Epigenetic regulation of cholinergic receptor M1 (CHRM1) by histone H3K9me3 impairs Ca2+ signaling in Huntington's disease

Title
Epigenetic regulation of cholinergic receptor M1 (CHRM1) by histone H3K9me3 impairs Ca2+ signaling in Huntington's disease
Authors
이정희황유진신정연이원철위진홍김기윤이민영황대희Rajiv R. Ratan배애님Neil W. KowallInsuk SoJong-Il Kim류훈
Keywords
epigenetic; CHRM1; H3K9me3; huntington; Epigenomes; Cholinergic receptor M1; Heterochromatin; Huntington's disease
Issue Date
2013-05
Publisher
Acta neuropathologica
Citation
VOL 125, NO 5, 727-739
Abstract
Huntington’s disease (HD) is an autosomal dominant neurodegenerative disease caused by an expanded trinucleotide CAG repeat in the gene coding for huntingtin. Deregulation of chromatin remodeling is linked to the pathogenesis of HD but the mechanism remains elusive. To identify what genes are deregulated by trimethylated histone H3K9 (H3K9me3)-dependent heterochromatin, we performed H3K9me3-ChIP genome-wide sequencing combined with RNA sequencing followed by platform integration analysis in stable striatal HD cell lines (STHdhQ7/7 and STHdhQ111/111) cells. We found that genes involving neuronal synaptic transmission including cholinergic receptor M1 (CHRM1), cell motility, and neuronal differentiation pathways are downregulated while their promoter regions are highly occupied with H3K9me3 in HD. Moreover, we found that repression of CHRM1 gene expression by H3K9me3 impairs Ca2+-dependent neuronal signal transduction in stable cell lines expressing mutant HD protein. Thus, our data indicate that the epigenetic modifications, such as aberrant H3K9me3-dependent heterochromatin plasticity, directly contribute to the pathogenesis of HD.
URI
http://pubs.kist.re.kr/handle/201004/46246
ISSN
00016322
Appears in Collections:
KIST Publication > Article
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