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.
Original language | English (US) |
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Pages (from-to) | 460-475.e6 |
Journal | Molecular cell |
Volume | 65 |
Issue number | 3 |
DOIs | |
State | Published - Feb 2 2017 |
Funding
We thank Stacy Marshall and Emily Rendleman for help with Illumina sequencing. We are grateful to the Stowers Molecular Biology core and Tissue Culture core for assistance with the generation of some of the NGS data and maintenance of cell lines. We thank Andrea Piunti for critical reading of the manuscript and Laura Shilatifard for editorial assistance. D.H. was supported by the Robert H. Lurie Comprehensive Cancer Center – Translational Bridge Program Fellowship in Lymphoma Research. G.M. received the support of Ia Convocatoria de Ayudas Fundación BBVA a Investigadores, Innovadores y Creadores Culturales. A.V. was supported by NIH training grant T32CA080621. These studies were further supported by grants from the Spanish “Ministerio de Educación y Ciencia” (SAF2013-48926-P) and AGAUR to L.D.C., and NIH grants R01CA101774 to J.D.C., R50CA211428 to E.R.S., and R35CA197569 to A.S.
Keywords
- CXXC domain
- Histone-Lysine N-Methyltransferase
- Kmt2b
- Mll2
- chromatin
- embryonic development
- gene expression regulation
- histone
- mouse embryonic stem cell
- primordial germ cell
ASJC Scopus subject areas
- Molecular Biology
- Cell Biology