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

Yichao Cai,Zhendong Cao,Ying Zhang,Vinay Tergaonkar,Anandhkumar Raju,Shang Li,Melissa Jane Fullwood,Jia Qi Tng,Greg Tucker-Kellogg,Yan Ping Loh,Mei Chee Lim,Lakshmanan Manikandan,Erez Lieberman Aiden

doi:10.1038/s41467-021-20940-y

Yichao Cai, Zhendong Cao + Show 11 more

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https://doi.org/10.1038/s41467-021-20940-y

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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.

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IntroductionWe investigate the hypothesis that H3K27me3-rich regions of the genome, defined from clusters of H3K27me[3] peaks, may be used to identify silencers that can regulate gene expression via proximity or looping
The mechanisms underlying gene repression and silencers are poorly understood
We overlapped our list of MRRs in K562 with the list of silencers that identified by ReSE and found that 10.66% of ReSE silencer elements overlap with our MRRs (Fig. 1c)

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Introduction

We investigate the hypothesis that H3K27me3-rich regions of the genome, defined from clusters of H3K27me[3] 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. We observe that H3K27me3-rich regions-associated genes and long-range chromatin interactions are susceptible to H3K27me[3] depletion. Our results characterize H3K27me3-rich regions and their mechanisms of functioning via looping. TFs can bind to proximal enhancers in the genome, and enhancers distal to genes can loop to gene promoters via chromatin interactions to activate gene expression[3]. Distant silencers are thought to loop over to target genes to silence them[10,11], and this mechanism has been demonstrated in studies of polycomb-mediated chromatin loops in Drosophila[12] and in mice. PRC1 and PRC2 have the ability to orchestrate genome architecture and repress gene expression[15]

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