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.”
https://www.mdlinx.com/neurology/top-medical-news/article/2016/12/15/5
___________________________________________________________________________
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.
Highlights
•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
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.
No comments:
Post a Comment