Epigenetic regulation of cholinergic receptor M1 (CHRM1) by histone H3K9me3 impairs Ca2+ signaling in Huntington's disease
- Epigenetic regulation of cholinergic receptor M1 (CHRM1) by histone H3K9me3 impairs Ca2+ signaling in Huntington's disease
- 이정희; 황유진; 신정연; 이원철; 위진홍; 김기윤; 이민영; 황대희; Rajiv R. Ratan; 배애님; Neil W. Kowall; Insuk So; Jong-Il Kim; 류훈
- epigenetic; CHRM1; H3K9me3; huntington; Epigenomes; Cholinergic receptor M1; Heterochromatin; Huntington's disease
- Issue Date
- Acta neuropathologica
- VOL 125, NO 5, 727-739
- 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.
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