title: Mosaic epigenetic dysregulation of ectodermal cells in autism spectrum disorder.
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.
authors.affiliation: Center for Epigenomics and Department of Genetics (Division of Computational Genetics), Albert Einstein College of Medicine, Bronx, New York, United States of America.
authors.forename: Esther R
authors.initials: ER
authors.lastname: Berko
authors.affiliation: Center for Epigenomics and Department of Genetics (Division of Computational Genetics), Albert Einstein College of Medicine, Bronx, New York, United States of America.
authors.forename: Masako
authors.initials: M
authors.lastname: Suzuki
authors.affiliation: Stern College for Women, Yeshiva University, New York, New York, United States of America.
authors.forename: Faygel
authors.initials: F
authors.lastname: Beren
authors.affiliation: Center for Epigenomics and Department of Genetics (Division of Computational Genetics), Albert Einstein College of Medicine, Bronx, New York, United States of America.
authors.forename: Christophe
authors.initials: C
authors.lastname: Lemetre
authors.affiliation: The Sheryl and Daniel R. Tishman Cognitive Neurophysiology Laboratory, Children's Evaluation and Rehabilitation Center, and Departments of Pediatrics and Neuroscience, Albert Einstein College of Medicine, Bronx, New York, United States of America.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Alaimo
authors.affiliation: Center for Epigenomics and Department of Genetics (Division of Computational Genetics), Albert Einstein College of Medicine, Bronx, New York, United States of America.
authors.forename: R Brent
authors.initials: RB
authors.lastname: Calder
authors.affiliation: Department of Neurology, Children's Hospital at Montefiore, Bronx, New York, United States of America.
authors.forename: Karen
authors.initials: K
authors.lastname: Ballaban-Gil
authors.affiliation: Stern College for Women, Yeshiva University, New York, New York, United States of America.
authors.forename: Batya
authors.initials: B
authors.lastname: Gounder
authors.affiliation: Stern College for Women, Yeshiva University, New York, New York, United States of America.
authors.forename: Kaylee
authors.initials: K
authors.lastname: Kampf
authors.affiliation: Center for Epigenomics and Department of Genetics (Division of Computational Genetics), Albert Einstein College of Medicine, Bronx, New York, United States of America.
authors.forename: Jill
authors.initials: J
authors.lastname: Kirschen
authors.affiliation: Center for Epigenomics and Department of Genetics (Division of Computational Genetics), Albert Einstein College of Medicine, Bronx, New York, United States of America.
authors.forename: Shahina B
authors.initials: SB
authors.lastname: Maqbool
authors.affiliation: Center for Epigenomics and Department of Genetics (Division of Computational Genetics), Albert Einstein College of Medicine, Bronx, New York, United States of America.
authors.forename: Zeineen
authors.initials: Z
authors.lastname: Momin
authors.affiliation: Center for Epigenomics and Department of Genetics (Division of Computational Genetics), Albert Einstein College of Medicine, Bronx, New York, United States of America.
authors.forename: David M
authors.initials: DM
authors.lastname: Reynolds
authors.affiliation: The Sheryl and Daniel R. Tishman Cognitive Neurophysiology Laboratory, Children's Evaluation and Rehabilitation Center, and Departments of Pediatrics and Neuroscience, Albert Einstein College of Medicine, Bronx, New York, United States of America; Department of Psychology, The College of Arts and Sciences, Syracuse University, Syracuse, New York, United States of America.
authors.forename: Natalie
authors.initials: N
authors.lastname: Russo
authors.affiliation: Children's Evaluation and Rehabilitation Center, Department of Pediatrics, Albert Einstein College of Medicine, Bronx, New York, United States of America.
authors.forename: Lisa
authors.initials: L
authors.lastname: Shulman
authors.affiliation: Center for Epigenomics and Department of Genetics (Division of Computational Genetics), Albert Einstein College of Medicine, Bronx, New York, United States of America.
authors.forename: Edyta
authors.initials: E
authors.lastname: Stasiek
authors.affiliation: Center for Epigenomics and Department of Genetics (Division of Computational Genetics), Albert Einstein College of Medicine, Bronx, New York, United States of America.
authors.forename: Jessica
authors.initials: J
authors.lastname: Tozour
authors.affiliation: Children's Evaluation and Rehabilitation Center, Department of Pediatrics, Albert Einstein College of Medicine, Bronx, New York, United States of America.
authors.forename: Maria
authors.initials: M
authors.lastname: Valicenti-McDermott
authors.affiliation: Information Technology Services, New York University, New York, New York, United States of America.
authors.forename: Shenglong
authors.initials: S
authors.lastname: Wang
authors.affiliation: Center for Epigenomics and Department of Genetics (Division of Computational Genetics), Albert Einstein College of Medicine, Bronx, New York, United States of America; Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York, United States of America.
authors.forename: Brett S
authors.initials: BS
authors.lastname: Abrahams
authors.affiliation: Center for Epigenomics and Department of Genetics (Division of Computational Genetics), Albert Einstein College of Medicine, Bronx, New York, United States of America.
authors.forename: Joseph
authors.initials: J
authors.lastname: Hargitai
authors.affiliation: Child Development and Rehabilitation Institute, Schneider Children's Medical Center, Petach Tikvah, Israel.
authors.forename: Dov
authors.initials: D
authors.lastname: Inbar
authors.affiliation: Center for Epigenomics and Department of Genetics (Division of Computational Genetics), Albert Einstein College of Medicine, Bronx, New York, United States of America.
authors.forename: Zhengdong
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Seaver Autism Center for Research and Treatment, Departments of Psychiatry, Neuroscience, and Genetics and Genomic Sciences, and the Friedman Brain Institute, Mount Sinai School of Medicine, New York, New York, United States of America.
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Buxbaum
authors.affiliation: The Sheryl and Daniel R. Tishman Cognitive Neurophysiology Laboratory, Children's Evaluation and Rehabilitation Center, and Departments of Pediatrics and Neuroscience, Albert Einstein College of Medicine, Bronx, New York, United States of America.
authors.forename: Sophie
authors.initials: S
authors.lastname: Molholm
authors.affiliation: The Sheryl and Daniel R. Tishman Cognitive Neurophysiology Laboratory, Children's Evaluation and Rehabilitation Center, and Departments of Pediatrics and Neuroscience, Albert Einstein College of Medicine, Bronx, New York, United States of America.
authors.forename: John J
authors.initials: JJ
authors.lastname: Foxe
authors.affiliation: Children's Evaluation and Rehabilitation Center, Department of Pediatrics, Albert Einstein College of Medicine, Bronx, New York, United States of America.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Marion
authors.affiliation: Center for Epigenomics and Department of Genetics (Division of Computational Genetics), Albert Einstein College of Medicine, Bronx, New York, United States of America.
authors.forename: Adam
authors.initials: A
authors.lastname: Auton
authors.affiliation: Center for Epigenomics and Department of Genetics (Division of Computational Genetics), Albert Einstein College of Medicine, Bronx, New York, United States of America.
authors.forename: John M
authors.initials: JM
authors.lastname: Greally
mesh_terms: D000328:Adult; D000367:Age Factors; D002659:Child Development Disorders, Pervasive / Q000235:genetics* / Q000473:pathology; D002869:Chromosome Aberrations; D019175:DNA Methylation / Q000235:genetics*; D044127:Epigenesis, Genetic; D005260:Female; D020869:Gene Expression Profiling; D015894:Genome, Human; D006239:Haplotypes; D006801:Humans; D008297:Male; D033261:Maternal-Fetal Relations; D008875:Middle Aged; D009030:Mosaicism; D011247:Pregnancy