Elucidate How Two Major Mammalian Nucleosome Assembly Pathways are Regulated
Impacts of nucleosome assembly pathways in normal and cancer cells.
In mammalian cells, there are two major forms of histone H3, canonical H3 (H3.1 and H3.2) and the histone H3 variant H3.3. While differing by only five amino acids, H3.1 and H3.3 specify distinct chromatin domains. For instance, H3.1 is localized at heterochromatin, whereas H3.3 is enriched at active chromatin. It is generally believed that (H3.1-H4)2 tetramers are assembled into nucleosomes by CAF-1 in a replication-coupled nucleosome assembly pathway. In contrast, assembly of H3.3-H4 molecules into nucleosomes is mediated by other histone chaperones, including HIRA and Daxx. A challenging question in the chromatin assembly field is how assembly of these two forms of histone H3 with such limited sequence variations are specified into distinct nucleosome assembly pathways. We are studying histone modifications and histone modifying enzymes that may aid in specifying nucleosome assembly pathways. Furthermore, we are addressing how these two major nucleosome assembly pathways go awry in cancer cells. We are testing the hypothesis that alterations in these two pathways in cancer cells will lead to changes in epigenetic program that contributes to the development of cancer as well as resistant of cancer to chemotherapeutic agents.