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

• Published in: Nature genetics Vol. 52; no. 6; pp. 615 - 625
• Main Authors: Douillet, Delphine, Sze, Christie C., Ryan, Caila, Piunti, Andrea, Shah, Avani P., Ugarenko, Michal, Marshall, Stacy A., Rendleman, Emily J., Zha, Didi, Helmin, Kathryn A., Zhao, Zibo, Cao, Kaixiang, Morgan, Marc A., Singer, Benjamin D., Bartom, Elizabeth T., Smith, Edwin R., Shilatifard, Ali
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01-06-2020; Nature Publishing Group
• Subjects: 42/40; 45/15; 631/337; 631/45; Activation; Agriculture; Animal Genetics and Genomics; Animals; Biomedical and Life Sciences; Biomedicine; Cancer Research; Chromatin; Chromosomal Proteins, Non-Histone - genetics; Clustered Regularly Interspaced Short Palindromic Repeats; Context; CpG islands; CRISPR; Demethylation; Deoxyribonucleic acid; DNA; DNA Methylation; Embryo cells; Embryonic stem cells; Epigenetic inheritance; Epigenetics; Gene expression; Gene Expression Regulation, Developmental; Gene Function; Gene Knockdown Techniques; Gene regulation; Gene silencing; Genes; Genetic transcription; Genomes; Histone H3; Histone-Lysine N-Methyltransferase - genetics; Histone-Lysine N-Methyltransferase - metabolism; Histones; Histones - genetics; Histones - metabolism; Human Genetics; Insects; Lysine - metabolism; Mammals; Methylation; Methyltransferases; Mice; Mice, Transgenic; Mouse Embryonic Stem Cells - metabolism; Mouse Embryonic Stem Cells - physiology; Myeloid-Lymphoid Leukemia Protein - genetics; Myeloid-Lymphoid Leukemia Protein - metabolism; Polycomb group proteins; Polycomb-Group Proteins - genetics; Polycomb-Group Proteins - metabolism; Population; Promoter Regions, Genetic; Proteins; Stem cell transplantation; Stem cells; Trans-Activators - genetics; Transcription
• ISSN: 1061-4036; 1546-1718
• DOI: 10.1038/s41588-020-0618-1

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.
A CRISPR screen for MLL2-dependent transcription identifies a compensatory repressive mechanism involving PRC2 and DNA methylation. PRC2 inactivation or DNA demethylation activates gene expression in the absence of H3K4me3.