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

被引：55

作者：

Dunaway, Keith W. ^{[1
,2
,3
,4
]}

Islam, M. Saharul ^{[1
,2
,3
,4
]}

Coulson, Rochelle L. ^{[1
,2
,3
,4
]}

Lopez, S. Jesse ^{[1
,2
,3
,4
]}

Ciernia, Annie Vogel ^{[1
,2
,3
,4
]}

Chu, Roy G. ^{[1
,2
,3
,4
]}

Yasui, Dag H. ^{[1
,2
,3
,4
]}

Pessah, Isaac N. ^{[4
,5
]}

Lott, Paul ^{[2
]}

Mordaunt, Charles ^{[1
,2
,3
,4
]}

Meguro-Horike, Makiko ^{[6
]}

Horike, Shin-ichi ^{[6
]}

Korf, Ian ^{[2
]}

LaSalle, Janine M. ^{[1
,2
,3
,4
]}

机构：

[1] Univ Calif Davis, Med Microbiol & Immunol, Davis, CA 95616 USA

[2] Univ Calif Davis, Genome Ctr, Davis, CA 95616 USA

[3] Univ Calif Davis, MIND Inst, Davis, CA 95616 USA

[4] Univ Calif Davis, Ctr Childrens Environm Hlth, Davis, CA 95616 USA

[5] Univ Calif Davis, Vet Mol Biosci, Davis, CA 95616 USA

[6] Kanazawa Univ, Adv Sci Res Ctr, 13-1 Takaramachi, Kanazawa, Ishikawa 9208640, Japan

来源：

CELL REPORTS | 2016年 / 17卷 / 11期

关键词：

SPECTRUM DISORDER; COPY NUMBER; RISK; CHILDHOOD; GENETICS; HERITABILITY; ARCHITECTURE; METABOLISM; PESTICIDES; LANDSCAPE;

D O I：

10.1016/j.celrep.2016.11.058

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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.

引用

页码：3035 / 3048

页数：14

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