RT Journal Article
SR Electronic
T1 H3K27me3-rich genomic regions can function as silencers to repress gene expression via chromatin interactions
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 684712
DO 10.1101/684712
A1 Yichao Cai
A1 Ying Zhang
A1 Yan Ping Loh
A1 Jia Qi Tng
A1 Mei Chee Lim
A1 Zhendong Cao
A1 Anandhkumar Raju
A1 Shang Li
A1 Lakshmanan Manikandan
A1 Vinay Tergaonkar
A1 Greg Tucker-Kellogg
A1 Melissa Jane Fullwood
YR 2019
UL http://biorxiv.org/content/early/2019/07/09/684712.abstract
AB Gene repression and silencers are poorly understood. H3K27me3 is a repressive histone modification; we reason 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. We found that MRRs are associated with chromatin interactions and tend to interact preferentially with each other. EZH2 inhibition or knockout showed that H3K27me3 was not required for maintenance of chromatin interactions, but genes at or looping to MRRs were upregulated upon loss of H3K27me3. To understand the function of MRRs, we used CRISPR to excise components of MRRs at interaction anchors and functionally characterized the knockouts in cellular assays and xenograft models. MRR removal can lead to upregulation of interacting target genes, altered chromatin interactions, changes in phenotype associated with cell identity, and altered xenograft tumor growth. Our results characterize silencers and their mechanisms of functioning.