A two-state activation mechanism controls the histone methyltransferase Suv39h1.

TitleA two-state activation mechanism controls the histone methyltransferase Suv39h1.
Publication TypeJournal Article
Year of Publication2016
AuthorsMüller, MM, Fierz, B, Bittova, L, Liszczak, G, Muir, TW
JournalNat Chem Biol
Date Published2016 Mar
KeywordsAnimals, Cell Line, Chromatin, Enzyme Activation, Feedback, Physiological, Genomic Structural Variation, Histones, Humans, Insecta, Methylation, Methyltransferases, Models, Molecular, Protein Conformation, Recombinant Proteins, Repressor Proteins

<p>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.</p>

Alternate JournalNat Chem Biol
PubMed ID26807716
PubMed Central IDPMC4876634
Grant ListF32 GM110880 / GM / NIGMS NIH HHS / United States
P01 CA196539 / CA / NCI NIH HHS / United States
R01 GM107047 / GM / NIGMS NIH HHS / United States
R01-GM107047 / GM / NIGMS NIH HHS / United States