Not All H3K4 methylations are Created Equal: Mll2/COMPASS Dependency in Primordial Germ Cell Specification. Mus musculus

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 the epigenetic states at cis-regulatory elements. Previously, we reported that Mll2 (KMT2B)/COMPASS is responsible for the implementation of H3K4me3 at promoters of bivalent genes. Here, we show that Mll2/COMPASS can also implements H3K4me3 at some of the non-TSS regulatory elements, a subset of which share epigenetic signatures of active enhancers. Our mechanistic studies reveal that the 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 sites, it appears to be essential for the expression of a subset of genes, including those functioning in the control of transcriptional programs during embryonic development, indicating that not all H3K4 trimethylations implemented by MLL2/COMPASS are functionally equivalent. Overall design: Characterization of H3K4me3 and Mll2 occupancy by ChIP-seq in mouse embryonic stem cells and identifying their role in gene expression and during differentiation by RNA-seq studies. A high resolution 4C-seq experiments involving two restriction digests (HindIII and NlaIII) were performed to investigate the interaction bewteen promoters of Prdm1 and Prdm14 (viewponts) and cis-regulatory elements whose H3K4me3 is catalyzed by Mll2 in mouse embryonic stem cells.