title: A conformational switch in HP1 releases auto-inhibition to drive heterochromatin assembly.
abstract: A hallmark of histone H3 lysine 9 (H3K9)-methylated heterochromatin, conserved from the fission yeast Schizosaccharomyces pombe to humans, is its ability to spread to adjacent genomic regions. Central to heterochromatin spread is heterochromatin protein 1 (HP1), which recognizes H3K9-methylated chromatin, oligomerizes and forms a versatile platform that participates in diverse nuclear functions, ranging from gene silencing to chromosome segregation. How HP1 proteins assemble on methylated nucleosomal templates and how the HP1-nucleosome complex achieves functional versatility remain poorly understood. Here we show that binding of the key S. pombe HP1 protein, Swi6, to methylated nucleosomes drives a switch from an auto-inhibited state to a spreading-competent state. In the auto-inhibited state, a histone-mimic sequence in one Swi6 monomer blocks methyl-mark recognition by the chromodomain of another monomer. Auto-inhibition is relieved by recognition of two template features, the H3K9 methyl mark and nucleosomal DNA. Cryo-electron-microscopy-based reconstruction of the Swi6-nucleosome complex provides the overall architecture of the spreading-competent state in which two unbound chromodomain sticky ends appear exposed. Disruption of the switch between the auto-inhibited and spreading-competent states disrupts heterochromatin assembly and gene silencing in vivo. These findings are reminiscent of other conditionally activated polymerization processes, such as actin nucleation, and open up a new class of regulatory mechanisms that operate on chromatin in vivo.
authors.affiliation: Department of Biochemistry and Biophysics, University of California San Francisco, California 94158, USA.
authors.forename: Daniele
authors.initials: D
authors.lastname: Canzio
authors.forename: Maofu
authors.initials: M
authors.lastname: Liao
authors.forename: Nariman
authors.initials: N
authors.lastname: Naber
authors.forename: Edward
authors.initials: E
authors.lastname: Pate
authors.forename: Adam
authors.initials: A
authors.lastname: Larson
authors.forename: Shenping
authors.initials: S
authors.lastname: Wu
authors.forename: Diana B
authors.initials: DB
authors.lastname: Marina
authors.forename: Jennifer F
authors.initials: JF
authors.lastname: Garcia
authors.forename: Hiten D
authors.initials: HD
authors.lastname: Madhani
authors.forename: Roger
authors.initials: R
authors.lastname: Cooke
authors.forename: Peter
authors.initials: P
authors.lastname: Schuck
authors.forename: Yifan
authors.initials: Y
authors.lastname: Cheng
authors.forename: Geeta J
authors.initials: GJ
authors.lastname: Narlikar
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D042002:Chromatin Assembly and Disassembly; D000090266:Chromobox Protein Homolog 5; D002868:Chromosomal Proteins, Non-Histone / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism* / Q000648:ultrastructure; D020285:Cryoelectron Microscopy; D020868:Gene Silencing; D006570:Heterochromatin / Q000737:chemistry / Q000378:metabolism* / Q000648:ultrastructure; D006657:Histones / Q000737:chemistry / Q000378:metabolism; D008745:Methylation; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009707:Nucleosomes / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000648:ultrastructure; D017434:Protein Structure, Tertiary; D012568:Schizosaccharomyces / Q000235:genetics / Q000378:metabolism*; D029702:Schizosaccharomyces pombe Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism* / Q000648:ultrastructure; D014982:Xenopus laevis
chemical_list: D002868:Chromosomal Proteins, Non-Histone; D006570:Heterochromatin; D006657:Histones; D009707:Nucleosomes; D029702:Schizosaccharomyces pombe Proteins; C465958:Swi6 protein, S pombe; D000090266:Chromobox Protein Homolog 5