Chromatin interaction analyses elucidate the roles of PRC2-bound silencers in mouse development.

Document Type

Article

Publication Date

3-2020

Keywords

JGM, JMG, JAXCC

JAX Source

Nat Genet 2020 Mar; 52(3):264-272

Volume

52

Issue

3

First Page

264

Last Page

272

ISSN

1546-1718

PMID

32094912

DOI

https://doi.org/10.1038/s41588-020-0581-x

Grant

CA034196,DK107967, GM127531,HG009409

Abstract

Lineage-specific gene expression is modulated by a balance between transcriptional activation and repression during animal development. Knowledge about enhancer-centered transcriptional activation has advanced considerably, but silencers and their roles in normal development remain poorly understood. Here, we performed chromatin interaction analyses of Polycomb repressive complex 2 (PRC2), a key inducer of transcriptional gene silencing, to uncover silencers, their molecular identity and associated chromatin connectivity. Systematic analysis of cis-regulatory silencer elements reveals their chromatin features and gene-targeting specificity. Deletion of certain PRC2-bound silencers in mice results in transcriptional derepression of their interacting genes and pleiotropic developmental phenotypes, including embryonic lethality. While some PRC2-bound elements function as silencers in pluripotent cells, they can transition into active tissue-specific enhancers during development, highlighting their regulatory versatility. Our study characterizes the molecular profile of silencers and their associated chromatin architectures, and suggests the possibility of targeted reactivation of epigenetically silenced genes.

Comments

We thank R. Tewhey and C. Robinett for their feedback and comments on the manuscript, J. Denegre for coordinating mouse KO model generation and A. Lau for assistance with art images.

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