Epigenetic silencing, the heritable repression of transcription within chromatin domains, is important in regulating gene expression, maintaining genomic stability and cell fate determination. Inappropriate gain of silencing such as inactivation of tumor suppressor genes by DNA hyper-methylation at the promoter regions is linked directly to carcinogenesis. We are interested in how silent chromatin structures are inherited, commonly known as epigenetic inheritance during S phase of the cell cycle and how this process goes awry in cancer cells.

DNA replication-coupled chromatin assembly participates in epigenetic inheritance. In the replication-coupled chromatin assembly, newly synthesized histones H3 and H4 are deposited by histone chaperones such as chromatin assembly factor 1 (CAF-1), ASF-1 and probably other unknown factors in a PCNA dependent process. Histones H2A and H2B are then deposited to form nucleosomes. PCNA is essential for DNA replication and DNA repair. PCNA interacts DNMT1, a DNA cytosine methyltransferase required for maintaining DNA methylation patterns in normal and cancer cells.

We explore two approaches to study epigenetic inheritance. First, we use yeast S. cerevisiae as a model system to study the mechanisms of DNA replication proteins in epigenetic inheritance. Using the power of yeast genetics, we have identified three new genes involved in silencing. Characterization of one of new gene products, we called EPA1, have shown that it is a novel histone chaperone modulating silencing. We also identified about 15 new modifiers functioning in repair of chromosome breaks. Characterization of these new modifiers is now underway. Second, we will extend our studies in yeast to mammalian cells to study epigenetic inheritance and epigenetic causes of cancer. We are investigating how DNMT1 is recruited to the replication foci and how histone-modifying enzymes replicate the "histone code". We hope these studies will lead to design therapeutic agents for activation of tumor suppressor genes silenced in cancer cells.