Specialized replication of heterochromatin domains ensures self- templated chromatin assembly and epigenetic inheritance

• 成果类型: Article
• 署名作者: Nathanailidou, Patroula; Dhakshnamoorthy, Jothy; Xiao, Hua; Zofall, Martin; Holla, Sahana; O'Neill, Maura; Andresson, Thorkell; Wheeler, David; Grewal, Shiv I. S.
• 署名单位: National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI); National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI); Frederick National Laboratory for Cancer Research
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-13994
• DOI: 10.1073/pnas.2315596121
• 发表日期: 2024-01-29
• 关键词: dna-polymerase-alpha; expression-state boundaries; mating-type region; fission yeast; histone h3; lysine 9; eukaryotic replisome; chromodomain protein; phase-separation; fact contributes

摘要

Heterochromatin, defined by histone H3 lysine 9 methylation (H3K9me), spreads across large domains and can be epigenetically inherited in a self- propagating manner. Heterochromatin propagation depends upon a read-write mechanism, where the Clr4/ Suv39h methyltransferase binds to preexisting trimethylated H3K9 (H3K9me3) and further deposits H3K9me. How the parental methylated histone template is preserved during DNA replication is not well understood. Here, we demonstrate using Schizosaccharomyces pombe that heterochromatic regions are specialized replication domains demarcated by their surrounding boundary elements. DNA replication throughout these domains is distinguished by an abundance of replisome components and is coordinated by Swi6/ HP1. Although mutations in the replicative helicase subunit Mcm2 that affect histone binding impede the maintenance of a heterochromatin domain at an artificially targeted ectopic site, they have only a modest impact on heterochromatin propagation via the read-write mechanism at an endogenous site. Instead, our findings suggest a crucial role for the replication factor Mcl1 in retaining parental histones and promoting heterochromatin propagation via a mechanism involving the histone chaperone FACT. Engagement of FACT with heterochromatin requires boundary elements, which position the heterochromatic domain at the nuclear peripheral subdomain enriched for heterochromatin factors. Our findings highlight the importance of replisome components and boundary elements in creating a specialized environment for the retention of parental methylated histones, which facilitates epigenetic inheritance of heterochromatin.