Determinants of Histone H3K4 Methylation Patterns

Luis M. Soares, P. Cody He, Yujin Chun, Hyunsuk Suh, Tae Soo Kim, Stephen Buratowski

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Various factors differentially recognize trimethylated histone H3 lysine 4 (H3K4me3) near promoters, H3K4me2 just downstream, and promoter-distal H3K4me1 to modulate gene expression. This methylation “gradient” is thought to result from preferential binding of the H3K4 methyltransferase Set1/complex associated with Set1 (COMPASS) to promoter-proximal RNA polymerase II. However, other studies have suggested that location-specific cues allosterically activate Set1. Chromatin immunoprecipitation sequencing (ChIP-seq) experiments show that H3K4 methylation patterns on active genes are not universal or fixed and change in response to both transcription elongation rate and frequency as well as reduced COMPASS activity. Fusing Set1 to RNA polymerase II results in H3K4me2 throughout transcribed regions and similarly extended H3K4me3 on highly transcribed genes. Tethered Set1 still requires histone H2B ubiquitylation for activity. These results show that higher-level methylations reflect not only Set1/COMPASS recruitment but also multiple rounds of transcription. This model provides a simple explanation for non-canonical methylation patterns at some loci or in certain COMPASS mutants. Soares et al. show that the H3K4 methylation gradient, an important chromatin modification at active genes, is determined not only by targeted recruitment of the Set1 methyltransferase but also by transcription frequency and elongation rate. Fusing Set1 to RNA polymerase results in extended H3K4 methylation throughout the gene.

Original languageEnglish
Pages (from-to)773-785.e6
JournalMolecular Cell
Issue number4
StatePublished - 16 Nov 2017

Bibliographical note

Funding Information:
We thank Fred Winston, Scott Briggs, and Jeffrey Strathern for strains. This work was supported by the NIH ( GM46498 and GM56663 to S.B.) and the Korean National Research Foundation ( 2013S1A2A2035342 to T.S.K. and S.B.). P.C.H. was a Herchel Smith-Harvard Undergraduate Science Research Fellow and received support from the Harvard College Research Program .

Publisher Copyright:
© 2017 Elsevier Inc.


  • RNA polymerase II
  • Set1
  • histone H3 lysine 4
  • histone methylation
  • transcription elongation


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