Author Information
1Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
2Department of Biological Sciences, National University of Singapore, Singapore, Singapore.
3Cancer and Stem Cell Biology Programme, Duke-NUS Medical School, Singapore, Singapore.
4Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
5Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Proteos, Singapore.
6Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
7Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
8Department of Biological Sciences, National University of Singapore, Singapore, Singapore. dbsgtk@nus.edu.sg.
9Computational Biology Programme, National University of Singapore, Singapore, Singapore. dbsgtk@nus.edu.sg.
10Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore. mfullwood@ntu.edu.sg.
11Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Proteos, Singapore. mfullwood@ntu.edu.sg.
12School of Biological Sciences, Nanyang Technological University, Singapore, Singapore. mfullwood@ntu.edu.sg.
#Contributed equally.
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.
PMID: 33514712 DOI: 10.1038/s41467-021-20940-y