title: DNA-Methylation Patterns in Trisomy 21 Using Cells from Monozygotic Twins.
abstract: DNA methylation is essential in mammalian development. We have hypothesized that methylation differences induced by trisomy 21 (T21) contribute to the phenotypic characteristics and heterogeneity in Down syndrome (DS). In order to determine the methylation differences in T21 without interference of the interindividual genomic variation, we have used fetal skin fibroblasts from monozygotic (MZ) twins discordant for T21. We also used skin fibroblasts from MZ twins concordant for T21, normal MZ twins without T21, and unrelated normal and T21 individuals. Reduced Representation Bisulfite Sequencing (RRBS) revealed 35 differentially methylated promoter regions (DMRs) (Absolute methylation differences = 25%, FDR < 0.001) in MZ twins discordant for T21 that have also been observed in comparison between unrelated normal and T21 individuals. The identified DMRs are enriched for genes involved in embryonic organ morphogenesis (FDR = 1.60 e -03) and include genes of the HOXB and HOXD clusters. These DMRs are maintained in iPS cells generated from this twin pair and are correlated with the gene expression changes. We have also observed an increase in DNA methylation level in the T21 methylome compared to the normal euploid methylome. This observation is concordant with the up regulation of DNA methyltransferase enzymes (DNMT3B and DNMT3L) and down regulation of DNA demethylation enzymes (TET2 and TET3) observed in the iPSC of the T21 versus normal twin. Altogether, the results of this study highlight the epigenetic effects of the extra chromosome 21 in T21 on loci outside of this chromosome that are relevant to DS associated phenotypes.
authors: Department of Genetic Medicine and Development, University of Geneva, Geneva, Switzerland; National Center of Competence in Research Frontiers in Genetics Program, University of Geneva, Geneva, Switzerland.
authors: M Reza
authors: MR
authors: Sailani
authors: Department of Genetic Medicine and Development, University of Geneva, Geneva, Switzerland.
authors: Federico A
authors: FA
authors: Santoni
authors: Department of Genetic Medicine and Development, University of Geneva, Geneva, Switzerland; National Center of Competence in Research Frontiers in Genetics Program, University of Geneva, Geneva, Switzerland.
authors: Audrey
authors: A
authors: Letourneau
authors: Department of Genetic Medicine and Development, University of Geneva, Geneva, Switzerland.
authors: Christelle
authors: C
authors: Borel
authors: Department of Genetic Medicine and Development, University of Geneva, Geneva, Switzerland.
authors: Periklis
authors: P
authors: Makrythanasis
authors: Stem Cell Research Laboratory, Department of Obstetrics and Gynecology, Geneva University Hospitals, Geneva, Switzerland; Department of Obstetrics and Gynecology, Hôpital Cantonal Fribourgeois, Fribourg, Switzerland.
authors: Youssef
authors: Y
authors: Hibaoui
authors: Department of Genetic Medicine and Development, University of Geneva, Geneva, Switzerland.
authors: Konstantin
authors: K
authors: Popadin
authors: Department of Genetic Medicine and Development, University of Geneva, Geneva, Switzerland.
authors: Ximena
authors: X
authors: Bonilla
authors: Department of Genetic Medicine and Development, University of Geneva, Geneva, Switzerland.
authors: Michel
authors: M
authors: Guipponi
authors: Department of Genetic Medicine and Development, University of Geneva, Geneva, Switzerland.
authors: Corinne
authors: C
authors: Gehrig
authors: Department of Genetic Medicine and Development, University of Geneva, Geneva, Switzerland.
authors: Anne
authors: A
authors: Vannier
authors: Centre Hospitalier Universitaire Reims, Service de Genetique et de Biologie de la Reproduction, CECOS, Hopital Maison Blanche, F-51092 Reims, France.
authors: Frederique
authors: F
authors: Carre-Pigeon
authors: Stem Cell Research Laboratory, Department of Obstetrics and Gynecology, Geneva University Hospitals, Geneva, Switzerland; Department of Obstetrics and Gynecology, Hôpital Cantonal Fribourgeois, Fribourg, Switzerland.
authors: Anis
authors: A
authors: Feki
authors: The Blizard Institute, Barts and The London School of Medicine, Queen Mary University of London, 4 Newark Street, London E1 2AT, United Kingdom; Lee Kong Chian School of Medicine, Nanyang Technological University, Unit 04-11, Proteos Building, 61 Biopolis Drive, Singapore 138673, Singapore.
authors: Dean
authors: D
authors: Nizetic
authors: Department of Genetic Medicine and Development, University of Geneva, Geneva, Switzerland; National Center of Competence in Research Frontiers in Genetics Program, University of Geneva, Geneva, Switzerland; iGE3 institute of Genetics and Genomics of Geneva, University of Geneva, Geneva, Switzerland.
authors: Stylianos E
authors: SE
authors: Antonarakis
mesh_terms: D018899:CpG Islands; D019175:DNA Methylation; D004314:Down Syndrome / Q000235:genetics* / Q000378:metabolism; D044127:Epigenesis, Genetic; D005347:Fibroblasts; D005786:Gene Expression Regulation; D015723:Gene Library; D006657:Histones / Q000378:metabolism; D006801:Humans; D010641:Phenotype; D011401:Promoter Regions, Genetic; D014430:Twins, Monozygotic
chemical_list: D006657:Histones