Roles of Chromatin-modifying Factors in Epigenetic Control of the Genome

Division Of Basic Sciences - Nci

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Abstract

The assembly and maintenance of repressive heterochromatin domains is achieved through modification of histones, particularly H3K9me3 that is recognized and deposited by Clr4/SUV39h via its ability to both "read" and "write". Using a carefully designed genetic system, we have identified several factors that ensure faithful inheritance of heterochromatin by suppressing histone turnover. We have also provided direct evidence that histones are carriers of epigenetic information and discovered that a critical density of H3K9me3 is required to provide an epigenetic template for the spreading and epigenetic inheritance of heterochromatin. This work elucidated a fundamental theme in which the activities of multiple silencing factors converge to maintain H3K9me3 density, which in turn promotes epigenetic inheritance of heterochromatin through both mitosis and meiosis. Our recent work has revealed that histone deacetylation, a conserved feature of heterochromatin domains, blocks SWI/SNF subfamily remodelers involved in chromatin unraveling, thereby stabilizing H3K9me3 modified nucleosomes, to promote heterochromatin propagation. Moreover, we have reported that heterochromatin domains are specialized replication zones, enriched in replisome components, that collaborate with a histone chaperone complex to transfer parental modified histones to daughter DNA strands to preserve epigenetic memory. By elucidating these mechanisms, we provided a molecular basis for understanding how epigenetic information is maintained and transmitted. This insight not only enhances our fundamental knowledge of chromatin biology but also has potential implications for understanding biological processes including gene regulation, cellular differentiation, and disease states associated with epigenetic dysregulation.