Cumulative Impact of Polychlorinated Biphenyl and Large Chromosomal Duplications on DNA Methylation, Chromatin, and Expression of Autism Candidate Genes.

Abstract

Rare variants enriched for functions in chromatin regulation and neuronal synapses have been linked to autism. How chromatin and DNA methylation interact with environmental exposures at synaptic genes in autism etiologies is currently unclear. Using whole-genome bisulfite sequencing in brain tissue and a neuronal cell culture model carrying a 15q11.2-q13.3 maternal duplication, we find that significant global DNA hypomethylation is enriched over autism candidate genes and affects gene expression. The cumulative effect of multiple chromosomal duplications and exposure to the pervasive persistent organic pollutant PCB 95 altered methylation of more than 1,000 genes. Hypomethylated genes were enriched for H2A.Z, increased maternal UBE3A in Dup15q corresponded to reduced levels of RING1B, and bivalently modified H2A.Z was altered by PCB 95 and duplication. These results demonstrate the compounding effects of genetic and environmental insults on the neuronal methylome that converge upon dysregulation of chromatin and synaptic genes.

• Authors: Keith W Dunaway, M Saharul Islam, Rochelle L Coulson, S Jesse Lopez, Annie Vogel Ciernia, Roy G Chu, Dag H Yasui, Isaac N Pessah, Paul Lott, Charles Mordaunt, Makiko Meguro-Horike, Shin-Ichi Horike, Ian Korf, Janine M LaSalle
• Journal: Cell reports (Cell Rep) Vol. 17 Issue 11 Pg. 3035-3048 (12 13 2016) ISSN: 2211-1247 [Electronic] United States
• PMID: 27974215 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

Chemical References

• Chromatin
• 2,2',3,5',6-pentachlorobiphenyl
• Polychlorinated Biphenyls
• UBE3A protein, human
• Polycomb Repressive Complex 1
• RNF2 protein, human
• Ubiquitin-Protein Ligases

Topics

• Autistic Disorder (genetics, pathology)
• Base Sequence (drug effects)
• Brain (drug effects, metabolism, pathology)
• Chromatin (drug effects)
• Chromosome Duplication (genetics)
• DNA Methylation (drug effects, genetics)
• Epigenesis, Genetic
• Gene Expression Regulation (drug effects)
• Gene-Environment Interaction
• Genetic Association Studies
• Genome, Human
• Genomic Imprinting (genetics)
• Humans
• Polychlorinated Biphenyls (toxicity)
• Polycomb Repressive Complex 1 (genetics)
• Ubiquitin-Protein Ligases (genetics)