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Histone H3K4 monomethylation catalyzed by Trr and mammalian COMPASS-like proteins at enhancers is dispensable for development and viability

Nature Genetics volume 49, pages 16471653 (2017) | Download Citation


Histone H3 lysine 4 monomethylation (H3K4me1) is an evolutionarily conserved feature of enhancer chromatin catalyzed by the COMPASS-like methyltransferase family, which includes Trr in Drosophila melanogaster and MLL3 (encoded by KMT2C) and MLL4 (encoded by KMT2D) in mammals1,2,3. Here we demonstrate that Drosophila embryos expressing catalytically deficient Trr eclose and develop to productive adulthood. Parallel experiments with a trr allele that augments enzyme product specificity show that conversion of H3K4me1 at enhancers to H3K4me2 and H3K4me3 is also compatible with life and results in minimal changes in gene expression. Similarly, loss of the catalytic SET domains of MLL3 and MLL4 in mouse embryonic stem cells (mESCs) does not disrupt self-renewal. Drosophila embryos with trr alleles encoding catalytic mutants manifest subtle developmental abnormalities when subjected to temperature stress or altered cohesin levels. Collectively, our findings suggest that animal development can occur in the context of Trr or mammalian COMPASS-like proteins deficient in H3K4 monomethylation activity and point to a possible role for H3K4me1 on cis-regulatory elements in specific settings to fine-tune transcriptional regulation in response to environmental stress.

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We thank members of the Shilatifard laboratory for their critical feedback during preparation of the manuscript and L. Shilatifard for editorial assistance. R.R. is supported by the NIH/NCI under the Ruth L. Kirschstein National Research Service Award (F31CA213928). A.P. is an EMBO postdoctoral fellow (ALTF 372-2015), and his work in the Shilatifard laboratory is supported by AIRC and Marie Curie Actions–People–COFUND. H.-M.H. is supported by the NIH (R00CA181506). E.R.S. is supported by the NIH (R50CA211428). C.C.S. is supported in part by an NIH/NCI training grant (T32CA09560). Studies on Drosophila Trr and the mammalian MLL3 and MLL4 COMPASS-like family in the Shilatifard laboratory are supported in part by a generous Outstanding Investigator Award from the National Institute of Health to A.S. (R35CA197569).

Author information

Author notes

    • Hans-Martin Herz

    Present address: Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.

    • Ryan Rickels
    •  & Hans-Martin Herz

    These authors contributed equally to this work.


  1. Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.

    • Ryan Rickels
    • , Christie C Sze
    • , Kaixiang Cao
    • , Marc A Morgan
    • , Clayton K Collings
    • , Yoh-hei Takahashi
    • , Lu Wang
    • , Emily J Rendleman
    • , Stacy A Marshall
    • , Elizabeth T Bartom
    • , Andrea Piunti
    • , Edwin R Smith
    •  & Ali Shilatifard
  2. Stowers Institute for Medical Research, Kansas City, Missouri, USA.

    • Hans-Martin Herz
    •  & Annika Krueger
  3. Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, Missouri, USA.

    • Maria Gause
    •  & Dale Dorsett
  4. Department of Chemistry, Northwestern University, Evanston, Illinois, USA.

    • Nebiyu A Abshiru
    •  & Neil L Kelleher
  5. Robert H. Lurie NCI Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.

    • Ali Shilatifard


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A.S. and H.-M.H. conceived and initiated the project. R.R. performed Drosophila ChIP–seq studies, conducted genetic tests and stress response assays, and wrote the manuscript. C.C.S. and A.K. assisted with Drosophila experiments. Y.T. performed Trr/WRAD reconstitution and in vitro methyltransferase assays. K.C. and M.A.M. generated mutant mESCs, and L.W., A.P., and C.C.S. assisted with mammalian studies. Sequencing data were analyzed by C.K.C. and E.T.B. while libraries were generated and sequenced by E.J.R. and S.A.M. Mass spectrometry was performed and results analyzed by N.A.A. and N.L.K. Cohesin genetic interaction data were contributed by M.G. and D.D. Critical feedback and advice were provided by E.R.S. throughout the course of this project.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Ali Shilatifard.

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