H3K27ME3-RICH GENOMIC REGIONS CAN FUNCTION AS SILENCERS TO REPRESS GENE EXPRESSION VIA CHROMATIN INTERACTIONS

Abstract

Gene repression and silencers are poorly understood. Although active elements such as enhancers and super-enhancers have been identified and extensively studied, repressive elements in the human genome are less well understood. We reasoned that H3K27me3-rich regions (MRRs) of the genome defined from clusters of H3K27me3 peaks may be used to identify silencers that can regulate gene expression via proximity or looping. MRRs are associated with chromatin interactions and interact preferentially with each other. MRR-associated genes and long-range chromatin interactions were susceptible to H3K27me3 depletion. MRR component removal at interaction anchors by CRISPR can lead to upregulation of target genes and altered chromatin interactions, suggesting that H3K27me3-rich regions can function as silencers via chromatin interactions. The MRR knockout cells also underwent changes in phenotype associated with cell identity, and altered xenograft tumor growth. Taken together, our results characterize H3K27me3-rich regions and their mechanisms of functioning.