Uncoupling histone H3K4 trimethylation from developmental gene expression via an equilibrium of COMPASS, Polycomb and DNA methylation

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*

*Corresponding author for this work

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)615-625
Number of pages11
JournalNature Genetics
Volume52
Issue number6
DOIs
StatePublished - Jun 1 2020

ASJC Scopus subject areas

  • Genetics

Fingerprint Dive into the research topics of 'Uncoupling histone H3K4 trimethylation from developmental gene expression via an equilibrium of COMPASS, Polycomb and DNA methylation'. Together they form a unique fingerprint.

  • Cite this

    Douillet, D., Sze, C. C., Ryan, C., Piunti, A., Shah, A. P., Ugarenko, M., Marshall, S. A., Rendleman, E. J., Zha, D., Helmin, K. A., Zhao, Z., Cao, K., Morgan, M. A., Singer, B. D., Bartom, E. T., Smith, E. R., & Shilatifard, A. (2020). Uncoupling histone H3K4 trimethylation from developmental gene expression via an equilibrium of COMPASS, Polycomb and DNA methylation. Nature Genetics, 52(6), 615-625. https://doi.org/10.1038/s41588-020-0618-1