Journal
MOLECULAR CELL
Volume 66, Issue 4, Pages 568-+Publisher
CELL PRESS
DOI: 10.1016/j.molcel.2017.04.018
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Funding
- Howard Hughes Medical Institute
- NIH [R01 GM112720, GM110174, CA196539]
- March of Dimes Foundation [1-FY15-312]
- NIGMS IRACDA K12 award
- NIH, National Institute of Environmental Health Sciences [Z01 ES101987]
- Leukemia and Lymphoma Society Robert Arceci Scholar award
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Monomethylation of histone H3 at lysine 4 (H3K4me1) and acetylation of histone H3 at lysine 27 (H3K27ac) are correlated with transcriptionally engaged enhancer elements, but the functional impact of these modifications on enhancer activity is not well understood. Here we used CRISPR/Cas9 genome editing to separate catalytic activity-dependent and independent functions of Mll3 (Kmt2c) and Mll4 (Kmt2d, Mll2), the major enhancer H3K4 monomethyltransferases. Loss of H3K4me1 from enhancers in Mll3/4 catalytically deficient cells causes partial reduction of H3K27ac, but has surprisingly minor effects on transcription from either enhancers or promoters. In contrast, loss of Mll3/4 proteins leads to strong depletion of enhancer Pol II occupancy and eRNA synthesis, concomitant with downregulation of target genes. Interestingly, downregulated genes exhibit reduced polymerase levels in gene bodies, but not at promoters, suggestive of pause-releasedefects. Altogether, our results suggest that enhancer H3K4me1 provides only a minor contribution to the long-range coactivator functionof Mll3/4.
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