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Mosaic epigenetic dysregulation of ectodermal cells in autism spectrum disorder.

Authors :
Esther R Berko
Masako Suzuki
Faygel Beren
Christophe Lemetre
Christine M Alaimo
R Brent Calder
Karen Ballaban-Gil
Batya Gounder
Kaylee Kampf
Jill Kirschen
Shahina B Maqbool
Zeineen Momin
David M Reynolds
Natalie Russo
Lisa Shulman
Edyta Stasiek
Jessica Tozour
Maria Valicenti-McDermott
Shenglong Wang
Brett S Abrahams
Joseph Hargitai
Dov Inbar
Zhengdong Zhang
Joseph D Buxbaum
Sophie Molholm
John J Foxe
Robert W Marion
Adam Auton
John M Greally
Source :
PLoS Genetics, Vol 10, Iss 5, p e1004402 (2014)
Publication Year :
2014
Publisher :
Public Library of Science (PLoS), 2014.

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.

Subjects

Subjects :
Genetics
QH426-470

Details

Language :
English
ISSN :
15537390, 15537404, and 87957442
Volume :
10
Issue :
5
Database :
Directory of Open Access Journals
Journal :
PLoS Genetics
Publication Type :
Academic Journal
Accession number :
edsdoj.803dd8795744243ae732bdcac7b9739
Document Type :
article
Full Text :
https://doi.org/10.1371/journal.pgen.1004402