DOCSLIB.ORG

Induction of Invasive Mouse Skin Carcinomas in Transgenic Mice with Mutations in Both H-Ras and P53

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Induction of Invasive Mouse Skin Carcinomas in Transgenic Mice with Mutations in Both H-Ras and P53 Induction of Invasive Mouse Skin Carcinomas in Transgenic Mice with Mutations in Both H-ras and p53 Zhongqiu Zhang,1 Ruisheng Yao,1 Jie Li,1 Yian Wang,1 Charles W. Boone,2 Ronald A. Lubet,2 and Ming You1 1Department of Surgery and The Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri and 2Chemoprevention Branch, National Cancer Institute, Bethesda, Maryland Abstract kinase pathways. The present study provides Synergistic interaction between H-ras and p53 were the first in vivo evidence that a germ line p53 systematically examined during skin tumorigenesis. mutation and activated H-ras act synergistically to Concurrent expression of an activated H-ras gene and a profoundly enhance tumor progression. mutant p53 gene was accomplished by crossing (Mol Cancer Res 2005;3(10):563–74) p53Val135/wt mice with TGÁAC mice. Topical application to wild-type mice with benzo(a)pyrene (BaP) alone Introduction produced f26% skin tumor incidence, whereas BaP Nonmelanoma skin cancer is the most common cancer in the treatment of p53wt/wtHrasTGÁAC/wt, p53Val135/wtHraswt/wt, United States. Eighty percent of these skin cancers are basal cell and p53Val135/wtHrasTGÁAC/wt mice produced a 75%, 77%, carcinomas and 20% are squamous cell carcinomas (SCC; and 100% incidence of skin tumors, respectively. An ref. 1). SCCs of the skin develop through a multistep process average of 0.33 tumor per mouse was observed in that involves activation of proto-oncogenes and/or inactivation wt/wt wt/wt f wild-type (p53 Hras ) mice, whereas 1.54, of tumor suppressor genes in keratinocytes. The p53 tumor 1.96, and 3.08 tumors per mouse were seen in wt/wt TGÁAC/wt Val135/wt wt/wt suppressor gene is mutated in numerous human cancers, BaP-treated p53 Hras , p53 Hras , f Val135/wt TGÁAC/wt including 50% of human skin cancers (2). Forty-six percent and p53 Hras mice, respectively. The and 31% of human primary SCCs and basal cell carcinomas, effects on total tumor volume were even more striking respectively, contain H-ras mutations (3). Similar to human with 7-, 48-, and 588-fold increases in tumor skin cancer, chemically induced mouse skin cancers are caused volume compared with wild-type (p53wt/wtHraswt/wt) wt/wt TGÁAC/wt Val135/wt wt/wt by the presence of multiple genetic alterations, including in p53 Hras , p53 Hras , and activation of proto-oncogenes and loss of tumor suppressor p53Val135/wtHrasTGÁAC/wt mice, respectively. wt/wt wt/wt genes (4). Activated H-ras proto-oncogene has been found in Histopathologically, all tumors from p53 Hras >50% of chemically induced mouse skin papillomas and SCCs mice were either papillomas or well-differentiated (5). Inactivation of several tumor suppressor genes, including squamous cell carcinomas, whereas the tumors p53, p15, and p16, occurs principally in late-stage tumors, such wt/wt TGÁAC/wt Val135/wt wt/wt in p53 Hras , p53 Hras , and as SCCs (p53) or spindle carcinomas (p15 and p16). p53 Val135/wt TGÁAC/wt p53 Hras mice were principally squamous mutations have been detected in both chemically induced and cell carcinomas with varying degree of invasiveness. UV-induced mouse skin tumors (6, 7). Loss of heterozygosity Val135/wt TGÁAC/wt Particularly, tumors in p53 Hras mice studies have been conducted to identify the regions of frequent exhibited the most rapid growth and the extreme form of allele loss in skin tumors of various F1 hybrid mouse strains to tumor invasion. Microarray analysis revealed that localize important tumor suppressor genes (8). Loci were most 135 dominant-negative p53 (Val ) and activated H-ras commonly detected on chromosomes 4, 6, 7, and 11 (8). affected several cellular processes involved in Chromosome 4 was shown to harbor p15 and p16 genes, tumorigenesis possibly through its effects on apoptosis, whereas chromosome 11 contains the p53 gene. These losses of cell cycle arrest, and Ras-mitogen-activated protein heterozygosity were only detected in SCCs (chromosome 11) and spindle cell carcinomas (chromosomes 4, 6, and 7), suggesting a role for resident tumor suppressor loci in the Received 8/19/05; revised 9/15/05; accepted 9/16/05. malignant conversion of mouse skin tumors. Alterations in the Grant support: NIH grants R01CA58554 and R01CA78797. expression of several genes have been reported in mouse skin The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in carcinogenesis (9-12). For example, overexpression of cyclin accordance with 18 U.S.C. Section 1734 solely to indicate this fact. D1 was observed in chemically induced papillomas and SCCs Note: Z. Zhang and R. Yao contributed equally to this work. Requests for reprints: Ming You, Department of Surgery and The Alvin J. (11, 12). In UV-treated mice, c-fos,c-myc, and H-ras genes Siteman Cancer Center, Washington University School of Medicine, 660 Euclid were overexpressed in both exposed skin and skin tumors (9). Avenue, Box 8109, St. Louis, MO 63110. Phone: 314-362-9294; Fax: 314-362- Several transgenic mouse models for skin carcinogenesis 9366. E-mail: [email protected] Copyright D 2005 American Association for Cancer Research. have been developed (4). One of these models is the v-H-ras doi:10.1158/1541-7786.MCR-05-0144 transgenic TGÁAC mouse line. TGÁAC mice were created by the Mol Cancer Res 2005;3(10). October 2005 563 Downloaded from mcr.aacrjournals.org on October 1, 2021. © 2005 American Association for Cancer Research. 564 Zhang et al. introduction of an activated v-H-ras transgene linked to a ~-globin promoter into FVB/N mice (13, 14). Consequently, the TGÁAC mouse is a genetically initiated model for skin carcinogenesis that has a short latency period and a high susceptibility for skin papilloma induction by tumor promoters or carcinogens (15). Interestingly, this mouse model has been used to screen for agents with carcinogenic or tumor-promoting properties. Another potential tumor model for mouse skin carcinogenesis is the p53 transgenic mouse. Inactivation of the p53 gene in the germ line of mice by a dominant-negative transgene has made possible research with a model analogous in many respects to the human inherited cancer predisposition, Li-Fraumeni syndrome. Germ line p53 mutations were found to significantly increase the number of skin tumors and the propensity for multiple tumor development when treated with UV radiation (16). p53 transgenic mice are also a potential model for human Li-Fraumeni syndrome, because patients with this disease usually carry a germ line p53 mutation that predisposes them to multiple primary tumors, including breast and lung cancer, as well as diverse types of soft-tissue sarcomas and carcinomas (17). In the present study, we investigated the role of germ line H-ras and p53 mutations in skin tumorigenesis in vivo.We hypothesized that the compound transgenic mice carrying activated H-ras and dominant-negative p53 could greatly accelerate mouse skin tumorigenesis because the mutant p53 acts synergistically with mutant ras to cause malignant transformation of primary rat embryo cells (18). In addition, the altered gene expression associated with H-ras and p53 FIGURE 1. Skin tumor induction in p53Val135/wtHrasTGÁAC/wt mice by topical application of BaP. A. Cumulative percentage of mice with skin genes was evaluated in normal skin and skin SCC following tumors in relation to time (weeks) after the onset of treatment. B. carcinogen exposure. Effects of genotypes on skin tumor multiplicity and tumor load. Six- to 8-week-old females were used. There were 27 p53wt/wtHraswt/wt,28p53wt/wt HrasTGÁAC/wt, 26 p53Val135/wtHraswt/wt, and 26 p53Val135/wtHrasTGÁAC/wt mice. Bars, SD. *, P < 0.05, Student’s t test. Results To examine the interactions between p53 and ras genes in encrusted ulcers or massive necrosis within the tumors. Some of the development of skin SCCs, we crossed p53 transgenic mice them exhibited a cauliflower-like appearance. In some advanced Val135/wt TGÁAC/wt with v-H-ras transgenic TGÁAC mice. All F1 mice were treated cases in the p53 Hras , carcinomas exhibited an with a topical application of benzo(a)pyrene (BaP) alone twice extremely rapid growth rate. For example, carcinomas in Fig. weekly (100 nmol/mouse) for 5 months. As shown in Fig. 1A, 2D developed to the sizes shown in 1 to 2 weeks without any Val135/wt wt/ treatment of (TGÁAC Â p53 )F1 wild-type (p53 apparent precursor lesion. The surfaces of these tumors were wtHraswt/wt) mice with BaP produced a 26% skin tumor irregular and they had areas of necrosis and hemorrhage. incidence, whereas treatment of p53wt/wtHrasTGÁAC/wt, A total of 9 tumors from p53wt/wtHraswt/wt wild-type p53Val135/wtHraswt/wt, and p53Val135/wtHrasTGÁAC/wt mice yielded mice, 43 tumors from p53wt/wtHrasTGÁAC/wt mice, 50 tumors tumor incidences of 75%, 77%, and 100%, respectively. from p53Val135/wtHraswt/wt mice, and 76 tumors from p53Val135/wt Interestingly, p53 transgenic mice, TGÁAC transgenic mice, HrasTGÁAC/wt mice were examined pathologically. The and compound transgenic mice developed early-onset SCC. majority of the skin tumors found in wild-type (p53wt/wt This was particularly striking for double transgenic mice, with Hraswt/wt) mice were papillomas or well-differentiated SCCs, the first carcinoma appearing after 8 weeks of treatment consistent with numerous previous studies (6, 19). As shown (Fig. 1A). Furthermore, an average of 0.33 tumor per in Fig. 2E and G, these tumors are characterized by well- mouse was observed in wild-type (p53wt/wtHraswt/wt) mice, differentiated cells and monomorphic growth pattern. In whereas f1.54, 1.96, and 3.08 tumors per mouse were contrast, f60% of tumors from p53wt/wtHrasTGÁAC/wt mice, observed in p53wt/wtHrasTGÁAC/wt, p53Val135/wtHraswt/wt, and 70% of tumors from p53Val135/wtHraswt/wt mice, and 100% from p53Val135/wtHrasTGÁAC/wt mice, respectively (Fig.
Load more

Recommended publications
  • Modes of Interaction of KMT2 Histone H3 Lysine 4 Methyltransferase/COMPASS Complexes with Chromatin
    cells Review Modes of Interaction of KMT2 Histone H3 Lysine 4 Methyltransferase/COMPASS Complexes with Chromatin Agnieszka Bochy ´nska,Juliane Lüscher-Firzlaff and Bernhard Lüscher * ID Institute of Biochemistry and Molecular Biology, Medical School, RWTH Aachen University, Pauwelsstrasse 30, 52057 Aachen, Germany; [email protected] (A.B.); jluescher-fi[email protected] (J.L.-F.) * Correspondence: [email protected]; Tel.: +49-241-8088850; Fax: +49-241-8082427 Received: 18 January 2018; Accepted: 27 February 2018; Published: 2 March 2018 Abstract: Regulation of gene expression is achieved by sequence-specific transcriptional regulators, which convey the information that is contained in the sequence of DNA into RNA polymerase activity. This is achieved by the recruitment of transcriptional co-factors. One of the consequences of co-factor recruitment is the control of specific properties of nucleosomes, the basic units of chromatin, and their protein components, the core histones. The main principles are to regulate the position and the characteristics of nucleosomes. The latter includes modulating the composition of core histones and their variants that are integrated into nucleosomes, and the post-translational modification of these histones referred to as histone marks. One of these marks is the methylation of lysine 4 of the core histone H3 (H3K4). While mono-methylation of H3K4 (H3K4me1) is located preferentially at active enhancers, tri-methylation (H3K4me3) is a mark found at open and potentially active promoters. Thus, H3K4 methylation is typically associated with gene transcription. The class 2 lysine methyltransferases (KMTs) are the main enzymes that methylate H3K4. KMT2 enzymes function in complexes that contain a necessary core complex composed of WDR5, RBBP5, ASH2L, and DPY30, the so-called WRAD complex.
    [Show full text]
  • A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus
    Page 1 of 781 Diabetes A Computational Approach for Defining a Signature of β-Cell Golgi Stress in Diabetes Mellitus Robert N. Bone1,6,7, Olufunmilola Oyebamiji2, Sayali Talware2, Sharmila Selvaraj2, Preethi Krishnan3,6, Farooq Syed1,6,7, Huanmei Wu2, Carmella Evans-Molina 1,3,4,5,6,7,8* Departments of 1Pediatrics, 3Medicine, 4Anatomy, Cell Biology & Physiology, 5Biochemistry & Molecular Biology, the 6Center for Diabetes & Metabolic Diseases, and the 7Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202; 2Department of BioHealth Informatics, Indiana University-Purdue University Indianapolis, Indianapolis, IN, 46202; 8Roudebush VA Medical Center, Indianapolis, IN 46202. *Corresponding Author(s): Carmella Evans-Molina, MD, PhD ([email protected]) Indiana University School of Medicine, 635 Barnhill Drive, MS 2031A, Indianapolis, IN 46202, Telephone: (317) 274-4145, Fax (317) 274-4107 Running Title: Golgi Stress Response in Diabetes Word Count: 4358 Number of Figures: 6 Keywords: Golgi apparatus stress, Islets, β cell, Type 1 diabetes, Type 2 diabetes 1 Diabetes Publish Ahead of Print, published online August 20, 2020 Diabetes Page 2 of 781 ABSTRACT The Golgi apparatus (GA) is an important site of insulin processing and granule maturation, but whether GA organelle dysfunction and GA stress are present in the diabetic β-cell has not been tested. We utilized an informatics-based approach to develop a transcriptional signature of β-cell GA stress using existing RNA sequencing and microarray datasets generated using human islets from donors with diabetes and islets where type 1(T1D) and type 2 diabetes (T2D) had been modeled ex vivo. To narrow our results to GA-specific genes, we applied a filter set of 1,030 genes accepted as GA associated.
    [Show full text]
  • 4-6 Weeks Old Female C57BL/6 Mice Obtained from Jackson Labs Were Used for Cell Isolation
    Methods Mice: 4-6 weeks old female C57BL/6 mice obtained from Jackson labs were used for cell isolation. Female Foxp3-IRES-GFP reporter mice (1), backcrossed to B6/C57 background for 10 generations, were used for the isolation of naïve CD4 and naïve CD8 cells for the RNAseq experiments. The mice were housed in pathogen-free animal facility in the La Jolla Institute for Allergy and Immunology and were used according to protocols approved by the Institutional Animal Care and use Committee. Preparation of cells: Subsets of thymocytes were isolated by cell sorting as previously described (2), after cell surface staining using CD4 (GK1.5), CD8 (53-6.7), CD3ε (145- 2C11), CD24 (M1/69) (all from Biolegend). DP cells: CD4+CD8 int/hi; CD4 SP cells: CD4CD3 hi, CD24 int/lo; CD8 SP cells: CD8 int/hi CD4 CD3 hi, CD24 int/lo (Fig S2). Peripheral subsets were isolated after pooling spleen and lymph nodes. T cells were enriched by negative isolation using Dynabeads (Dynabeads untouched mouse T cells, 11413D, Invitrogen). After surface staining for CD4 (GK1.5), CD8 (53-6.7), CD62L (MEL-14), CD25 (PC61) and CD44 (IM7), naïve CD4+CD62L hiCD25-CD44lo and naïve CD8+CD62L hiCD25-CD44lo were obtained by sorting (BD FACS Aria). Additionally, for the RNAseq experiments, CD4 and CD8 naïve cells were isolated by sorting T cells from the Foxp3- IRES-GFP mice: CD4+CD62LhiCD25–CD44lo GFP(FOXP3)– and CD8+CD62LhiCD25– CD44lo GFP(FOXP3)– (antibodies were from Biolegend). In some cases, naïve CD4 cells were cultured in vitro under Th1 or Th2 polarizing conditions (3, 4).
    [Show full text]
  • Expression Profiling of KLF4
    Expression Profiling of KLF4 AJCR0000006 Supplemental Data Figure S1. Snapshot of enriched gene sets identified by GSEA in Klf4-null MEFs. Figure S2. Snapshot of enriched gene sets identified by GSEA in wild type MEFs. 98 Am J Cancer Res 2011;1(1):85-97 Table S1: Functional Annotation Clustering of Genes Up-Regulated in Klf4 -Null MEFs ILLUMINA_ID Gene Symbol Gene Name (Description) P -value Fold-Change Cell Cycle 8.00E-03 ILMN_1217331 Mcm6 MINICHROMOSOME MAINTENANCE DEFICIENT 6 40.36 ILMN_2723931 E2f6 E2F TRANSCRIPTION FACTOR 6 26.8 ILMN_2724570 Mapk12 MITOGEN-ACTIVATED PROTEIN KINASE 12 22.19 ILMN_1218470 Cdk2 CYCLIN-DEPENDENT KINASE 2 9.32 ILMN_1234909 Tipin TIMELESS INTERACTING PROTEIN 5.3 ILMN_1212692 Mapk13 SAPK/ERK/KINASE 4 4.96 ILMN_2666690 Cul7 CULLIN 7 2.23 ILMN_2681776 Mapk6 MITOGEN ACTIVATED PROTEIN KINASE 4 2.11 ILMN_2652909 Ddit3 DNA-DAMAGE INDUCIBLE TRANSCRIPT 3 2.07 ILMN_2742152 Gadd45a GROWTH ARREST AND DNA-DAMAGE-INDUCIBLE 45 ALPHA 1.92 ILMN_1212787 Pttg1 PITUITARY TUMOR-TRANSFORMING 1 1.8 ILMN_1216721 Cdk5 CYCLIN-DEPENDENT KINASE 5 1.78 ILMN_1227009 Gas2l1 GROWTH ARREST-SPECIFIC 2 LIKE 1 1.74 ILMN_2663009 Rassf5 RAS ASSOCIATION (RALGDS/AF-6) DOMAIN FAMILY 5 1.64 ILMN_1220454 Anapc13 ANAPHASE PROMOTING COMPLEX SUBUNIT 13 1.61 ILMN_1216213 Incenp INNER CENTROMERE PROTEIN 1.56 ILMN_1256301 Rcc2 REGULATOR OF CHROMOSOME CONDENSATION 2 1.53 Extracellular Matrix 5.80E-06 ILMN_2735184 Col18a1 PROCOLLAGEN, TYPE XVIII, ALPHA 1 51.5 ILMN_1223997 Crtap CARTILAGE ASSOCIATED PROTEIN 32.74 ILMN_2753809 Mmp3 MATRIX METALLOPEPTIDASE
    [Show full text]
  • Supplemental Table S1 (A): Microarray Datasets Characteristics
    Supplemental table S1 (A): Microarray datasets characteristics Title Summary Samples Literature ref. GEO ref. Acquisition of granule Gene expression profiling of 27 (1) GSE 11859 neuron precursor identity cerebellar tumors generated and Hedgehog‐induced from various early and late medulloblastoma in mice. stage CNS progenitor cells Medulloblastomas derived Study of mouse 5 (2) GSE 7212 from Cxcr6 mutant mice medulloblastoma in response respond to treatment with to inhibitor of Smoothened a Smoothened inhibitor Expression profiles of Identification of distinct classes 10 (3) GSE 9299 mouse medulloblastoma of up‐regulated or down‐ 339 & 340 regulated genes during Hh dependent tumorigenesis Genetic alterations in Identification of differently 10 (4) GSE 6463 mouse medulloblastomas expressed genes among CGNPs 339 & and generation of tumors and CGNPs transfected with 340 from cerebellar granule retroviruses that express nmyc neuron precursors or cyclin‐d1 Patched heterozygous Analysis of granule cell 14 (5) GSE 2426 model of medulloblastoma precursors, pre‐neoplastic cells, GDS1110 and tumor cells 1. Schuller U, Heine VM, Mao J, Kho AT, Dillon AK, Han YG, et al. Acquisition of granule neuron precursor identity is a critical determinant of progenitor cell competence to form Shh‐induced medulloblastoma. Cancer Cell 2008;14:123‐134. 2. Sasai K, Romer JT, Kimura H, Eberhart DE, Rice DS, Curran T. Medulloblastomas derived from Cxcr6 mutant mice respond to treatment with a smoothened inhibitor. Cancer Res 2007;67:3871‐3877. 3. Mao J, Ligon KL, Rakhlin EY, Thayer SP, Bronson RT, Rowitch D, et al. A novel somatic mouse model to survey tumorigenic potential applied to the Hedgehog pathway. Cancer Res 2006;66:10171‐10178.
    [Show full text]
  • 1714 Gene Comprehensive Cancer Panel Enriched for Clinically Actionable Genes with Additional Biologically Relevant Genes 400-500X Average Coverage on Tumor
    xO GENE PANEL 1714 gene comprehensive cancer panel enriched for clinically actionable genes with additional biologically relevant genes 400-500x average coverage on tumor Genes A-C Genes D-F Genes G-I Genes J-L AATK ATAD2B BTG1 CDH7 CREM DACH1 EPHA1 FES G6PC3 HGF IL18RAP JADE1 LMO1 ABCA1 ATF1 BTG2 CDK1 CRHR1 DACH2 EPHA2 FEV G6PD HIF1A IL1R1 JAK1 LMO2 ABCB1 ATM BTG3 CDK10 CRK DAXX EPHA3 FGF1 GAB1 HIF1AN IL1R2 JAK2 LMO7 ABCB11 ATR BTK CDK11A CRKL DBH EPHA4 FGF10 GAB2 HIST1H1E IL1RAP JAK3 LMTK2 ABCB4 ATRX BTRC CDK11B CRLF2 DCC EPHA5 FGF11 GABPA HIST1H3B IL20RA JARID2 LMTK3 ABCC1 AURKA BUB1 CDK12 CRTC1 DCUN1D1 EPHA6 FGF12 GALNT12 HIST1H4E IL20RB JAZF1 LPHN2 ABCC2 AURKB BUB1B CDK13 CRTC2 DCUN1D2 EPHA7 FGF13 GATA1 HLA-A IL21R JMJD1C LPHN3 ABCG1 AURKC BUB3 CDK14 CRTC3 DDB2 EPHA8 FGF14 GATA2 HLA-B IL22RA1 JMJD4 LPP ABCG2 AXIN1 C11orf30 CDK15 CSF1 DDIT3 EPHB1 FGF16 GATA3 HLF IL22RA2 JMJD6 LRP1B ABI1 AXIN2 CACNA1C CDK16 CSF1R DDR1 EPHB2 FGF17 GATA5 HLTF IL23R JMJD7 LRP5 ABL1 AXL CACNA1S CDK17 CSF2RA DDR2 EPHB3 FGF18 GATA6 HMGA1 IL2RA JMJD8 LRP6 ABL2 B2M CACNB2 CDK18 CSF2RB DDX3X EPHB4 FGF19 GDNF HMGA2 IL2RB JUN LRRK2 ACE BABAM1 CADM2 CDK19 CSF3R DDX5 EPHB6 FGF2 GFI1 HMGCR IL2RG JUNB LSM1 ACSL6 BACH1 CALR CDK2 CSK DDX6 EPOR FGF20 GFI1B HNF1A IL3 JUND LTK ACTA2 BACH2 CAMTA1 CDK20 CSNK1D DEK ERBB2 FGF21 GFRA4 HNF1B IL3RA JUP LYL1 ACTC1 BAG4 CAPRIN2 CDK3 CSNK1E DHFR ERBB3 FGF22 GGCX HNRNPA3 IL4R KAT2A LYN ACVR1 BAI3 CARD10 CDK4 CTCF DHH ERBB4 FGF23 GHR HOXA10 IL5RA KAT2B LZTR1 ACVR1B BAP1 CARD11 CDK5 CTCFL DIAPH1 ERCC1 FGF3 GID4 HOXA11 IL6R KAT5 ACVR2A
    [Show full text]
  • Bioinformatic Analysis of Autism Positional Candidate Genes Using Biological Databases and Computational Gene Network Prediction
    Genes, Brain and Behavior (2003) 2: 303–320 Copyright # Blackwell Munksgaard 2003 Bioinformatic analysis of autism positional candidate genes using biological databases and computational gene network prediction A. L. Yonan†,‡, A. A. Palmer†, K. C. Smith†, inform studies of autism, and to illustrate and explore I. Feldman†,††, H. K. Lee†, J. M. Yonan§, the increasing potential of bioinformatic approaches as † †,†† *,†,‡, S. G. Fischer , P. Pavlidis and T. C. Gilliam { a compliment to linkage analysis. Keywords: 17q, AGRE sample, autism, association studies, †Columbia Genome Center, Columbia University, New York, bioinformatics, candidate genes ‡ Department of Genetics and Development, Columbia University, Received 30 June 2003, revised 20 August 2003, accepted New York, for publication 21 August 2003 ¶Department of Psychiatry, Columbia University and New York State Psychiatric Institute, New York, §Division of Molecular Genetics, Departments of Pediatrics and Medicine, Columbia University, New York, Autism is a pervasive neurodevelopmental disorder that ††Department of Biomedical Informatics, Columbia University, severely impairs development of normal social and emotional New York, USA interactions and related forms of communication. Disease *Corresponding author: T. C. Gilliam, Columbia Genome Center, symptoms characteristically include unusually restricted and 1150 St. Nicholas Avenue, Room 508, New York, NY 10032, USA. E-mail: [email protected] stereotyped patterns of behaviors and interests. Autism describes the most severe manifestation
    [Show full text]
  • Transcriptional and Post-Transcriptional Regulation of ATP-Binding Cassette Transporter Expression
    Transcriptional and Post-transcriptional Regulation of ATP-binding Cassette Transporter Expression by Aparna Chhibber DISSERTATION Submitted in partial satisfaction of the requirements for the degree of DOCTOR OF PHILOSOPHY in Pharmaceutical Sciences and Pbarmacogenomies in the Copyright 2014 by Aparna Chhibber ii Acknowledgements First and foremost, I would like to thank my advisor, Dr. Deanna Kroetz. More than just a research advisor, Deanna has clearly made it a priority to guide her students to become better scientists, and I am grateful for the countless hours she has spent editing papers, developing presentations, discussing research, and so much more. I would not have made it this far without her support and guidance. My thesis committee has provided valuable advice through the years. Dr. Nadav Ahituv in particular has been a source of support from my first year in the graduate program as my academic advisor, qualifying exam committee chair, and finally thesis committee member. Dr. Kathy Giacomini graciously stepped in as a member of my thesis committee in my 3rd year, and Dr. Steven Brenner provided valuable input as thesis committee member in my 2nd year. My labmates over the past five years have been incredible colleagues and friends. Dr. Svetlana Markova first welcomed me into the lab and taught me numerous laboratory techniques, and has always been willing to act as a sounding board. Michael Martin has been my partner-in-crime in the lab from the beginning, and has made my days in lab fly by. Dr. Yingmei Lui has made the lab run smoothly, and has always been willing to jump in to help me at a moment’s notice.
    [Show full text]
  • Cpg Islands and the Regulation of Transcription
    Downloaded from genesdev.cshlp.org on September 24, 2021 - Published by Cold Spring Harbor Laboratory Press REVIEW CpG islands and the regulation of transcription Aime´e M. Deaton and Adrian Bird1 The Wellcome Trust Centre for Cell Biology, University of Edinburgh, Edinburgh EH9 3JR, United Kingdom Vertebrate CpG islands (CGIs) are short interspersed DNA In spite of their link with transcription, the functional sequences that deviate significantly from the average significance of CGIs is only just beginning to emerge. CGI genomic pattern by being GC-rich, CpG-rich, and pre- promoters turn out to have distinctive patterns of tran- dominantly nonmethylated. Most, perhaps all, CGIs are scription initiation and chromatin configuration. Their sites of transcription initiation, including thousands that regulation involves proteins (some of which specifically are remote from currently annotated promoters. Shared bind nonmethylated CpG) that influence the modifica- DNA sequence features adapt CGIs for promoter function tion status of CGI chromatin. In addition, the CpG moieties by destabilizing nucleosomes and attracting proteins that themselves are sometimes subject to cytosine methylation, create a transcriptionally permissive chromatin state. which correlates with stable shutdown of the associated Silencing of CGI promoters is achieved through dense promoter. Here we examine the properties shared by ver- CpG methylation or polycomb recruitment, again using tebrate CGIs and how transcription is regulated at these their distinctive DNA sequence composition. CGIs are sites. Recent related reviews include Illingworth and Bird therefore generically equipped to influence local chroma- (2009), Mohn and Schubeler (2009), and Blackledge and tin structure and simplify regulation of gene activity. Klose (2011). Vertebrate genomes are methylated predominantly at the Evolutionary conservation of CGIs dinucleotide CpG, and consequently are CpG-deficient owing to the mutagenic properties of methylcytosine CGIs are distinct in vertebrates due to their lack of DNA (Coulondre et al.
    [Show full text]
  • Human Induced Pluripotent Stem Cell–Derived Podocytes Mature Into Vascularized Glomeruli Upon Experimental Transplantation
    BASIC RESEARCH www.jasn.org Human Induced Pluripotent Stem Cell–Derived Podocytes Mature into Vascularized Glomeruli upon Experimental Transplantation † Sazia Sharmin,* Atsuhiro Taguchi,* Yusuke Kaku,* Yasuhiro Yoshimura,* Tomoko Ohmori,* ‡ † ‡ Tetsushi Sakuma, Masashi Mukoyama, Takashi Yamamoto, Hidetake Kurihara,§ and | Ryuichi Nishinakamura* *Department of Kidney Development, Institute of Molecular Embryology and Genetics, and †Department of Nephrology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan; ‡Department of Mathematical and Life Sciences, Graduate School of Science, Hiroshima University, Hiroshima, Japan; §Division of Anatomy, Juntendo University School of Medicine, Tokyo, Japan; and |Japan Science and Technology Agency, CREST, Kumamoto, Japan ABSTRACT Glomerular podocytes express proteins, such as nephrin, that constitute the slit diaphragm, thereby contributing to the filtration process in the kidney. Glomerular development has been analyzed mainly in mice, whereas analysis of human kidney development has been minimal because of limited access to embryonic kidneys. We previously reported the induction of three-dimensional primordial glomeruli from human induced pluripotent stem (iPS) cells. Here, using transcription activator–like effector nuclease-mediated homologous recombination, we generated human iPS cell lines that express green fluorescent protein (GFP) in the NPHS1 locus, which encodes nephrin, and we show that GFP expression facilitated accurate visualization of nephrin-positive podocyte formation in
    [Show full text]
  • Polygenic Scores for Major Depressive Disorder and Depressive Symptoms Predict Response to Lithium in Patients with Bipolar Disorder
    bioRxiv preprint doi: https://doi.org/10.1101/449363; this version posted October 22, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Polygenic scores for major depressive disorder and depressive symptoms predict response to lithium in patients with bipolar disorder Azmeraw T. Amare, MPH, MSc, PhD1,2*; Klaus Oliver Schubert, MD, PhD1,3*; Liping Hou, PhD4; Scott R. Clark, MBBS, PhD 1; Sergi Papiol, PhD5,6; Micah Cearns, BSc (Hons)1; Urs Heilbronner, PhD5,7; Franziska Degenhardt, MD8; Fasil Tekola-Ayele, PhD9; Yi-Hsiang Hsu, PhD10,11; Tatyana Shekhtman, MSc12; Mazda Adli, MD13; Nirmala Akula, PhD4; Kazufumi Akiyama, MD14; Raffaella Ardau, MD15; Bárbara Arias, PhD16; Jean-Michel Aubry, MD17; Lena Backlund, MD, PhD18; Abesh Kumar Bhattacharjee, MD12; Frank Bellivier, MD, PhD19; Antonio Benabarre, MD, PhD20; Susanne Bengesser, MD21; Joanna M. Biernacka, PhD22,23; Armin Birner, MD21; Clara Brichant-Petitjean, MD19; Pablo Cervantes, MD24; Hsi-Chung Chen, MD, PhD25; Caterina Chillotti, MD15; Sven Cichon, PhD8,26; Cristiana Cruceanu, PhD27; Piotr M. Czerski, PhD28; Nina Dalkner, MSc21; Alexandre Dayer, MD17; Maria Del Zompo, MD29; J. Raymond DePaulo, MD30; Bruno Étain, MD, PhD19; Peter Falkai, MD32; Andreas J. Forstner, MD8,26,33; Louise Frisen, MD18; Mark A. Frye, MD23; Janice M. Fullerton, PhD34, 35; Sébastien Gard, MD36; Julie S. Garnham, BN37; Fernando S. Goes, MD30; Maria Grigoroiu-Serbanescu, PhD38; Paul Grof, MD, PhD39; Ryota Hashimoto, MD, PhD40,41; Joanna Hauser, MD28; Stefan Herms, Dipl.Biol.8,26; Per Hoffmann, PhD8,26; Andrea Hofmann, PhD8; Stephane Jamain, PhD31; Esther Jiménez, PhD20; Jean-Pierre Kahn, MD, PhD42; Layla Kassem, PhD4; Po-Hsiu Kuo, PhD43; Tadafumi Kato, MD, PhD44; John Kelsoe, MD12; Sarah Kittel-Schneider, MD45; Sebastian Kliwicki, MD46; Barbara König, MSc47; Ichiro Kusumi, MD48; Gonzalo Laje, MD4; Mikael Landén, MD49,50; Catharina Lavebratt, PhD18; Marion Leboyer, MD, PhD51; Susan G.
    [Show full text]
  • Trim24-Regulated Estrogen Response Is Dependent on Specific Histone Modifications in Breast Cancer Cells
    The Texas Medical Center Library DigitalCommons@TMC The University of Texas MD Anderson Cancer Center UTHealth Graduate School of The University of Texas MD Anderson Cancer Biomedical Sciences Dissertations and Theses Center UTHealth Graduate School of (Open Access) Biomedical Sciences 12-2012 TRIM24-REGULATED ESTROGEN RESPONSE IS DEPENDENT ON SPECIFIC HISTONE MODIFICATIONS IN BREAST CANCER CELLS Teresa T. Yiu Follow this and additional works at: https://digitalcommons.library.tmc.edu/utgsbs_dissertations Part of the Biochemistry Commons, Cancer Biology Commons, Medicine and Health Sciences Commons, and the Molecular Biology Commons Recommended Citation Yiu, Teresa T., "TRIM24-REGULATED ESTROGEN RESPONSE IS DEPENDENT ON SPECIFIC HISTONE MODIFICATIONS IN BREAST CANCER CELLS" (2012). The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences Dissertations and Theses (Open Access). 313. https://digitalcommons.library.tmc.edu/utgsbs_dissertations/313 This Dissertation (PhD) is brought to you for free and open access by the The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences at DigitalCommons@TMC. It has been accepted for inclusion in The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences Dissertations and Theses (Open Access) by an authorized administrator of DigitalCommons@TMC. For more information, please contact [email protected]. TRIM24-REGULATED ESTROGEN RESPONSE IS DEPENDENT ON SPECIFIC HISTONE
    [Show full text]