Uncoupling histone H3K4 trimethylation from developmental gene expression via an equilibrium of COMPASS, Polycomb and DNA methylation
| Autor: | Elizabeth T. Bartom, Delphine Douillet, Caila Ryan, Kaixiang Cao, Zibo Zhao, Benjamin D. Singer, Edwin R. Smith, Emily J. Rendleman, Michal Ugarenko, Christie C. Sze, Andrea Piunti, Avani P. Shah, Ali Shilatifard, Kathryn A. Helmin, Marc A. Morgan, Stacy A. Marshall, Didi Zha |
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| Rok vydání: | 2019 |
| Předmět: |
Chromosomal Proteins
Non-Histone Polycomb-Group Proteins Mice Transgenic macromolecular substances Methylation Article Histones 03 medical and health sciences Mice 0302 clinical medicine Genetics Transcriptional regulation Animals Clustered Regularly Interspaced Short Palindromic Repeats Epigenetics Promoter Regions Genetic 030304 developmental biology Regulation of gene expression 0303 health sciences biology Lysine Gene Expression Regulation Developmental Mouse Embryonic Stem Cells Histone-Lysine N-Methyltransferase DNA Methylation Cell biology Chromatin Histone DNA demethylation Gene Knockdown Techniques DNA methylation biology.protein Trans-Activators 030217 neurology & neurosurgery Myeloid-Lymphoid Leukemia Protein |
| Zdroj: | Nat Genet BASE-Bielefeld Academic Search Engine |
| ISSN: | 1546-1718 |
| Popis: | The COMPASS protein family catalyzes histone H3 lysine 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 (mESCs) and 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, recruitment of DNA demethylation machineries 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 H3K4me3 underlies transcriptional regulation on MLL2/COMPASS targets. |
| Databáze: | OpenAIRE |
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