Thursday, December 15, 2016

Genetics and environment combine to influence autism-associated genes

Researchers at UC Davis have shown that a well–known neurotoxin (PCB 95) and a chromosomal duplication (Dup15q) have a profound impact on DNA methylation, the epigenetic process that can influence gene activity. These cumulative genetic and environmental “hits” alter the epigenetic landscape during development, altering genes linked to autism spectrum disorder (ASD).

The study was published in the journal Cell Reports.

“We found multi–hit, cumulative impacts that are affecting epigenetic signatures in a common group of genes involved in synapses and autism,” said Janine LaSalle, professor in the Department of Medical Microbiology and Immunology. “This study is an example of how you can have two independent effects that, when combined, affect a larger set of genes important in the developing brain.”

Researchers have linked hundreds of genes to ASD, but it’s rare to find any specific gene variation in more than 1 percent of cases. Most often, multiple genes are involved. This work shows that environmental factors can also accentuate these genetic effects, LaSalle said.
Dup15q syndrome is the duplication of genetic material in chromosome 15 and is one of the more common ASD–associated variations. PCB (polychlorinated biphenyl) 95 is a widespread environmental contaminant that also alters methylation, influencing function in a variety of genes, including some modulated by Dup15q.

By studying Dup15q brain samples and normal controls, the team identified thousands of epigenetic variations that influenced 975 genes. To differentiate the effects of Dup15q and PCB 95, the researchers cultured Dup15q cells and exposed them to the toxin. In some cases, these two mechanisms affected the same molecular processes. In addition, the cultured cells showed a second duplication, called 22q duplication, which added another hit to the epigenetic landscape.

The study found that 65 percent of the genes with reduced methylation in the PCB 95 samples were also affected by Dup15q. In addition, the combined impact of PCB 95 and Dup15q generated a unique set of genes comprising 15 percent of the genes with reduced methylation that were not seen when the two factors were studied separately.

“Some of the same genes were coming up independently,” said LaSalle. “We saw a lot of functions associated with cell membranes and neuronal synapses. Those genes were affected by multiple hits.”

A number of alterations pointed to specific ASD mechanisms. Dup15q increased UBE3A, which codes for a protein that marks other proteins for destruction, reducing levels of RING1B and H2A.Z, two proteins that control DNA packaging and genome stability.

While a number of the genes identified in this study are potential drug targets, the early payoff may be diagnostics. LaSalle and her team are now working to identify markers that could predict autism.

“The placenta is like a time capsule of exposures during pregnancy and records epigenetic signatures,” said LaSalle. “These epigenetic signatures are something we could potentially test at birth.”

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.  Cumulative Impact of Polychlorinated Biphenyl and Large Chromosomal Duplications on DNA Methylation, Chromatin, and Expression of Autism Candidate Genes. Cell Reports Volume 17, Issue 11, p3035–3048.

•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

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. 

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