Mosaic Epigenetic Dysregulation of Ectodermal Cells in Autism Spectrum Disorder
| Autor: | Sophie Molholm, Zeineen Momin, Joseph D. Buxbaum, Karen Ballaban-Gil, Faygel Beren, Dov Inbar, Joseph Hargitai, John J. Foxe, Adam Auton, Masako Suzuki, Zhengdong D. Zhang, Jill Kirschen, Christophe Lemetre, John M. Greally, Robert W. Marion, David Reynolds, Maria Valicenti-McDermott, Brett S. Abrahams, Batya Gounder, Natalie Russo, Shahina Maqbool, Shenglong Wang, Jessica Tozour, Edyta Stasiek, Christine M. Alaimo, Kaylee Kampf, Lisa H. Shulman, R. Brent Calder, Esther R. Berko |
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| Rok vydání: | 2014 |
| Předmět: |
Epigenomics
Male Cancer Research Microarrays Gene Expression Developmental and Pediatric Neurology Biochemistry Pediatrics Epigenesis Genetic Chromosomal Disorders 0302 clinical medicine Child Development Pregnancy Medicine and Health Sciences Gene Regulatory Networks Genetics (clinical) Epigenesis Genetics 0303 health sciences Chromosome Biology Mosaicism Age Factors Genomics Middle Aged Chromatin Bioassays and Physiological Analysis Neurology Maternal-Fetal Relations DNA methylation Epigenetics Female DNA modification Research Article Adult lcsh:QH426-470 Biology Research and Analysis Methods Molecular Genetics 03 medical and health sciences Humans Gene Regulation Molecular Biology Gene Ecology Evolution Behavior and Systematics 030304 developmental biology Clinical Genetics Chromosome Aberrations Evolutionary Biology Biology and life sciences Population Biology Genome Human Gene Expression Profiling Haplotype Computational Biology Human Genetics DNA Cell Biology Epigenome DNA Methylation Aneuploidy lcsh:Genetics Haplotypes Child Development Disorders Pervasive Structural Genomics Human genome Departures from Diploidy 030217 neurology & neurosurgery Population Genetics |
| Zdroj: | PLoS Genetics PLoS Genetics, Vol 10, Iss 5, p e1004402 (2014) |
| ISSN: | 1553-7404 |
| Popis: | 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. Author Summary Older mothers have a higher than expected risk of having a child with an autism spectrum disorder (ASD). The reason for this increased risk is unknown. The eggs of older mothers are more prone to abnormalities of chromosome numbers, suggesting this as one possible mechanism of the increased ASD risk. Age is also associated with a loss of control of epigenetic regulatory patterns that govern gene expression, indicating a second potential mechanism. To test both possibilities, we sampled cells from the same developmental origin as the brain, and performed genome-wide tests looking for unusual chromosome numbers and DNA methylation patterns. The studies were performed on individuals with ASD and typically developing controls, all born to mothers at least 35 years of age at the time of birth. We found the cells from individuals with ASD to have changes in DNA methylation at a number of loci, especially near genes encoding proteins known to interact with those already implicated in ASD. We conclude that epigenetic dysregulation occurring in gametes or early embryonic life may be one of the contributors to the development of ASD. |
| Databáze: | OpenAIRE |
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