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

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 F Korf, Janine M LaSalle

Research output: Contribution to journalArticle

23 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)3035-3048
Number of pages14
JournalCell Reports
Volume17
Issue number11
DOIs
StatePublished - Dec 13 2016

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Keywords

  • autism
  • chromatin
  • copy number variants
  • DNA methylation
  • epigenetic
  • gene x environment interaction
  • persistent organic pollutants

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Dunaway, K. W., Islam, M. S., Coulson, R. L., Lopez, S. J., Vogel Ciernia, A., Chu, R. G., Yasui, D. H., Pessah, I. N., Lott, P., Mordaunt, C., Meguro-Horike, M., Horike, S. I., Korf, I. F., & LaSalle, J. M. (2016). Cumulative Impact of Polychlorinated Biphenyl and Large Chromosomal Duplications on DNA Methylation, Chromatin, and Expression of Autism Candidate Genes. Cell Reports, 17(11), 3035-3048. https://doi.org/10.1016/j.celrep.2016.11.058