NSD3's function in chromatin-mediated processes and oncogenesis

Chromatin structural dynamics regulate diverse cellular functions that influence survival, growth, and proliferation. Disruption of chromatin homeostasis is thought to fundamentally impact the development and progression of cancers. One of the major mechanisms for regulating chromatin structure involves the reversible covalent post-translational modification of histone proteins by chemical moieties such as acetyl-, methyl- and phospho- groups. These chemical marks constitute an epigenetic code that can be maintained in dividing cells, and inherited across generations. The methylation of lysine residues on histones is performed by histone lysine methyltransferases (KMT). The NSD3 (Nuclear receptor binding SET Domain 3) protein is a candidate KMT that is amplified in breast cancer and involved in a recurrent translocation implicated in the pathogenesis of acute myeloid leukemia. Preliminary work in the Gozani lab indicates that NSD3 has a novel methylase activity on histone H3, however the role of this activity in regulation of chromatin structure and oncogenesis are currently uncharacterized. Two aims are proposed: In the first Aim, I plan to characterize the enzymatic activity of NSD3 and identify its substrates utilizing biochemical, chemical biological, and proteomic approaches. The goal of the second Aim is to elucidate the chromatin regulatory functions of NSD3 in normal cells and in cancer. The overall goal of this proposal is to develop comprehensive understanding of the role protein lysine methylation plays in chromatin biology and in modulating cancer regulatory signaling pathways.