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© 2014 Berko et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited: Berko ER, Suzuki M, Beren F, Lemetre C, Alaimo CM, et al. (2014) Mosaic Epigenetic Dysregulation of Ectodermal Cells in Autism Spectrum Disorder. PLoS Genet 10(5): e1004402. doi:10.1371/journal.pgen.1004402

Abstract

DNA mutational events are increasingly being identified in autism spectrum disorder (ASD), but the potential additional role of dysregulation of the epigenome in the pathogenesis of the condition remains unclear. The epigenome is of interest as a possible mediator of environmental effects during development, encoding a cellular memory reflected by altered function of progeny cells. Advanced maternal age (AMA) is associated with an increased risk of having a child with ASD for reasons that are not understood. To explore whether AMA involves covert aneuploidy or epigenetic dysregulation leading to ASD in the offspring, we tested a homogeneous ectodermal cell type from 47 individuals with ASD compared with 48 typically developing (TD) controls born to mothers of ≥35 years, using a quantitative genome-wide DNA methylation assay. We show that DNA methylation patterns are dysregulated in ectodermal cells in these individuals, having accounted for confounding effects due to subject age, sex and ancestral haplotype. We did not find mosaic aneuploidy or copy number variability to occur at differentially-methylated regions in these subjects. Of note, the loci with distinctive DNA methylation were found at genes expressed in the brain and encoding protein products significantly enriched for interactions with those produced by known ASD-causing genes, representing a perturbation by epigenomic dysregulation of the same networks compromised by DNA mutational mechanisms. The results indicate the presence of a mosaic subpopulation of epigenetically-dysregulated, ectodermally-derived cells in subjects with ASD. The epigenetic dysregulation observed in these ASD subjects born to older mothers may be associated with aging parental gametes, environmental influences during embryogenesis or could be the consequence of mutations of the chromatin regulatory genes increasingly implicated in ASD. The results indicate that epigenetic dysregulatory mechanisms may complement and interact with DNA mutations in the pathogenesis of the disorder.

Details

Title
Mosaic Epigenetic Dysregulation of Ectodermal Cells in Autism Spectrum Disorder
Author
Berko, Esther R; Suzuki, Masako; Beren, Faygel; Lemetre, Christophe; Alaimo, Christine M; Calder, R Brent; Ballaban-Gil, Karen; Gounder, Batya; Kampf, Kaylee; Kirschen, Jill; Maqbool, Shahina B; Momin, Zeineen; Reynolds, David M; Russo, Natalie; Shulman, Lisa; Stasiek, Edyta; Tozour, Jessica; Valicenti-McDermott, Maria; Wang, Shenglong; Abrahams, Brett S; Hargitai, Joseph; Inbar, Dov; Zhang, Zhengdong; Buxbaum, Joseph D; Molholm, Sophie; Foxe, John J; Marion, Robert W; Auton, Adam; Greally, John M
Section
Research Article
Publication year
2014
Publication date
May 2014
Publisher
Public Library of Science
ISSN
15537390
e-ISSN
15537404
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
1536054007
Copyright
© 2014 Berko et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited: Berko ER, Suzuki M, Beren F, Lemetre C, Alaimo CM, et al. (2014) Mosaic Epigenetic Dysregulation of Ectodermal Cells in Autism Spectrum Disorder. PLoS Genet 10(5): e1004402. doi:10.1371/journal.pgen.1004402