1. H3K27me3-rich genomic regions can function as silencers to repress gene expression via chromatin interactions
- Author
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Greg Tucker-Kellogg, Ying Zhang, Zhendong Cao, Mei Chee Lim, Yichao Cai, Melissa J. Fullwood, Shang Li, Erez Lieberman Aiden, Yan Ping Loh, Lakshmanan Manikandan, Anandhkumar Raju, Vinay Tergaonkar, Jia Qi Tng, School of Biological Sciences, Cancer Science Institute of Singapore, National University of Singapore, Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Department of Biological Sciences, National University of Singapore, Cancer and Stem Cell Biology Programme, Duke-NUS Medical School, Computational Biology Programme, National University of Singapore, Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Department of Genetics, Baylor College of Medicine, and Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania
- Subjects
0301 basic medicine ,General Physics and Astronomy ,Genome ,Histones ,Gene Knockout Techniques ,Mice ,0302 clinical medicine ,Neoplasms ,Gene expression ,CRISPR ,RNA-Seq ,Regulation of gene expression ,Multidisciplinary ,biology ,Silencers ,Phenotype ,Chromatin ,Cell biology ,Gene Expression Regulation, Neoplastic ,Histone ,Biological sciences::Molecular biology [Science] ,Gene Knockdown Techniques ,030220 oncology & carcinogenesis ,Chromatin Immunoprecipitation Sequencing ,Epigenetics ,Female ,Transcription ,Science ,Epigenetic code ,macromolecular substances ,Epigenetic Repression ,Chromatin structure ,Article ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,Downregulation and upregulation ,Insulin-Like Growth Factor II ,Cell Line, Tumor ,Silencer Elements, Transcriptional ,Animals ,Humans ,Cancer models ,Enhancer ,Gene ,Gene knockout ,General Chemistry ,Xenograft Model Antitumor Assays ,Gene regulation ,Fibroblast Growth Factors ,030104 developmental biology ,biology.protein ,Function (biology) - Abstract
The mechanisms underlying gene repression and silencers are poorly understood. Here we investigate the hypothesis that H3K27me3-rich regions of the genome, defined from clusters of H3K27me3 peaks, may be used to identify silencers that can regulate gene expression via proximity or looping. We find that H3K27me3-rich regions are associated with chromatin interactions and interact preferentially with each other. H3K27me3-rich regions component removal at interaction anchors by CRISPR leads to upregulation of interacting target genes, altered H3K27me3 and H3K27ac levels at interacting regions, and altered chromatin interactions. Chromatin interactions did not change at regions with high H3K27me3, but regions with low H3K27me3 and high H3K27ac levels showed changes in chromatin interactions. Cells with H3K27me3-rich regions knockout also show changes in phenotype associated with cell identity, and altered xenograft tumor growth. Finally, we observe that H3K27me3-rich regions-associated genes and long-range chromatin interactions are susceptible to H3K27me3 depletion. Our results characterize H3K27me3-rich regions and their mechanisms of functioning via looping., Mechanisms underlying gene repression and silencers remain poorly understood. Here the authors investigate the role of H3K27me3-rich regions in the genome, as defined from clusters of H3K27me3 peaks, in regulating gene expression via looping.
- Published
- 2021