM4, DMC1, ACVR1, HAUS3, CKS1B, USP9X, CTCFL, CDC73, CEP55, HSPA2, PAFAH1B1, GFI1, APC, BOD1, CSRP2BP, KAT2B, MSH2, PSRC1, CENPF, DBC1, CENPE, CDC25C, CEP63, SMC3, SMC4, CUL4A, IRF6, VPS24, ID4, SETD8, CUL4B ADCY1, PGF, PPARG, LHCGR, RHOQ, AP3S1, PDE3B, RPE65, RPS6KB1, FOXO4, LATS1, PRKAR2B, PRKAR2A, PDPK1, GOT1, GAB1, GNG2, SHC1, cellular response to PRKACB, SIK2, GHR, SOCS2, PRKCI, ADIPOR2, 51 1.06 2.15E-04 6.73E-01 2.63E-02 hormone stimulus LPIN1, GNB2, GNB1, DNAJC25, GNAS, DRD1, ENPP1, GRB2, PRKDC, TRH, AHSG, PHIP, PIK3R3, PIK3R1, WDTC1, KAT2B, PTPRA, ITGA2, STAT1, HDAC5, GCG, DUSP1, ADCY9, ALDH2, JAK2, PARP1, VLDLR SYT1, SLC6A1, ATL2, GLRA1, IDE, PEX5, GJA1, CTNNB1, LNX1, TRIM4, ZFP91, AQP11, TRIM6, CASP8, GOPC, ACOT13, FAS, SLC1A1, IRAK1, BRAF, SCUBE3, CCDC88C, DPAGT1, ACTN2, COLEC12, STXBP3, PFKM, DECR1, C10ORF2, RAD51, JUP, protein SPAG9, SBF2, ADSL, MAP3K11, PARVA, SMARCAD1, 63 1.31 2.37E-04 7.09E-01 2.83E-02 oligomerization CAV2, CAV1, GRB2, AASS, CDH2, HPRT1, PDSS1, PDSS2, GCH1, C1QTNF7, MTMR2, TNFRSF1A, DGKD, MAP3K1, NPM1, TGM2, OLFM1, SHMT1, GABRA6, MUC20, YWHAB, BIRC3, ADIPOQ, TSC1, VCP, ATG16L1 SYT1, XPO1, OXA1L, SLC6A1, CAPZA2, IDE, CAPZA1, TTN, TGFB1, CTNNB1, LNX1, GTF2E1, ZFP91, GTF2E2, PICALM, AQP11, KIFAP3, PDGFC, FAS, TBPL1, CHRNA3, SYK, CD3G, SCUBE3, BRAF, MAGI1, TAF4B, protein complex DPAGT1, COLEC12, ACTN2, C10ORF2, JUP, SPAG9, 154 3.20 3.04E-04 7.95E-01 3.54E-02 biogenesis PTRF, ADSL, VAMP3, CAV2, CAV1, EID2, NAPG, GRB2, DIAPH1, PKHD1, TAF9B, DAG1, HFE, AHCTF1, ANLN, RIMS1, PDSS1, PDSS2, RAC1, NPM1, TAF9, OLFM1, TAF2, PARD6B, RANBP17, TAF4, MLL,
１１７
Term Genes Count % P-Value Bonferroni FDR
GABRA6, CNKSR3, DVL1, TSC1, VCP, GTF2F2, MYH11, XPO7, ATG16L1, NDUFAF4, COX11, E2F3, RSF1, GLRA1, ATL2, GJA1, PEX5, SKAP2, TTLL3, TRIM4, NDUFS7, ARHGAP6, RANBP9, GTF2A1, TRIM6, IL1RAP, RTF1, GOPC, GTF2A2, CASP8, ACOT13, COX18, TUBB1, KPNB1, SLC1A1, COX15, ARL2, IRAK1, NLRP5, HSP90AA1, CCDC88C, STXBP3, DECR1, PFKM, HMGA1, RAD51, TAF11, NCK2, MED4, TAF13, TBCA, SBF2, IPO7, NUP205, IPO4, MDM2, WASL, MDM4, ATPAF1, PARVA, MAP3K11, SMARCAD1, STON1, POLR2J, AASS, FKBP1A, CDH2, HPRT1, CLDN14, GCH1, C1QTNF7, MTMR2, TNFRSF1A, DGKD, TAP2, MAP3K1, TGM2, PEX13, NEFL, GTF3C4, APC, GEMIN5, SHMT1, IPO11, MUC20, YWHAB, CENPF, CENPE, TRIM24, BIRC3, ADIPOQ, MNAT1, COG4, PSMG2, THRAP3 SYT1, XPO1, OXA1L, SLC6A1, CAPZA2, IDE, CAPZA1, TTN, TGFB1, CTNNB1, LNX1, GTF2E1, ZFP91, GTF2E2, PICALM, AQP11, KIFAP3, PDGFC, FAS, TBPL1, CHRNA3, SYK, CD3G, SCUBE3, BRAF, MAGI1, TAF4B, DPAGT1, COLEC12, ACTN2, C10ORF2, JUP, SPAG9, PTRF, ADSL, VAMP3, CAV2, CAV1, EID2, NAPG, GRB2, DIAPH1, PKHD1, TAF9B, DAG1, HFE, AHCTF1, ANLN, RIMS1, PDSS1, PDSS2, RAC1, NPM1, TAF9, OLFM1, TAF2, PARD6B, RANBP17, TAF4, MLL, GABRA6, CNKSR3, DVL1, TSC1, VCP, GTF2F2, MYH11, XPO7, ATG16L1, NDUFAF4, COX11, E2F3, RSF1, GLRA1, ATL2, GJA1, PEX5, SKAP2, TTLL3, protein complex TRIM4, NDUFS7, ARHGAP6, RANBP9, GTF2A1, 154 3.20 3.04E-04 7.95E-01 3.54E-02 assembly TRIM6, IL1RAP, RTF1, GOPC, GTF2A2, CASP8, ACOT13, COX18, TUBB1, KPNB1, SLC1A1, COX15, ARL2, IRAK1, NLRP5, HSP90AA1, CCDC88C, STXBP3, DECR1, PFKM, HMGA1, RAD51, TAF11, NCK2, MED4, TAF13, TBCA, SBF2, IPO7, NUP205, IPO4, MDM2, WASL, MDM4, ATPAF1, PARVA, MAP3K11, SMARCAD1, STON1, POLR2J, AASS, FKBP1A, CDH2, HPRT1, CLDN14, GCH1, C1QTNF7, MTMR2, TNFRSF1A, DGKD, TAP2, MAP3K1, TGM2, PEX13, NEFL, GTF3C4, APC, GEMIN5, SHMT1, IPO11, MUC20, YWHAB, CENPF, CENPE, TRIM24, BIRC3, ADIPOQ, MNAT1, COG4, PSMG2, THRAP3 NRP2, CCKAR, NRP1, SEPT2, PAX6, GJA1, GLI2, NR2E1, CXCL12, KLHL1, NRCAM, APP, CD44, ANK3, CXCR4, SS18L1, RPS27A, EGFR, EGR2, EFNB3, NRXN3, OTX2, KIF5C, TBCE, CTNNA2, SLITRK2, NCAM2, SLITRK4, FOXG1, TRAPPC4, OPHN1, CNTN4, SIAH1, EFNA5, VCAN, RELN, KALRN, DCC, neuron projection RAB3A, FGFR1, CDK5R1, RTN4RL1, PKHD1, DRD2, 86 1.79 3.06E-04 7.97E-01 3.48E-02 development ABI2, HPRT1, CDH4, EPHB1, SCARF1, MYCBP2, ARX, ALCAM, HOXA2, TNR, DMD, BCL2, RAC1, NUMB, PAFAH1B1, CD24, B3GNT2, LAMB1, NEFL, APC, PARD6B, IL6, NTF3, PTPRZ1, MAP1B, ITGA1, NR4A2, DPYSL5, NTNG1, DOCK7, LMX1A, ISL1, DVL1, EPHA7, S100B, NEDD4, MAP2, JAK2, APBB2, PTENP1, FEZ2, MYH10 MEF2C, UTRN, FOXO4, TTN, CXADR, CXCL10, ZFP91, APP, ATG5, RHOA, MKX, MKL2, JPH1, ACADM, RXRB, ARID5B, CHODL, MBNL1, SIX4, TNNT2, BVES, SMTN, VGLL2, PDGFRB, SGCE, CXADRP2, SERP1, CAV2, CAV1, EID2, CTF1, MRAS, TNC, TIPARP, muscle organ CACNB2, FKBP1A, TPM1, ITGB1, FAM65B, LIF, 73 1.52 3.52E-04 8.40E-01 3.91E-02 development MTM1, GPHN, SPEG, DMD, PPP3CB, OBSL1, EMD, UNC45B, FKTN, ACTC1, EVC, NF1, MET, LMNA, IGF1, CENPF, MSTN, CBY1, CSRP2, SIRT1, FOXP1, FXR1, DVL1, FOXP2, MEOX2, TSC1, LAMA5, MAPK14, PLN, SVIL, PTCD2, MYH11, PTENP1, MYH10 protein ubiquitination NEDD4, MAP3K1, DDB1, TRIM32, UBE4B, MDM2, during ubiquitin- 12 0.25 3.74E-04 8.57E-01 4.05E-02 RNF217, SIAH1, PARK2, SMURF1, LNX1, OS9 dependent protein catabolic process
１１８
Term Genes Count % P-Value Bonferroni FDR
MEF2C, ZNF781, RORC, NAA16, ZNF254, CTNNB1, ZNF778, APP, EPC2, FLI1, PHTF2, FOXF2, TIGD2, PHTF1, ZNF397, PATZ1, ZNF395, TIGD6, TBPL1, CCAR1, ZNF43, ZNF641, PTPRK, L3MBTL4, ZNF45, RCOR3, ZNF644, RXRB, TAF4B, ZNF507, ZHX1, ZNF648, ZNF501, HMG20A, HNF4G, ZNF793, ZNF37A, MAPK1, ZNF235, ZNF784, PTRF, JUN, SMARCAL1, FOXG1, ZZZ3, VGLL2, VGLL4, IRAK1BP1, CRTC3, ZNF614, ZNF517, ZNF131, ZNF511, ZNF230, MYBL1, ZNF514, ZNF513, ZNF229, ARX, T, ZNF124, ZNF71, ZNF69, TCF7, ESRRA, NTF3, ESRRB, TGFBR1, ZNF66, KLF11, ASXL1, L3MBTL, ESRRG, MSTN, ZNF498, ZSCAN2, SFMBT1, ZNF629, ZNF217, UBA3, PPRC1, SMURF2, RERE, ZNF19, BACH1, ELF1, HTATIP2, ZNF532, ELF5, EZH1, ZNF530, ZNF295, ZNF676, ZNF16, ZNF678, YBX1, YBX2, ZNF677, CCNE1, ZNF682, CREG1, ZNF491, ZNF540, ZNF732, MYB, SIK1, GATAD1, FGF2, ATF7IP, ZNF281, ZNF33A, ZNF547, ZNF479, GMEB2, ZNF141, TLE4, ZNF143, MXD1, ZNF549, TTF2, TAF11, ZNF138, SS18, TAF13, ZNF134, EREG, RIPK1, NAB1, C19ORF2, ZNF277, RUVBL2, KCNH8, KCNH2, ZNF33B, CLOCK, KCNH5, SCML4, ZNF275, ZNF554, ZNF274, ZNF468, ZNF558, ZNF557, CREM, ZNF367, MYCBP2, ZNF169, ZNF473, ZSCAN23, FOXD2, ZNF561, ZNF562, ZNF470, FOXD4, BRMS1L, ZNF266, SIM2, ZNF267, IL6, ZNF565, ZFP1, IGF1, ELAVL2, LMX1A, TRIM24, WWTR1, ZNF662, TP73, RLF, MNAT1, PHF17, RPS6KA4, PKNOX1, HNRNPUL1, BNC2, RBAK, ZBTB4, ZNF460, TCEB3, ZNF763, ZNF462, ZNF765, NR5A2, ZNF571, ZBTB1, ZNF257, ZNF572, DNM2, HMX2, LMO3, ZNF580, ZNF451, CNOT3, CNOT1, PDX1, TCEAL7, CNOT7, RBM9, NR2E1, ZIC3, TCEAL4, TGFB1, IL11, RCBTB1, GTF2E1, GTF2E2, RNF141, DPRXP4, CDKN2A, SMARCD2, MIER1, MIER3, PSIP1, ZNF442, RPS27A, ZNF449, ZNF441, ZNF440, PKIG, ARID1A, SIX5, SIX4, regulation of 14.2 ARID1B, GRHL1, CSDA, DDIT3, ASCL1, HIF1A, 683 4.15E-04 8.85E-01 4.40E-02 transcription 0 SMARCE1, TFAP2B, MGA, TFAP2D, NFE2L2, LRPPRC, ASCL4, XRN2, SMARCA4, CAMTA1, HMGB1, HMGB2, EID2, C14ORF169, ATF1, ARNT, NR2C1, ZNF324, OVOL2, ZNF326, TAF9, SSX5, HELLS, TAF2, TAF4, TRIP4, NR4A2, LMCD1, ARID3B, WHSC1, WHSC2, ESX1, HDAC5, CDKN1B, HDAC1, EBF3, DYRK1B, EBF2, EBF1, PNRC1, GTF2F2, HIVEP2, HDAC6, ZNF208, E2F3, RSF1, E2F5, ARID4A, E2F6, E2F7, DEDD, ARID4B, PAX6, RHOQ, ZKSCAN1, CTCF, ZKSCAN2, RPS3, ZNF207, GTF2A1, PRMT6, RTF1, HEY2, GTF2A2, PAX8, RHOA, ZNF407, LRRFIP1, PDE8A, KDM5B, KDM5C, NFX1, SSBP2, ZNF280D, ARID5B, OTX1, ZFX, OTX2, CDK8, NCOA7, TOPORS, PADI4, RB1, HMGA2, HLTF, ZFP28, HMGA1, PURA, NCOA3, HOXC13, JMJD1C, WASL, LCOR, ACVR1, BTAF1, ABLIM2, DPF3, BCLAF1, IRX6, STON1, FRYL, IRX2, NR3C2, ARID2, MACC1, HIC1, CHD9, HIC2, PRDM15, TSC22D2, PRDM10, CHD1, MYCBP, KDM3B, CHD6, CHD4, MAF, WDTC1, CEBPG, SFRS13A, ISL1, HIF3A, KDM4C, JAK2, ID4, KDM4A, TBL1X, EIF2C2, HKR1, CDX2, GDF6, SNIP1, SOHLH2, RAB1A, ZFP91, SIN3A, CSDAP1, ZFP90, ABRA, CREB3L1, SAP30L, IFNK, CREB3L3, CRY1, PITX2, TWIST1, RARG, STRN3, EMX2, C14ORF43, PPARGC1B, FRY, PRDM8, HES1, PRDM7, UHRF1, BAZ1A, PARP14, PRDM6, VEGFA, PRDM5, PRDM2, LRCH4, PRDM1, SUDS3, HOXA13, TADA3, GPBP1L1, SUMO1P3, HOXA11, TAF9B, HOXB13, TADA1, DUXA, ALS2CR8, LIF, TCF21, TCF20, DMD, PBRM1, LHX5, LHX8, LHX9, NR1H4, HNRNPAB, NKX2-3, BMP4, IKZF5, KLF5, AEBP2, IKZF4, NRBF2, IKZF2, MLL, IKZF1, KLF9, SMAD5, RYBP, ZBTB41, EN1, PMF1, EN2, ABCG4, DLX3, NOTCH2, DLX2, RNF6, NR1I3, TULP4, ZFHX4, DMTF1, MLX, JAZF1, SUPT16H, HOPX, TCF19, ZFHX2, NCOR2, KLF4, KLF3, CCNT2, GTF3A, TCEANC, ZBTB33, ZBTB34, TBX22, PPARG, ZBTB39,
１１９
Term Genes Count % P-Value Bonferroni FDR
ZEB2, NFKB1, ZEB1, HSBP1, GLI2, CAMKK2, ZBTB38, BLZF1, MBTD1, NR2F6, MKX, DEDD2, ZCCHC12, ICAM1, POGZ, ZNF354A, ZNF354B, ECSIT, ZBTB24, FOXR2, FOXD4L3, MED4, MED8, ASH1L, LIN54, SRCAP, FOXD4L6, FOXD4L5, ETV7, ZBTB10, ZBTB11, BDP1, EHF, SEC14L2, STAT6, STAT4, PGBD1, NR1D2, RB1CC1, BCL11A, HBP1, BCL6, BAZ2B, TLX1, ETV3, MLLT3, TBX6, POLR3F, NLK, TBX4, AFF4, YWHAB, ILF3, AFF1, STAT1, SNAI3, MEOX2, PPP1R8, YAF2, JMJD6, MAPK14, YWHAQ, NEUROD2, NHLH2, NEUROD4, APBB2, MORF4L1, THRB, MORF4L2, MAEL, CASK, HOXD1, FOXO3, FOXO4, CBX7, LASS6, ZNF829, PNN, GATA1, HOXC8, MLL5, CASP8AP2, MYOCD, TARDBP, GATA3, MYST2, AKIRIN2, MYST4, CIITA, SATB1, SATB2, GTF2IRD2, FOXN2, ZNF813, ARNTL, TRERF1, AHR, SLTM, PTHLH, ZNF195, TRIM33, GTF2IRD1, TIAL1, RIPK2, ERC1, ZNF845, TSHZ1, ONECUT1, SOX5, ELK1, SOX7, SP110, LIN28A, LIN28B, TRIM66, HOXA2, FOXQ1, ELK4, NPM1, HOXA9, RUNX1, RUNX2, SLC30A9, RNF14, RFX8, ZMYM2, MAFB, RFX6, RFX7, BRCA2, ATAD2, SNW1, FOXP4, FOXP1, SREBF2, FOXP2, MSL3, PPIE, NEDD4, HOXB5, LASS2, TMPO, PHF6, ZNF84, PRRX1, PRRX2, NFATC2IP, FUBP1, PCGF5, PCGF2, FUBP3, PCGF3, PCGF6, MKL2, ZNF720, PSMD9, EGR1, ZNF93, IRAK1, ELP2, KHDRBS2, SP100, EGR2, ZNF90, DMRT3, SOX12, RUNX1T1, RING1, DMRT2, FOXJ3, DMRTB1, NRIP1, GZF1, BTG2, HIPK1, CD80, NRL, ZNF716, KRTAP1-1, MDM2, NRK, MDM4, ZFP161, C1D, ZNF808, SMARCAD1, ING3, CTCFL, PRKDC, CTNND1, HCFC2, C5ORF41, CCDC59, TNFRSF1A, NPAS3, CDYL, C11ORF9, MAP3K1, POU2F3, POU2F2, POU3F4, POU2F1, POU3F2, GFI1, ZNF605, ERG, KAT2B, ZNF705A, L3MBTL3, PSRC1, SOX30, HMBOX1, ZNF705D, CENPF, SIRT5, CBY1, SAP30BP, SIRT1, MLF1IP, IRF6, SP3, DR1, THRAP3, SP4, IRF8, SETD8, TSSK4, CRK NRP2, CCKAR, NRP1, MYO7A, PAX6, GLI2, NR2E1, CXCL12, NRCAM, APP, SLC1A3, ANK3, CXCR4, RPS27A, CDH23, EGR2, EFNB3, NRXN3, OTX2, KIF5C, TBCE, CTNNA2, SLITRK2, HES1, NCAM2, SLITRK4, FOXG1, OPHN1, VCAN, EFNA5, RELN, SIAH1, cell morphogenesis CNTN4, KALRN, DCC, RAB3A, CDK5R1, RTN4RL1, involved in neuron 72 1.50 4.46E-04 9.02E-01 4.63E-02 DRD2, PKHD1, HPRT1, CDH4, EPHB1, MYCBP2, ARX, differentiation ALCAM, HOXA2, TNR, BCL2, NUMB, RAC1, PAFAH1B1, B3GNT2, NEFL, APC, PARD6B, NTF3, PTPRZ1, MAP1B, NTNG1, DPYSL5, NR4A2, DOCK7, LMX1A, ISL1, DVL1, EPHA7, S100B, JAK2, APBB2, FEZ2, MYH10 JUB, PDGFB, IL6ST, TACR1, SNCA, PAX6, JAG2, RPS6KB1, CXCL12, TGFB1, CXCL10, VCL, AGTR2, CXCR4, GAB1, ROBO4, FGF2, EGFR, ICAM1, PTPRK, GTPBP4, ADAM10, VASH1, MAPK1, SPAG9, BBS2, HIF1A, CLIC4, VEGFA, PRR5-ARHGAP8, PDGFRB, regulation of TSHR, DRD1, HS3ST5, ONECUT1, DRD2, ENPP2, 67 1.39 4.84E-04 9.19E-01 4.91E-02 locomotion CSF1, ABHD2, CBLL1, TPM1, BCL2, MAP3K1, RAC1, ANGPTL3, LAMB1, PIK3R1, APC, SCG2, COL18A1, SELP, PARD6B, IL6, FLT1, NF1, IGF1, ITGA2, FURIN, HDAC5, LAMA4, LAMA5, PTP4A1, JAK2, TRIP6, IGFBP3, PTENP1, HDAC6 NCBP2, SRP14, NCBP1, EIF2C2, CPEB2, EIF5B, EIF5A, EIF2A, CPEB1, YBX2, APP, RBM8A, PIWIL1, PUM1, QKI, EIF2B4, SAMD4A, ACO1, CDK4, BOLL, NCK2, 1.06 regulation of MAPK1, EIF4G3, EIF2AK1, MTRF1, EIF5A2, EIF2C3, 51 029 4.85E-04 9.20E-01 4.83E-02 translation EIF2AK4, EIF2C4, EIF4E3, IGF2BP2, IGF2BP3, GCN1L1, 1 TNRC6C, MTPN, SEPSECS, TNRC6B, TNRC6A, IL6, UPF1, PAIP2, SRP14P1, PAIP1, IREB2, ITGA2, ETF1, EIF4B, ATXN2, EIF4E, TSC1, DIO2, MIF4GD
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