Mosaic Epigenetic Dysregulation of Ectodermal Cells in Autism Spectrum Disorder

Esther R. Berko, Masako Suzuki, Faygel Beren, Christophe Lemetre, Christine M. Alaimo, R. Brent Calder, Karen R. Ballaban-Gil, Batya Gounder, Kaylee Kampf, Jill Kirschen, Shahina B. Maqbool, Zeineen Momin, David M. Reynolds, Natalie Russo, Lisa H. Shulman, Edyta Stasiek, Jessica Tozour, Maria D.R. Valicenti-McDermott, Shenglong Wang, Brett S. Abrahams & 9 others Joseph Hargitai, Dov Inbar, Zhengdong Zhang, Joseph D. Buxbaum, Sophie Molholm, John J. Foxe, Robert W. Marion, Adam Auton, John M. Greally

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Article numbere1004402
JournalPLoS Genetics
Volume10
Issue number5
DOIs
StatePublished - 2014

Fingerprint

Epigenomics
epigenetics
DNA
methylation
DNA methylation
DNA Methylation
cells
aneuploidy
Maternal Age
Aneuploidy
gene
mutation
pathogenesis
Mothers
Mutation
autism
Autism Spectrum Disorder
mosaic
protein products
gamete

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Ecology, Evolution, Behavior and Systematics
  • Cancer Research
  • Genetics(clinical)
  • Medicine(all)

Cite this

Mosaic Epigenetic Dysregulation of Ectodermal Cells in Autism Spectrum Disorder. / Berko, Esther R.; Suzuki, Masako; Beren, Faygel; Lemetre, Christophe; Alaimo, Christine M.; Calder, R. Brent; Ballaban-Gil, Karen R.; Gounder, Batya; Kampf, Kaylee; Kirschen, Jill; Maqbool, Shahina B.; Momin, Zeineen; Reynolds, David M.; Russo, Natalie; Shulman, Lisa H.; Stasiek, Edyta; Tozour, Jessica; Valicenti-McDermott, Maria D.R.; 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.

In: PLoS Genetics, Vol. 10, No. 5, e1004402, 2014.

Research output: Contribution to journalArticle

Berko, ER, Suzuki, M, Beren, F, Lemetre, C, Alaimo, CM, Calder, RB, Ballaban-Gil, KR, Gounder, B, Kampf, K, Kirschen, J, Maqbool, SB, Momin, Z, Reynolds, DM, Russo, N, Shulman, LH, Stasiek, E, Tozour, J, Valicenti-McDermott, MDR, Wang, S, Abrahams, BS, Hargitai, J, Inbar, D, Zhang, Z, Buxbaum, JD, Molholm, S, Foxe, JJ, Marion, RW, Auton, A & Greally, JM 2014, 'Mosaic Epigenetic Dysregulation of Ectodermal Cells in Autism Spectrum Disorder', PLoS Genetics, vol. 10, no. 5, e1004402. https://doi.org/10.1371/journal.pgen.1004402
Berko, Esther R. ; Suzuki, Masako ; Beren, Faygel ; Lemetre, Christophe ; Alaimo, Christine M. ; Calder, R. Brent ; Ballaban-Gil, Karen R. ; Gounder, Batya ; Kampf, Kaylee ; Kirschen, Jill ; Maqbool, Shahina B. ; Momin, Zeineen ; Reynolds, David M. ; Russo, Natalie ; Shulman, Lisa H. ; Stasiek, Edyta ; Tozour, Jessica ; Valicenti-McDermott, Maria D.R. ; 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. / Mosaic Epigenetic Dysregulation of Ectodermal Cells in Autism Spectrum Disorder. In: PLoS Genetics. 2014 ; Vol. 10, No. 5.
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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.",
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AU - Suzuki, Masako

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AU - Lemetre, Christophe

AU - Alaimo, Christine M.

AU - Calder, R. Brent

AU - Ballaban-Gil, Karen R.

AU - Gounder, Batya

AU - Kampf, Kaylee

AU - Kirschen, Jill

AU - Maqbool, Shahina B.

AU - Momin, Zeineen

AU - Reynolds, David M.

AU - Russo, Natalie

AU - Shulman, Lisa H.

AU - Stasiek, Edyta

AU - Tozour, Jessica

AU - Valicenti-McDermott, Maria D.R.

AU - Wang, Shenglong

AU - Abrahams, Brett S.

AU - Hargitai, Joseph

AU - Inbar, Dov

AU - Zhang, Zhengdong

AU - Buxbaum, Joseph D.

AU - Molholm, Sophie

AU - Foxe, John J.

AU - Marion, Robert W.

AU - Auton, Adam

AU - Greally, John M.

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