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

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...

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Published in:	Cell reports (Cambridge) Vol. 17; no. 11; pp. 3035 - 3048
Main Authors:	Dunaway, Keith W., Islam, M. Saharul, Coulson, Rochelle L., Lopez, S. Jesse, Vogel Ciernia, Annie, Chu, Roy G., Yasui, Dag H., Pessah, Isaac N., Lott, Paul, Mordaunt, Charles, Meguro-Horike, Makiko, Horike, Shin-ichi, Korf, Ian, LaSalle, Janine M.
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 13-12-2016
Subjects:	autism Autistic Disorder - genetics Autistic Disorder - pathology Base Sequence - drug effects Brain - drug effects Brain - metabolism Brain - pathology chromatin Chromatin - drug effects Chromosome Duplication - genetics copy number variants DNA methylation DNA Methylation - drug effects DNA Methylation - genetics Epigenesis, Genetic epigenetic Gene Expression Regulation - drug effects gene x environment interaction Gene-Environment Interaction Genetic Association Studies Genome, Human Genomic Imprinting - genetics Humans persistent organic pollutants Polychlorinated Biphenyls - toxicity Polycomb Repressive Complex 1 - genetics Ubiquitin-Protein Ligases - genetics epigenetic DNA methylation gene x environment interaction persistent organic pollutants copy number variants chromatin autism
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Summary:	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. [Display omitted] •The Dup15q postmortem brain exhibited global DNA hypomethylation over synaptic genes•The Dup15q cell model revealed cumulative effects of duplications and PCB 95 exposure•Increased UBE3A in Dup15q reduced RING1, affecting transcription of synaptic genes•Known druggable autism genes were enriched in cumulative genetic and PCB 95 lists Dunaway et al. find that postmortem brain and cell culture models of an autism chromosomal duplication syndrome show altered DNA methylation over genes encoding synaptic functions. The cumulative effects of multiple genetic and environmental hits were investigated genome-wide, revealing enrichment of genes for known autism mutations and drug targets.
Bibliography:	equal contribution Lead contact: jmlasalle@ucdavis.edu
ISSN:	2211-1247 2211-1247
DOI:	10.1016/j.celrep.2016.11.058