Not All H3K4 Methylations Are Created Equal: Mll2/COMPASS Dependency in Primordial Germ Cell Specification

• Published in: Molecular cell Vol. 65; no. 3; pp. 460 - 475.e6
• Main Authors: Hu, Deqing, Gao, Xin, Cao, Kaixiang, Morgan, Marc A., Mas, Gloria, Smith, Edwin R., Volk, Andrew G., Bartom, Elizabeth T., Crispino, John D., Di Croce, Luciano, Shilatifard, Ali
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 02-02-2017; Elsevier
• Subjects: Animals; Cell Differentiation; Cells, Cultured; Chromatin; CXXC domain; DNA-Binding Proteins - chemistry; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Embryonic development; Fibroblasts - cytology; Fibroblasts - metabolism; Gene expression regulation; Gene Expression Regulation, Developmental; Gene Regulatory Networks; Genetic Speciation; Germ Cells - cytology; Germ Cells - metabolism; HEK293 Cells; Histone; Histone-Lysine N-Methyltransferase; Histones - metabolism; Humans; Kmt2b; Mice; Mll2; Mouse embryonic stem cell; Mouse Embryonic Stem Cells - cytology; Mouse Embryonic Stem Cells - metabolism; Myeloid-Lymphoid Leukemia Protein - chemistry; Myeloid-Lymphoid Leukemia Protein - genetics; Myeloid-Lymphoid Leukemia Protein - metabolism; Neoplasm Proteins - chemistry; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Primordial germ cell; Promoter Regions, Genetic; Protein Domains; gene expression regulation; Mll2; Histone-Lysine N-Methyltransferase; embryonic development; Kmt2b; histone; chromatin; CXXC domain; mouse embryonic stem cell; primordial germ cell
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2017.01.013

The spatiotemporal regulation of gene expression is central for cell-lineage specification during embryonic development and is achieved through the combinatorial action of transcription factors/co-factors and epigenetic states at cis-regulatory elements. Here, we show that in addition to implementing H3K4me3 at promoters of bivalent genes, Mll2 (KMT2B)/COMPASS can also implement H3K4me3 at a subset of non-TSS regulatory elements, a subset of which shares epigenetic signatures of active enhancers. Our mechanistic studies reveal that association of Mll2's CXXC domain with CpG-rich regions plays an instrumental role for chromatin targeting and subsequent implementation of H3K4me3. Although Mll2/COMPASS is required for H3K4me3 implementation on thousands of loci, generation of catalytically mutant MLL2/COMPASS demonstrated that H3K4me3 implemented by this enzyme was essential for expression of a subset of genes, including those functioning in the control of transcriptional programs during embryonic development. Our findings suggest that not all H3K4 trimethylations implemented by MLL2/COMPASS are functionally equivalent.
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•Mll2/COMPASS occupies and catalyzes H3K4me3 at non-TSS elements•The CXXC domain of Mll2/COMPASS mediates its chromatin targeting•Mll2 regulates transcription of some genes including PGC specification genes•PGC specification requires Mll2/COMPASS’s methyltransferase activity
Hu et al. analyzed the contribution of MLL2’s methyltransferase and CXXC domain in the trimethylation of H3K4 in mouse ES cells and find that while it trimethylates H3K4 at both bivalent gene promoters and non-TSS elements, it regulates transcription at a limited number of genes including those required for PGC specification.