Epigenetic regulation of cholinergic receptor M1 (CHRM1) by histone H3K9me3 impairs Ca(2+) signaling in Huntington's disease.

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 Ca(2+)-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.

journal_name

Acta Neuropathol

journal_title

Acta neuropathologica

authors

Lee J,Hwang YJ,Shin JY,Lee WC,Wie J,Kim KY,Lee MY,Hwang D,Ratan RR,Pae AN,Kowall NW,So I,Kim JI,Ryu H

doi

10.1007/s00401-013-1103-z

subject

Has Abstract

pub_date

2013-05-01 00:00:00

pages

727-39

issue

5

eissn

0001-6322

issn

1432-0533

journal_volume

125

pub_type

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