1. Uncoupling histone H3K4 trimethylation from developmental gene expression via an equilibrium of COMPASS, Polycomb and DNA methylation.
- Author
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Douillet D, Sze CC, Ryan C, Piunti A, Shah AP, Ugarenko M, Marshall SA, Rendleman EJ, Zha D, Helmin KA, Zhao Z, Cao K, Morgan MA, Singer BD, Bartom ET, Smith ER, and Shilatifard A
- Subjects
- Animals, Chromosomal Proteins, Non-Histone genetics, Clustered Regularly Interspaced Short Palindromic Repeats, Gene Knockdown Techniques, Histone-Lysine N-Methyltransferase genetics, Histones genetics, Lysine metabolism, Methylation, Mice, Mice, Transgenic, Mouse Embryonic Stem Cells physiology, Myeloid-Lymphoid Leukemia Protein genetics, Polycomb-Group Proteins genetics, Polycomb-Group Proteins metabolism, Promoter Regions, Genetic, Trans-Activators genetics, DNA Methylation, Gene Expression Regulation, Developmental, Histone-Lysine N-Methyltransferase metabolism, Histones metabolism, Mouse Embryonic Stem Cells metabolism, Myeloid-Lymphoid Leukemia Protein metabolism
- 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.
- Published
- 2020
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