Uncoupling Histone H3K4 Trimethylation from Developmental Gene Expression Via an Equilibrium of COMPASS, Polycomb and DNA Methylation

Overview

Journal Nat Genet

Specialty Genetics

Date 2020 May 13

PMID 32393859

Citations 56

Authors

Delphine Douillet

Christie C Sze

Caila Ryan

Andrea Piunti

Avani P Shah

Michal Ugarenko

Stacy A Marshall

Emily J Rendleman

Didi Zha

Kathryn A Helmin

Zibo Zhao

Kaixiang Cao

Marc A Morgan

Benjamin D Singer

Elizabeth T Bartom

Edwin R Smith

Ali Shilatifard

Affiliations

Soon will be listed here.

Abstract

The COMPASS protein family catalyzes histone H3 Lys 4 (H3K4) methylation and its members are essential for regulating gene expression. MLL2/COMPASS methylates H3K4 on many developmental genes and bivalent clusters. To understand MLL2-dependent transcriptional regulation, we performed a CRISPR-based screen with an MLL2-dependent gene as a reporter in mouse embryonic stem cells. We found that MLL2 functions in gene expression by protecting developmental genes from repression via repelling PRC2 and DNA methylation machineries. Accordingly, repression in the absence of MLL2 is relieved by inhibition of PRC2 and DNA methyltransferases. Furthermore, DNA demethylation on such loci leads to reactivation of MLL2-dependent genes not only by removing DNA methylation but also by opening up previously CpG methylated regions for PRC2 recruitment, diluting PRC2 at Polycomb-repressed genes. These findings reveal how the context and function of these three epigenetic modifiers of chromatin can orchestrate transcriptional decisions and demonstrate that prevention of active repression by the context of the enzyme and not H3K4 trimethylation underlies transcriptional regulation on MLL2/COMPASS targets.

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