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The Mll2 branch of the COMPASS family regulates bivalent promoters in mouse embryonic stem cells

Nature Structural & Molecular Biology volume 20, pages 1093–1097 (2013)Cite this article

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Abstract

Promoters of many developmentally regulated genes, in the embryonic stem cell state, have a bivalent mark of H3K27me3 and H3K4me3, proposed to confer precise temporal activation upon differentiation. Although Polycomb repressive complex 2 is known to implement H3K27 trimethylation, the COMPASS family member responsible for H3K4me3 at bivalently marked promoters was previously unknown. Here, we identify Mll2 (KMT2b) as the enzyme catalyzing H3K4 trimethylation at bivalentlymarked promoters in embryonic stem cells. Although H3K4me3 at bivalent genes is proposed to prime future activation, we detected no substantial defect in rapid transcriptional induction after retinoic acid treatment in Mll2-depleted cells. Our identification of the Mll2 complex as the COMPASS family member responsible for H3K4me3 marking bivalent promoters provides an opportunity to reevaluate and experimentally test models for the function of bivalency in the embryonic stem cell state and in differentiation.

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Figure 1: Mll2 is required for the trimethylation of Histone H3 Lys4 at bivalent homeotic genes.
Figure 2: Mll2 is required for the implementation of bivalency genome wide.
Figure 3: Loss of bivalency has little effect on transcriptional induction kinetics in response to retinoic acid.

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Acknowledgements

We thank R. Egidy, A. Peak, A. Perera and the rest of the Stowers Molecular Biology core for help with Illumina sequencing. We are grateful to the Stowers Tissue Culture core for assistance with the generation and maintenance of cell lines. We thank L. Shilatifard and L. Kennedy for editorial assistance. These studies were supported in part by the US National Cancer Institute grant R01CA150265 to A.S.

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  1. Stowers Institute for Medical Research, Kansas City, Missouri, USA

    Deqing Hu, Alexander S Garruss, Xin Gao, Marc A Morgan, Malcolm Cook, Edwin R Smith & Ali Shilatifard

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  1. Deqing Hu
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  2. Alexander S Garruss
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Contributions

D.H., M.A.M., E.R.S. and A.S. designed the experiments, D.H. and M.A.M. performed the experiments, A.S.G., X.G. and M.C. performed bioinformatics analysis, and all authors were involved in interpretation of results and preparation of the manuscript.

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Correspondence to Ali Shilatifard.

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The authors declare no competing financial interests.

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Hu, D., Garruss, A., Gao, X. et al. The Mll2 branch of the COMPASS family regulates bivalent promoters in mouse embryonic stem cells. Nat Struct Mol Biol 20, 1093–1097 (2013). https://doi.org/10.1038/nsmb.2653

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