H3K27me3-rich genomic regions can function as silencers to repress gene expression via chromatin interactions

Yichao Cai, Ying Zhang, Yan Ping Loh, Jia Qi Tng, Mei Chee Lim, Zhendong Cao, Anandhkumar Raju, Erez Lieberman Aiden, Shang Li, Lakshmanan Manikandan, Vinay Tergaonkar, Greg Tucker-Kellogg () and Melissa Jane Fullwood ()
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Yichao Cai: National University of Singapore
Ying Zhang: National University of Singapore
Yan Ping Loh: National University of Singapore
Jia Qi Tng: National University of Singapore
Mei Chee Lim: National University of Singapore
Zhendong Cao: National University of Singapore
Anandhkumar Raju: Technology and Research (A*STAR)
Erez Lieberman Aiden: Department of Molecular and Human Genetics, Baylor College of Medicine
Shang Li: Duke-NUS Medical School
Lakshmanan Manikandan: Technology and Research (A*STAR)
Vinay Tergaonkar: Technology and Research (A*STAR)
Greg Tucker-Kellogg: National University of Singapore
Melissa Jane Fullwood: National University of Singapore

Nature Communications, 2021, vol. 12, issue 1, 1-22

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-20940-y

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