title: 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.
authors: Veteran's Affairs Boston Healthcare System, Boston, MA 02130, USA.
authors: Junghee
authors: J
authors: Lee
authors: Yu Jin
authors: YJ
authors: Hwang
authors: Jong-Yeon
authors: JY
authors: Shin
authors: Won-Chul
authors: WC
authors: Lee
authors: Jinhong
authors: J
authors: Wie
authors: Ki Yoon
authors: KY
authors: Kim
authors: Min Young
authors: MY
authors: Lee
authors: Daehee
authors: D
authors: Hwang
authors: Rajiv R
authors: RR
authors: Ratan
authors: Ae Nim
authors: AN
authors: Pae
authors: Neil W
authors: NW
authors: Kowall
authors: Insuk
authors: I
authors: So
authors: Jong-Il
authors: JI
authors: Kim
authors: Hoon
authors: H
authors: Ryu
mesh_terms: D000818:Animals; D020013:Calcium Signaling / Q000502:physiology*; D004195:Disease Models, Animal; D044127:Epigenesis, Genetic / Q000502:physiology*; D005260:Female; D006657:Histones / Q000502:physiology*; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000209:etiology* / Q000378:metabolism*; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009473:Neuronal Plasticity / Q000502:physiology; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D043643:Receptor, Muscarinic M1; D011976:Receptors, Muscarinic / Q000235:genetics / Q000378:metabolism*
chemical_list: C086088:CHRM1 protein, human; C086055:HTT protein, human; D006657:Histones; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D043643:Receptor, Muscarinic M1; D011976:Receptors, Muscarinic