A two-state activation mechanism controls the histone methyltransferase Suv39h1

Manuel M. Müller, Beat Fierz, Lenka Bittova, Glen Liszczak, Tom W. Muir

Research output: Contribution to journalArticlepeer-review

74 Scopus citations


Specialized chromatin domains contribute to nuclear organization and regulation of gene expression. Gene-poor regions are di-and trimethylated at lysine 9 of histone H3 (H3K9me2 and H3K9me3) by the histone methyltransferase Suv39h1. This enzyme harnesses a positive feedback loop to spread H3K9me2 and H3K9me3 over extended heterochromatic regions. However, little is known about how feedback loops operate on complex biopolymers such as chromatin, in part because of the difficulty in obtaining suitable substrates. Here we describe the synthesis of multidomain 'designer chromatin' templates and their application to dissecting the regulation of human Suv39h1. We uncovered a two-step activation switch where H3K9me3 recognition and subsequent anchoring of the enzyme to chromatin allosterically promotes methylation activity and confirmed that this mechanism contributes to chromatin recognition in cells. We propose that this mechanism serves as a paradigm in chromatin biochemistry, as it enables highly dynamic sampling of chromatin state combined with targeted modification of desired genomic regions.

Original languageEnglish (US)
Pages (from-to)188-193
Number of pages6
JournalNature Chemical Biology
Issue number3
StatePublished - Feb 1 2016

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology


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