A conformational switch in HP1 releases auto-inhibition to drive heterochromatin assembly

The Schizosaccharomyces pombe HP1 protein, Swi6, is shown to exist in an auto-inhibited state when unbound to chromatin, switching to a spreading-competent state upon binding to the HK9 methyl mark; disrupting this switch affects heterochromatin assembly and gene silencing. On–off switch for heterochromatin assembly Heterochromatin silences large regions of the genome and is crucial for many nuclear processes. Spreading of heterochromatin is mediated by HP1 proteins that assemble on histone H3K9-methylated chromatin. Here, Geeta Narlikar and colleagues use a variety of approaches to show that the fission yeast HP1 protein, Swi6, exists in an auto-inhibited state when not bound to chromatin. But upon binding to the H3K9 methyl mark and nucleosomal DNA, it switches to a state that is competent for spreading. Disruption of this switching disrupts heterochromatin assembly and gene silencing. 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 1 , 2 , 3 , 4 , 5 , 6 . 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 1 , 2 , 3 , 4 , 5 , 6 . 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 tha