title: Genome-wide profiling of chromatin signatures reveals epigenetic regulation of MicroRNA genes in colorectal cancer.
abstract: Altered expression of microRNAs (miRNA) occurs commonly in human cancer, but the mechanisms are generally poorly understood. In this study, we examined the contribution of epigenetic mechanisms to miRNA dysregulation in colorectal cancer by carrying out high-resolution ChIP-seq. Specifically, we conducted genome-wide profiling of trimethylated histone H3 lysine 4 (H3K4me3), trimethylated histone H3 lysine 27 (H3K27me3), and dimethylated histone H3 lysine 79 (H3K79me2) in colorectal cancer cell lines. Combining miRNA expression profiles with chromatin signatures enabled us to predict the active promoters of 233 miRNAs encoded in 174 putative primary transcription units. By then comparing miRNA expression and histone modification before and after DNA demethylation, we identified 47 miRNAs encoded in 37 primary transcription units as potential targets of epigenetic silencing. The promoters of 22 transcription units were associated with CpG islands (CGI), all of which were hypermethylated in colorectal cancer cells. DNA demethylation led to increased H3K4me3 marking at silenced miRNA genes, whereas no restoration of H3K79me2 was detected in CGI-methylated miRNA genes. DNA demethylation also led to upregulation of H3K4me3 and H3K27me3 in a number of CGI-methylated miRNA genes. Among the miRNAs we found to be dysregulated, many of which are implicated in human cancer, miR-1-1 was methylated frequently in early and advanced colorectal cancer in which it may act as a tumor suppressor. Our findings offer insight into the association between chromatin signatures and miRNA dysregulation in cancer, and they also suggest that miRNA reexpression may contribute to the effects of epigenetic therapy.
authors: Department of Molecular Biology, First Department of Internal Medicine, Scholarly Information Center, Department of Public Health, and Medical Genome Science, Research Institute for Frontier Medicine, Sapporo Medical University, Sapporo, Japan. hsuzuki@sapmed.ac.jp
authors: Hiromu
authors: H
authors: Suzuki
authors: Shintaro
authors: S
authors: Takatsuka
authors: Hirofumi
authors: H
authors: Akashi
authors: Eiichiro
authors: E
authors: Yamamoto
authors: Masanori
authors: M
authors: Nojima
authors: Reo
authors: R
authors: Maruyama
authors: Masahiro
authors: M
authors: Kai
authors: Hiro-O
authors: HO
authors: Yamano
authors: Yasushi
authors: Y
authors: Sasaki
authors: Takashi
authors: T
authors: Tokino
authors: Yasuhisa
authors: Y
authors: Shinomura
authors: Kohzoh
authors: K
authors: Imai
authors: Minoru
authors: M
authors: Toyota
mesh_terms: D002843:Chromatin / Q000378:metabolism*; D015179:Colorectal Neoplasms / Q000235:genetics*; D044127:Epigenesis, Genetic; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D055106:Genome-Wide Association Study; D045325:HCT116 Cells; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D011401:Promoter Regions, Genetic
chemical_list: D002843:Chromatin; D035683:MicroRNAs