Epigenetic inheritance of heterochromatin

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Project Summary The long-term goal of this work is to understand how histone H3 lysine 9 methylation (H3K9me) and heterochromatic gene silencing are epigenetically inherited. Heterochromatin is a conserved feature of eukaryotic chromosmes and plays important roles in regulation of gene expression and maintenance of chromosome stability in organisms ranging from yeast to human. Using the fission yeast Schiozosaccharomyces pombe as a model organism, we recently demonstrated that ectopically induced domains of H3K9me and silencing can be epigenetically inherited in the absence of sequence-specific recruitment when the rate of H3K9me demethylation is reduced by deletion of the Epe1 anti-silencing factor. In addition, we have discovered that, in wildtype epe1+ cells, small noncoding RNAs (siRNAs) or transcription factor binding sites play critical roles in epigenetic maintenance of H3K9me. More recently, we have uncovered roles for an RNAi-independent RNA decay pathaway, autoregulation of the conserved histone H3K9 methyltransferase, and core replication fork-associated proteins in epigenetic maintenance of heterochromatin. In this proposal we will use a combination of in vivo approaches and biochemical assays to investigate (1) the functions of a newly discovered RNA decay complex, called the rixosome, in epigenetic inheritance, (2) the role of a replication fork-associated chromatin assembly complex in retention of histones and epigenetic inheritance during DNA replication, and (3) the role of a conserved ubiquitin ligase in regulation of H3K9 methylation and accurate heterochromatin formation. The ultimate goal of these studies is a molecular understanding of the mechanisms that epigenetically maintain silent chromatin domains.