Not all H3K4 Methylations are created equal: Mll2/COMPASS dependency in primordial germ cell specification

Hu, Deqing; Gao, Xin; Cao, Kaixiang; Morgan, Marc Alard J.; Mas Martín, Glòria; Smith, Edwin R.; Volk, Andrew G.; Bartom, Elizabeth T.; Crispino, John D.; Di Croce, Luciano; Shilatifard, Ali

doi:http://dx.doi.org/10.1016/j.molcel.2017.01.013

Not all H3K4 Methylations are created equal: Mll2/COMPASS dependency in primordial germ cell specification

Citation

Hu D, Gao X, Cao K, Morgan MA, Mas G, Smith ER et al. Not All H3K4 Methylations Are Created Equal: Mll2/COMPASS Dependency in Primordial Germ Cell Specification. Mol Cell. 2017 Feb 2;65(3):460-75. DOI: 10.1016/j.molcel.2017.01.013

Abstract

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.