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. In the fission yeast Schiozosaccharomyces pombe, the establishment of heterochromatin involves RNAi- and transcription factor-dependent recruitment mechanisms, but the mechanisms that mediate epigenetic inheritance, independently of the initial recruitment signals, have remained unclear. 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 demethylase. 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. In this proposal we will use a combination of in vivo approaches and biochemical assays to investigate (1) the functions of a newly discovered complex as well as known histone chapernones in epigenetic inheritance and the transfer of parental histones to newly replicated DNA, (2) the mechanism of siRNA- mediated epigenetic inheritance, and (3) the role of DNA sequence- and chromosomal context- dependent mechanisms in cis maintenance of epigenetic states. The ultimate goal of these studies is a molecular understanding of the mechanisms that epigenetically maintain silent chromatin domains.
Heterochromatin is a conserved feature of eukaryotic chromosomes with roles in the regulation of gene expression and maintenance of genome stability, and contributes to normal development and disease progression in humans. A basic understanding the mechanisms that mediate the assembly and epigenetic inheritance of heterochromatin will not only provide a frame work for understanding how the epigenetic regulatory mechanisms can fail, but also provides the substrate and knowledge to design therapeutic strategies based on intervention.
Showing the most recent 10 out of 29 publications
