DOCSLIB.ORG

The Genome-Wide Impact of Trisomy 21 on DNA Methylation and Its Implications for Hematopoiesis

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
The Genome-Wide Impact of Trisomy 21 on DNA Methylation and Its Implications for Hematopoiesis UCSF UC San Francisco Previously Published Works Title The genome-wide impact of trisomy 21 on DNA methylation and its implications for hematopoiesis. Permalink https://escholarship.org/uc/item/2dx458vx Journal Nature communications, 12(1) ISSN 2041-1723 Authors Muskens, Ivo S Li, Shaobo Jackson, Thomas et al. Publication Date 2021-02-05 DOI 10.1038/s41467-021-21064-z Peer reviewed eScholarship.org Powered by the California Digital Library University of California ARTICLE https://doi.org/10.1038/s41467-021-21064-z OPEN The genome-wide impact of trisomy 21 on DNA methylation and its implications for hematopoiesis Ivo S. Muskens1,2, Shaobo Li 1,2,13, Thomas Jackson3,13, Natalina Elliot3,13, Helen M. Hansen4, Swe Swe Myint1,2, Priyatama Pandey1,2, Jeremy M. Schraw5,6, Ritu Roy7, Joaquin Anguiano4, Katerina Goudevenou3, Kimberly D. Siegmund 8, Philip J. Lupo5,6, Marella F. T. R. de Bruijn 9, Kyle M. Walsh 10,11, Paresh Vyas 9, Xiaomei Ma12, Anindita Roy 3, Irene Roberts3, Joseph L. Wiemels1,2 & ✉ Adam J. de Smith 1,2 1234567890():,; Down syndrome is associated with genome-wide perturbation of gene expression, which may be mediated by epigenetic changes. We perform an epigenome-wide association study on neonatal bloodspots comparing 196 newborns with Down syndrome and 439 newborns without Down syndrome, adjusting for cell-type heterogeneity, which identifies 652 epigenome-wide significant CpGs (P < 7.67 × 10−8) and 1,052 differentially methylated regions. Differential methylation at promoter/enhancer regions correlates with gene expression changes in Down syndrome versus non-Down syndrome fetal liver hematopoietic stem/progenitor cells (P < 0.0001). The top two differentially methylated regions overlap RUNX1 and FLI1, both important regulators of megakaryopoiesis and hematopoietic devel- opment, with significant hypermethylation at promoter regions of these two genes. Excluding Down syndrome newborns harboring preleukemic GATA1 mutations (N = 30), identified by targeted sequencing, has minimal impact on the epigenome-wide association study results. Down syndrome has profound, genome-wide effects on DNA methylation in hematopoietic cells in early life, which may contribute to the high frequency of hematological problems, including leukemia, in children with Down syndrome. 1 Center for Genetic Epidemiology, Department of Preventive Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA. 2 Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, USA. 3 Department of Paediatrics and MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, Oxford University and BRC Blood Theme, NIHR Oxford Biomedical Centre, Oxford, UK. 4 Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, USA. 5 Department of Pediatrics, Section of Hematology- Oncology, Baylor College of Medicine, Houston, TX, USA. 6 Texas Children’s Cancer and Hematology Centers, Texas Children’s Hospital, Houston, TX, USA. 7 Computational Biology and Informatics, University of California San Francisco, San Francisco, CA, USA. 8 Department of Preventive Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA. 9 MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK. 10 Department of Neurosurgery, Duke University, Durham, NC, USA. 11 Department of Pediatrics, Duke University, Durham, NC, USA. 12 Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT, USA. 13These authors contributed equally: ✉ Shaobo Li, Thomas Jackson, Natalina Elliot. email: [email protected] NATURE COMMUNICATIONS | (2021) 12:821 | https://doi.org/10.1038/s41467-021-21064-z | www.nature.com/naturecommunications 1 ARTICLE NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-021-21064-z own syndrome (DS), caused by constitutive trisomy of Table 1 Baseline characteristics of newborns with and chromosome 21 (T21), is one of the most common genetic without Down syndrome included in our epigenome-wide D 1 disorders , and is associated with a spectrum of adverse association study. phenotypes2. DS is characterized by defects in immune system development and in hematopoiesis, with DS fetuses having per- N = N = P 3 Non-DS ( 439) DS ( 196) value turbed megakaryocyte/red cell and B-lymphoid development and N (%) N (%) 4 DS children having a higher frequency of lymphopenia and Sex infections5. Furthermore, children with DS have a 20–30-fold Female 182 (41.5%) 106 (54.1%) 0.0034a increased risk of acute lymphoblastic leukemia (ALL) and a 500- Male 257 (58.5%) 90 (45.9%) Race/ethnicity fold increased risk of acute megakaryoblastic leukemia (AMKL), Asian 38 (8.7%) 17 (8.7%) 0.00044a while displaying a decreased risk of common adult-onset solid Latino 253 (57.6%) 104 (53.1%) tumors6,7. Approximately 10% of DS newborns present with Non-Latino white 124 (28.2%) 54 (27.6%) Non-Latino black 13 (3.0%) 21 (10.7%) transient abnormal myelopoiesis (TAM), a preleukemic disorder Other 11 (2.5%) 0 (0%) associated with increased peripheral blood blast cells and pathog- Blood collection age (days) nomonic somatic mutations in the X-linked erythro-mega- Mean (SD) 1.33 (±0.70) 2.49 (±2.04) <0.0001b karyocytic transcription factor (TF) gene GATA18. A further Median (range) 1.13 (0–5.25) 1.75 (0–15.3) – Missing 3 (0.7%) 5 (2.6%) 15 20% have acquired GATA1 mutations without clinical features, Gestational age (weeks) so-called “Silent TAM8.” TAM and Silent TAM resolve sponta- Mean (SD) 39.2 (±2.0) 38.2 (±2.2) 0.041b neously in most cases, but up to 20% acquire additional oncogenic Median (range) 39.4 (26.4–44.7) 38.3 (26.4–44.7) 9,10 Preterm 44 (10.6%) 39 (22.0%) 0.0004a mutations and develop frank AMKL . (<37 weeks) DS-related phenotypes vary greatly in presentation and Missing 23 (5.2%) 19 (9.7%) penetrance2,11, and understanding the biological basis of that var- Birth weight (kg) Mean (SD) 3.39 (±0.55) 3.01 (±0.73) 0.001b iation may highlight novel therapeutic approaches, and shed light – – 11 Median (range) 3.41 (1.04 5.05) 3.01 (0.96 8.65) on the etiology of these conditions in non-DS individuals .Altered Small-for- 24 (6.1%) 33 (19.3%) <0.0001a expression of genes, both on Hsa21 and genome-wide, is widely gestational agec accepted to play a key role in the manifestation of DS-related Missing 0 (0%) 6 (3.1%) 3 Birth year phenotypes, many of which originate prenatally . Several studies, Median (range) 2004 (2000–2008) 1998 (1996–1999) <0.0001d including in monozygotic twins discordant for T21, provide strong Missing 3 (0.7%) 2 (1.0%) evidence for the effect of T21 on the human transcriptome12,13, 14 kg kilogram, SD standard deviation, DS Down syndrome. with substantial interindividual variability in expression patterns . aP values calculated by two-sided Fisher’s exact test. Studying baseline epigenetic effects of T21 at birth is a pow- bP values calculated by linear regression with the birth-related variable as the dependent variable, DS status as the independent variable, and adjusting for the remaining birth-related erful approach to pinpoint broad epigenetic landscapes and/or variables, sex, plate, and race/ethnicity. individual genes that underlie DS-related phenotypes. Never- cSmall-for-gestational age calculated according to the sex- and gestational age-based intrauterine growth curves previously developed using US data85. Note we were not able to theless, comprehensive analysis of genome-wide DNA methyla- calculate this for newborns born >42 weeks due to limitations of the reference data. tion changes in DS is lacking; previous studies comprised very few dP value calculated by the two-sided Wilcoxon rank-sum test. (N < 30) individuals, did not explore interethnic differences, nor account for the potential impact of somatic GATA1 mutation- harboring clones15–19. slightly lower mean gestational age at birth (P = 0.04) and birth Here, we investigate T21-associated changes in DNA methy- weight (P = 0.001) than non-DS newborns, and a higher frequency lation among 196 DS and 439 non-DS newborn blood samples, of DS newborns were preterm (P = 0.0004) and/or small-for- and consider the potential confounding effects of somatic GATA1 gestational age (P < 0.0001) than non-DS newborns (Table 1). Age mutations in DS newborns assessed by targeted sequencing. Our at sampling was higher in DS newborns, the majority being epigenome-wide association study (EWAS) of DS identifies sampled on day 3 of life compared to day 2 for non-DS neonates 652 significant CpGs and 1052 differentially methylated regions (P < 0.0001). (DMRs) associated with DS, including significant hypermethy- lation at promoter regions of RUNX1 and FLI1, both critical regulators of hematopoiesis. Further, we find that differential DNA methylation-based clustering separates DS and non-DS methylation at regulatory regions in newborns with DS correlates newborns. Visualization of principal components analysis (PCA) with gene expression patterns in DS fetal liver (FL) hematopoietic and t-distributed stochastic neighbor embedding (t-SNE) plots stem and progenitor cells (HSPC). This is the first multiethnic generated from genome-wide DNA methylation data, excluding study of its kind and the largest epigenome-wide analysis of DS CpG probes on sex chromosomes and Hsa21 and CpGs over- patients to-date, revealing insights into the etiology of DS-related lapping single-nucleotide polymorphisms (SNPs) with minor phenotypes. allele frequency
Load more

Recommended publications
  • Genetic Analysis of Retinopathy in Type 1 Diabetes
    Genetic Analysis of Retinopathy in Type 1 Diabetes by Sayed Mohsen Hosseini A thesis submitted in conformity with the requirements for the degree of Doctor of Philosophy Institute of Medical Science University of Toronto © Copyright by S. Mohsen Hosseini 2014 Genetic Analysis of Retinopathy in Type 1 Diabetes Sayed Mohsen Hosseini Doctor of Philosophy Institute of Medical Science University of Toronto 2014 Abstract Diabetic retinopathy (DR) is a leading cause of blindness worldwide. Several lines of evidence suggest a genetic contribution to the risk of DR; however, no genetic variant has shown convincing association with DR in genome-wide association studies (GWAS). To identify common polymorphisms associated with DR, meta-GWAS were performed in three type 1 diabetes cohorts of White subjects: Diabetes Complications and Control Trial (DCCT, n=1304), Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR, n=603) and Renin-Angiotensin System Study (RASS, n=239). Severe (SDR) and mild (MDR) retinopathy outcomes were defined based on repeated fundus photographs in each study graded for retinopathy severity on the Early Treatment Diabetic Retinopathy Study (ETDRS) scale. Multivariable models accounted for glycemia (measured by A1C), diabetes duration and other relevant covariates in the association analyses of additive genotypes with SDR and MDR. Fixed-effects meta- analysis was used to combine the results of GWAS performed separately in WESDR, ii RASS and subgroups of DCCT, defined by cohort and treatment group. Top association signals were prioritized for replication, based on previous supporting knowledge from the literature, followed by replication in three independent white T1D studies: Genesis-GeneDiab (n=502), Steno (n=936) and FinnDiane (n=2194).
    [Show full text]
  • Polyclonal Antibody to APC11 / ANAPC11 - Serum
    OriGene Technologies, Inc. OriGene Technologies GmbH 9620 Medical Center Drive, Ste 200 Schillerstr. 5 Rockville, MD 20850 32052 Herford UNITED STATES GERMANY Phone: +1-888-267-4436 Phone: +49-5221-34606-0 Fax: +1-301-340-8606 Fax: +49-5221-34606-11 [email protected] [email protected] R1503 Polyclonal Antibody to APC11 / ANAPC11 - Serum Alternate names: Anaphase-promoting complex subunit 11, Cyclosome subunit 11, HSPC214, Hepatocellular carcinoma-associated RING finger protein Quantity: 0.1 ml Concentration: 85 mg/ml (by Refractometry) Background: APC11 is also known as Anaphase promoting complex subunit 11, APC11, Cyclosome subunit 11, Hepatocellular carcinoma associated RING finger protein, and HSPC214. APC11 is a component of the anaphase promoting complex/cyclosome (APC/C), a cell cycle-regulated E3 ubiquitin ligase that controls progression through mitosis and the G1 phase of the cell cycle. APC11 may function to recruit the E2 ubiquitin-conjugating enzymes to the complex. APC11 interacts with the cullin domain of ANAPC2 and also interacts with UBE2D2. APC11 shows both a cytoplasmic and nuclear localization. APC11 is expressed at high levels in skeletal muscle and heart; in moderate levels in brain, kidney, and liver; and at low levels in colon, thymus, spleen, small intestine, placenta, lung and peripheral blood leukocyte. APC11 is a member of the RING-type zinc finger family and is auto-ubiquitinylated. Uniprot ID: Q9NYG5 NCBI: NP_001002244.1 GeneID: 51529 Host: Rabbit Immunogen: This APC11 antibody was prepared from whole rabbit serum produced by repeated immunizations with a synthetic peptide corresponding to amino acids 76-84 of Human APC11 (C-terminal) coupled to KLH.
    [Show full text]
  • Download Download
    Supplementary Figure S1. Results of flow cytometry analysis, performed to estimate CD34 positivity, after immunomagnetic separation in two different experiments. As monoclonal antibody for labeling the sample, the fluorescein isothiocyanate (FITC)- conjugated mouse anti-human CD34 MoAb (Mylteni) was used. Briefly, cell samples were incubated in the presence of the indicated MoAbs, at the proper dilution, in PBS containing 5% FCS and 1% Fc receptor (FcR) blocking reagent (Miltenyi) for 30 min at 4 C. Cells were then washed twice, resuspended with PBS and analyzed by a Coulter Epics XL (Coulter Electronics Inc., Hialeah, FL, USA) flow cytometer. only use Non-commercial 1 Supplementary Table S1. Complete list of the datasets used in this study and their sources. GEO Total samples Geo selected GEO accession of used Platform Reference series in series samples samples GSM142565 GSM142566 GSM142567 GSM142568 GSE6146 HG-U133A 14 8 - GSM142569 GSM142571 GSM142572 GSM142574 GSM51391 GSM51392 GSE2666 HG-U133A 36 4 1 GSM51393 GSM51394 only GSM321583 GSE12803 HG-U133A 20 3 GSM321584 2 GSM321585 use Promyelocytes_1 Promyelocytes_2 Promyelocytes_3 Promyelocytes_4 HG-U133A 8 8 3 GSE64282 Promyelocytes_5 Promyelocytes_6 Promyelocytes_7 Promyelocytes_8 Non-commercial 2 Supplementary Table S2. Chromosomal regions up-regulated in CD34+ samples as identified by the LAP procedure with the two-class statistics coded in the PREDA R package and an FDR threshold of 0.5. Functional enrichment analysis has been performed using DAVID (http://david.abcc.ncifcrf.gov/)
    [Show full text]
  • APC/C Is Essential for Hematopoiesis and Impaired in Aplastic Anemia
    www.impactjournals.com/oncotarget/ Oncotarget, 2017, Vol. 8, (No. 38), pp: 63360-63369 Research Paper APC/C is essential for hematopoiesis and impaired in aplastic anemia Jia Wang1,*, Min-Zhi Yin2,*, Ke-Wen Zhao1,*, Fang Ke1,*, Wen-Jie Jin3, Xiao-Lin Guo1, Tian-Hui Liu1, Xiao-Ye Liu1, Hao Gu1, Xiao-Min Yu1, Zhen Li1, Li-Li Mu1, Deng-Li Hong1, Jing Chen4 and Guo-Qiang Chen1 1Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Department of Pathophysiology, Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai, 200025, China 2Department of Pathology, Shanghai Children’s Medical Center, SJTU-SM, Shanghai, 200025, China 3Department of Orthopaedics, Shanghai Ninth People's Hospital, SJTU-SM, Shanghai, 200025, China 4Key Laboratory of Pediatric Hematology and Oncology Ministry of Health, Department of Hematology and Oncology, Shanghai Children’s Medical Center, SJTU-SM, Shanghai, 200127, China *These authors have contributed equally to this work Correspondence to: Guo-Qiang Chen, email: [email protected] Jing Chen, email: [email protected] Deng-Li Hong, email: [email protected] Keywords: anaphase promoting complex/cyclosome (APC/C), Anapc2, hematopoietic stem and progenitor cells (HSPCs), dormant HPSCs, aplastic anemia Received: November 22, 2016 Accepted: June 02, 2017 Published: June 28, 2017 Copyright: Wang et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT Anaphase promoting complex/cyclosome (APC/C) is essential for cell cycle progression.
    [Show full text]
  • Table S2.Up Or Down Regulated Genes in Tcof1 Knockdown Neuroblastoma N1E-115 Cells Involved in Differentbiological Process Anal
    Table S2.Up or down regulated genes in Tcof1 knockdown neuroblastoma N1E-115 cells involved in differentbiological process analysed by DAVID database Pop Pop Fold Term PValue Genes Bonferroni Benjamini FDR Hits Total Enrichment GO:0044257~cellular protein catabolic 2.77E-10 MKRN1, PPP2R5C, VPRBP, MYLIP, CDC16, ERLEC1, MKRN2, CUL3, 537 13588 1.944851 8.64E-07 8.64E-07 5.02E-07 process ISG15, ATG7, PSENEN, LOC100046898, CDCA3, ANAPC1, ANAPC2, ANAPC5, SOCS3, ENC1, SOCS4, ASB8, DCUN1D1, PSMA6, SIAH1A, TRIM32, RNF138, GM12396, RNF20, USP17L5, FBXO11, RAD23B, NEDD8, UBE2V2, RFFL, CDC GO:0051603~proteolysis involved in 4.52E-10 MKRN1, PPP2R5C, VPRBP, MYLIP, CDC16, ERLEC1, MKRN2, CUL3, 534 13588 1.93519 1.41E-06 7.04E-07 8.18E-07 cellular protein catabolic process ISG15, ATG7, PSENEN, LOC100046898, CDCA3, ANAPC1, ANAPC2, ANAPC5, SOCS3, ENC1, SOCS4, ASB8, DCUN1D1, PSMA6, SIAH1A, TRIM32, RNF138, GM12396, RNF20, USP17L5, FBXO11, RAD23B, NEDD8, UBE2V2, RFFL, CDC GO:0044265~cellular macromolecule 6.09E-10 MKRN1, PPP2R5C, VPRBP, MYLIP, CDC16, ERLEC1, MKRN2, CUL3, 609 13588 1.859332 1.90E-06 6.32E-07 1.10E-06 catabolic process ISG15, RBM8A, ATG7, LOC100046898, PSENEN, CDCA3, ANAPC1, ANAPC2, ANAPC5, SOCS3, ENC1, SOCS4, ASB8, DCUN1D1, PSMA6, SIAH1A, TRIM32, RNF138, GM12396, RNF20, XRN2, USP17L5, FBXO11, RAD23B, UBE2V2, NED GO:0030163~protein catabolic process 1.81E-09 MKRN1, PPP2R5C, VPRBP, MYLIP, CDC16, ERLEC1, MKRN2, CUL3, 556 13588 1.87839 5.64E-06 1.41E-06 3.27E-06 ISG15, ATG7, PSENEN, LOC100046898, CDCA3, ANAPC1, ANAPC2, ANAPC5, SOCS3, ENC1, SOCS4,
    [Show full text]
  • Centre for Arab Genomic Studies a Division of Sheikh Hamdan Award for Medical Sciences
    Centre for Arab Genomic Studies A Division of Sheikh Hamdan Award for Medical Sciences The atalogue for ransmission enetics in rabs C T G A CTGA Database Ankyrin Repeat- And SOCS Box-Containing Protein 3 Alternative Names Monies et al. (2017) investigated the findings of ASB3 1000 diagnostic panels and exomes carried out at a next generation sequencing lab in Saudi Arabia. Record Category One patient, a 10-year-old female, presented with Gene locus ataxia, dystonia and hypertonia. An MRI revealed bilateral basal ganglia disease. The patient was WHO-ICD from a consanguineous family and had a brother N/A to gene loci with epilepsy. Using whole exome sequencing, a homozygous mutation (c.386-3T>C) was identified Incidence per 100,000 Live Births in exon 5 of the patient’s ASB3 gene. This gene N/A to gene loci mutation was considered a candidate for pathogenicity as it was a novel variant located OMIM Number within the autozygome that was predicted to be 605760 deleterious, and the ASB3 gene is expressed in the forebrain. The authors noted that further studies are Mode of Inheritance required to independently confirm this association. N/A to gene loci References Gene Map Locus Monies D, Abouelhoda M, AlSayed M, Alhassnan 2p16.2 Z, Alotaibi M, Kayyali H, Al-Owain M, Shah A, Rahbeeni Z, Al-Muhaizea MA, Alzaidan HI, Description Cupler E, Bohlega S, Faqeih E, Faden M, Alyounes The ASB3 gene encodes a protein belonging to the B, Jaroudi D, Goljan E, Elbardisy H, Akilan A, ankyrin repeat and SOCS box-containing (ASB) Albar R, Aldhalaan H, Gulab S, Chedrawi A, Al family.
    [Show full text]
  • DNA Methylation Alterations in Blood Cells of Toddlers with Down Syndrome
    G C A T T A C G G C A T genes Article DNA Methylation Alterations in Blood Cells of Toddlers with Down Syndrome Oxana Yu. Naumova 1,2,* , Rebecca Lipschutz 2, Sergey Yu. Rychkov 1, Olga V. Zhukova 1 and Elena L. Grigorenko 2,3,4,* 1 Vavilov Institute of General Genetics RAS, 119991 Moscow, Russia; [email protected] (S.Y.R.); [email protected] (O.V.Z.) 2 Department of Psychology, University of Houston, Houston, TX 77204, USA; [email protected] 3 Department of Psychology, Saint-Petersburg State University, 199034 Saint Petersburg, Russia 4 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA * Correspondence: [email protected] or [email protected] (O.Y.N.); [email protected] (E.L.G.) Abstract: Recent research has provided evidence on genome-wide alterations in DNA methylation patterns due to trisomy 21, which have been detected in various tissues of individuals with Down syndrome (DS) across different developmental stages. Here, we report new data on the systematic genome-wide DNA methylation perturbations in blood cells of individuals with DS from a previously understudied age group—young children. We show that the study findings are highly consistent with those from the prior literature. In addition, utilizing relevant published data from two other developmental stages, neonatal and adult, we track a quasi-longitudinal trend in the DS-associated DNA methylation patterns as a systematic epigenomic destabilization with age. Citation: Naumova, O.Y.; Lipschutz, R.; Rychkov, S.Y.; Keywords: Down syndrome; infants and toddlers; trisomy 21; DNA methylation; Illumina 450K Zhukova, O.V.; Grigorenko, E.L.
    [Show full text]
  • Chapter 4.1 a 400 Kb Duplication, 2.4 Mb Triplication and 130 Kb
    High-resolution karyotyping by oligonucleotide microarrays : the next revolution in cytogenetics Gijsbers, A.C.J. Citation Gijsbers, A. C. J. (2010, November 30). High-resolution karyotyping by oligonucleotide microarrays : the next revolution in cytogenetics. Retrieved from https://hdl.handle.net/1887/16187 Version: Corrected Publisher’s Version Licence agreement concerning inclusion of doctoral thesis in the License: Institutional Repository of the University of Leiden Downloaded from: https://hdl.handle.net/1887/16187 Note: To cite this publication please use the final published version (if applicable). Chapter 4.1 A 400 kb duplication, 2.4 Mb triplication and 130 kb duplication of 9q34.3 in a patient with severe mental retardation Antoinet CJ Gijsbers, Emilia K Bijlsma, Marjan M Weiss, Egbert Bakker, Martijn H Breuning, Mariëtte JV Hoffer and Claudia AL Ruivenkamp Center for Human and Clinical Genetics; Leiden University Medical Center (LUMC), Leiden, The Netherlands Eur J Med Genet 2008;51:479-487 Chapter 4 Abstract The presence of a duplication as well as a triplication in one chromosome is a rare rearrangement and not easy to distinguish with routine chromosomal analysis. Recent developments in array technologies, however, not only allow screening of the whole genome at a higher resolution, but also make it possible to characterize complex chromosomal rearrangements in more detail. Here we report a molecular cytogenetic analysis of a 16-year old female with severe mental retardation and an abnormality on the end of the long arm of chromosome 9. Subtelomeric multiplex ligation-dependent probe amplification (MLPA) analysis revealed that the extra material originated from the telomeric end of chromosome 9q.
    [Show full text]
  • Using Gene Expression Databases for Classical Trait QTL Candidate Gene Discovery in the BXD Recombinant Inbred Genetic Reference Population: Mouse Forebrain Weight
    BMC Genomics BioMed Central Research article Open Access Using gene expression databases for classical trait QTL candidate gene discovery in the BXD recombinant inbred genetic reference population: Mouse forebrain weight Lu Lu*1,2, Lai Wei4,5, Jeremy L Peirce2, Xusheng Wang2, Jianhua Zhou6, Ramin Homayouni5, Robert W Williams2 and David C Airey*3 Address: 1Jiangsu Key Laboratory of Neuroregeneration, Nantong University, PR China, 2Department of Anatomy and Neurobiology, University of Tennessee Health Sciences Center, Memphis, TN, 38103, USA, 3Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN, 37232, USA, 4Department of Pathology and Laboratory Medicine, University of Tennessee Health Sciences Center, Memphis, TN, 38103, USA, 5Department of Neurology, University of Tennessee Health Sciences Center, Memphis, TN, 38103, USA and 6Department of Medicine, University of Massachusetts Medical School, Worcester, MA, 01605, USA Email: Lu Lu* - [email protected]; Lai Wei - [email protected]; Jeremy L Peirce - [email protected]; Xusheng Wang - [email protected]; Jianhua Zhou - [email protected]; Ramin Homayouni - [email protected]; Robert W Williams - [email protected]; David C Airey* - [email protected] * Corresponding authors Published: 25 September 2008 Received: 30 April 2008 Accepted: 25 September 2008 BMC Genomics 2008, 9:444 doi:10.1186/1471-2164-9-444 This article is available from: http://www.biomedcentral.com/1471-2164/9/444 © 2008 Lu et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
    [Show full text]
  • Lariat Intronic Rnas in the Cytoplasm of Vertebrate Cells
    Lariat intronic RNAs in the cytoplasm of vertebrate cells Gaëlle J. S. Talhouarnea,b,1 and Joseph G. Galla,2 aDepartment of Embryology, Carnegie Institution for Science, Baltimore, MD 21218; and bDepartment of Biology, Johns Hopkins University, Baltimore, MD 21218 Contributed by Joseph G. Gall, July 5, 2018 (sent for review May 22, 2018; reviewed by Lynne E. Maquat and Sandra L. Wolin) Most intronic RNAs are degraded within seconds or minutes after RBC maturation (5), some RNAs persist (6), including circular their excision from newly formed transcripts. However, stable intronic RNA or circRNA (7, 8). Intronic RNA has not yet been analyzed sequence RNAs (sisRNAs) have been described from oocytes of the in these cells. We purified RBCs from mouse blood by frac- frog Xenopus, from Drosophila embryos, and from human cell lines. In tionation on a Percoll gradient (9) and subjected the small Xenopus oocytes, sisRNAs are abundant in both the nucleus and cy- amount of recovered RNA to high-throughput sequencing. The toplasm, they occur in the form of lariats, and they are stable for days. 77 million single-end 100-bp reads that we obtained were ana- In this study we demonstrate that cytoplasmic sisRNAs are also found lyzed using a method developed by Taggart et al. (10). Of par- in human, mouse, chicken, and zebrafish cells. They exist as circular ticular interest, this method allows one to recover inverted reads (lariat) molecules, mostly 100–500 nucleotides in length, and are de- that would otherwise be thrown out by standard pipelines. We rived from many housekeeping genes.
    [Show full text]
  • Disruption of the Anaphase-Promoting Complex Confers Resistance to TTK Inhibitors in Triple-Negative Breast Cancer
    Disruption of the anaphase-promoting complex confers resistance to TTK inhibitors in triple-negative breast cancer K. L. Thua,b, J. Silvestera,b, M. J. Elliotta,b, W. Ba-alawib,c, M. H. Duncana,b, A. C. Eliaa,b, A. S. Merb, P. Smirnovb,c, Z. Safikhanib, B. Haibe-Kainsb,c,d,e, T. W. Maka,b,c,1, and D. W. Cescona,b,f,1 aCampbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada M5G 1L7; bPrincess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada M5G 1L7; cDepartment of Medical Biophysics, University of Toronto, Toronto, ON, Canada M5G 1L7; dDepartment of Computer Science, University of Toronto, Toronto, ON, Canada M5G 1L7; eOntario Institute for Cancer Research, Toronto, ON, Canada M5G 0A3; and fDepartment of Medicine, University of Toronto, Toronto, ON, Canada M5G 1L7 Contributed by T. W. Mak, December 27, 2017 (sent for review November 9, 2017; reviewed by Mark E. Burkard and Sabine Elowe) TTK protein kinase (TTK), also known as Monopolar spindle 1 (MPS1), ator of the spindle assembly checkpoint (SAC), which delays is a key regulator of the spindle assembly checkpoint (SAC), which anaphase until all chromosomes are properly attached to the functions to maintain genomic integrity. TTK has emerged as a mitotic spindle, TTK has an integral role in maintaining genomic promising therapeutic target in human cancers, including triple- integrity (6). Because most cancer cells are aneuploid, they are negative breast cancer (TNBC). Several TTK inhibitors (TTKis) are heavily reliant on the SAC to adequately segregate their abnormal being evaluated in clinical trials, and an understanding of karyotypes during mitosis.
    [Show full text]
  • ANAPC2 Antibody (C-Term) Purified Rabbit Polyclonal Antibody (Pab) Catalog # Ap21055a
    苏州工业园区双圩路9号1幢 邮 编 ： 215000 电 话 ： 0512-88856768 ANAPC2 Antibody (C-term) Purified Rabbit Polyclonal Antibody (Pab) Catalog # AP21055a Specification ANAPC2 Antibody (C-term) - Product info Application WB, IHC-P, IF Primary Accession Q9UJX6 Reactivity Human Host Rabbit Clonality Polyclonal Isotype Rabbit Ig Clone Names RB51676 Calculated MW 93828 ANAPC2 Antibody (C-term) - Additional info Gene ID 29882 Other Names Anaphase-promoting complex subunit 2, APC2, Cyclosome subunit 2, ANAPC2, APC2, KIAA1406 Immunofluorescent analysis of 4% Target/Specificity paraformaldehyde-fixed, 0. 1% Triton This ANAPC2 antibody is generated from a rabbit immunized X-100 permeabilized Hela (Human with a KLH conjugated synthetic peptide between 712-746 Cervical epithelial adenocarcinoma cell amino acids from the C-terminal region of human ANAPC2. line) cells labeling ANAPC2 with AP21055a at 1/25 dilution, followed by Dilution Alexa Fluor 488-conjugated goat IF~~1:25 anti-rabbit IgG (1583138) secondary IHC-P~~1:100~500 WB~~1:1000 antibody at 1/400 dilution (green). Confocal image showing nuclear staining Format on Hela cell line. Cytoplasmic actin is Purified polyclonal antibody supplied in PBS with 0.09% (W/V) detected with Alexa Fluor® 555 sodium azide. This antibody is purified through a protein A conjugated with Phalloidin (OB16636430) column, followed by peptide affinity purification. at 1/100 dilution (red). Storage Maintain refrigerated at 2-8°C for up to 2 weeks. For long term storage store at -20°C in small aliquots to prevent freeze-thaw cycles. Precautions ANAPC2 Antibody (C-term) is for research use only and not for use in diagnostic or therapeutic procedures.
    [Show full text]