We are interested in epigenetic mechanisms that control cellular memory and genome stability in eukaryotes and use yeast and mammalian cells as model systems to study these mechanisms.

We study how heterochromatin, a silent chromatin structure that regulates gene expression and genome stability, is established and epigenetically inherited. We have uncovered how nuclear RNAi participates in various aspects of heterochromatin formation from its assembly to its epigenetic inheritance. Our work has demonstrated that RNAi complexes localize to nascent noncoding RNAs at chromosome regions that are assembled into heterochromatin. This localization leads to co-transcriptional degradation of heterochromatic RNAs and also directly recruits downstream chromatin-modifying complexes that establish heterochromatin. In addition, we have shown that heterochromatin recruits other RNA degradation enzymes that play a critical role in keeping it completely silent. Our studies in this area have used fission yeast as a model system, but nuclear RNAi and RNA processing pathways also play broad and conserved roles in chromatin regulation in other eukaryotes.

Our work on epigenetic inheritance mechanisms has provided evidence that positive feedback mechanisms associated with histone post-translational modifications (PTMs) can mediate epigenetic inheritance. However, in wild-type cells, histone PTM positive feedback appears to be too weak to maintain epigenetic memory. We have shown that histone PTMs work together with specific DNA sequences to maintain epigenetic memory and would like to understand how DNA sequence contributes to epigenetics. We continue to use fission yeast, as well as mammalian cells, as a model systems to explore the roles of DNA sequence, noncoding RNA, RNA processing pathways, and histone modifications in epigenetic processes.