title: A two-state activation mechanism controls the histone methyltransferase Suv39h1.
abstract: 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.
authors.affiliation: Department of Chemistry, Princeton University, Princeton, New Jersey, USA.
authors.forename: Manuel M
authors.identifier: http://orcid.org/0000-0001-6701-0893
authors.initials: MM
authors.lastname: Müller
authors.affiliation: Department of Chemistry, Princeton University, Princeton, New Jersey, USA.
authors.forename: Beat
authors.initials: B
authors.lastname: Fierz
authors.affiliation: Department of Chemistry, Princeton University, Princeton, New Jersey, USA.
authors.forename: Lenka
authors.initials: L
authors.lastname: Bittova
authors.affiliation: Department of Chemistry, Princeton University, Princeton, New Jersey, USA.
authors.forename: Glen
authors.initials: G
authors.lastname: Liszczak
authors.affiliation: Department of Chemistry, Princeton University, Princeton, New Jersey, USA.
authors.forename: Tom W
authors.initials: TW
authors.lastname: Muir
mesh_terms: D000818:Animals; D002460:Cell Line; D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation / Q000502:physiology; D025461:Feedback, Physiological; D056914:Genomic Structural Variation; D006657:Histones / Q000378:metabolism; D006801:Humans; D007313:Insecta; D008745:Methylation; D008780:Methyltransferases / Q000235:genetics / Q000378:metabolism*; D008958:Models, Molecular; D011487:Protein Conformation; D011994:Recombinant Proteins / Q000737:chemistry; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D002843:Chromatin; D006657:Histones; D011994:Recombinant Proteins; D012097:Repressor Proteins; C407843:SUV39H1 protein, human; D008780:Methyltransferases