Nucleosome remodeling by a CHD enzyme promotes H3K9 methylation establishment and spreading via remodeler-writer feedback

Abstract

In Schizosaccharomyces pombe, the conserved CHD remodeler Mit1 function within the SHREC remodeler-deacetylase complex (a homolog of the metazoan Mi-2/NuRD complex), which is essential for H3K9 methylation-dependent heterochromatin establishment. However, the mechanism by which remodeler activity promotes silencing is unknown. Current models posit a hierarchical relationship between histone modifications and remodeler activity, with Mit1 acting exclusively downstream of H3K9 methylation. Here, we challenge this model by showing that tethering Mit1 at an ectopic site within euchromatin is sufficient to initiate heterochromatin assembly and generate extended domains of de novo H3K9 methylation. This process requires the Mit1 catalytic activity but does not involve direct physical interaction with Clr4, suggesting Mit1-mediated nucleosome remodeling creates a chromatin context that enhances Clr4 function. Using a genome-wide deletion screen, we determined that Mit1-initiated silencing requires all core heterochromatin factors and is critically dependent on Clr4 dosage. Furthermore, Mit1 activity facilitates heterochromatin spreading at subtelomeric regions and promotes H3K9 methylation at novel genomic sites implicated in cellular adaptation. Together, our findings support a model in which remodeler-writer pairs, analogous to reader-writer pairs, constitute conserved regulatory modules through which nucleosome organization directs the establishment of heritable epigenetic states.