Smith's research is focused on epigenetic mechanisms of gene expression, particularly their regulation through signaling pathways and their modulation by anti-cancer drugs. Epigenetic mechanisms play a very important role in transcriptional regulation of genes but the specifics of these mechanisms require ongoing study. Many studies focus on the role of post-translational modification of histone proteins, such as acetylation, methylation, and phosphorylation. Smith's view is that this is only part of the full picture. Non-histone proteins that associate with chromatin can also be post-translationally modified. Without knowledge of how modified histones and non-histone proteins work together to achieve regulation of gene expression, we will not have a comprehensive understanding of epigenetic mechanisms of gene regulation. Currently, we are focused on acetylation of transcriptional regulatory proteins. Proteomic studies have identified almost 2000 non-histone proteins that are modified by acetylation in different cellular compartments yet only a small fraction of these proteins have been studied to determine how the acetylation impacts their function. We currently have two active projects that focus on the role of acetylation in signaling to chromatin. Steroid receptors are ligand-activated transcription factors that serve to regulate many important physiological processes. Glucocorticoids regulate metabolism, immune function, stress and anxiety responses, and are important for lung development. They bind to the glucocorticoid receptor (GR) and activate it to bind to specific DNA sequences in target genes. The GR is known to associate with lysine acetyltransferases, which acetylate proteins and help the GR regulate transcription. Our work has also revealed an important role for lysine deacetylases (KDACs) in the activation of transcription by GR. This is surprising since KDACs are often cast as repressive to transcription because they remove histone acetylation. Our current goals for this project are to understand how KDACs cooperate with GR in the activation of target genes, identify which KDACs are involved (there are 11 possible candidates), and determine which proteins they deacetylate to facilitate transcription at GR target genes. The second project is focused on the role of KDACs in growth and survival signaling in Non-Hodgkin's Lymphoma (NHL). Over the last 20 years, drugs which target KDACs have been developed, resulting in recent FDA approvals for the treatment of a rare form of NHL, cutaneous T cell lymphoma. We have chosen to focus our efforts on the most common form of NHL, diffuse large B cell lymphoma (DLBCL). This is an aggressive lymphoma that must be treated. The current treatment strategy is highly efficient initially, but about 50% of patients relapse within 5 years. Thus, new drugs like KDAC inhibitors are needed to either prolong remission or effectively treat relapsed DLBCL. Our goal is to understand how KDAC-inhibiting drugs impact growth in survival signaling in this cancer. Through these studies, we have developed cell-based models of sensitivity and resistance to these drugs in DLBCL. We are focused on understanding the mechanisms behind sensitivity and resistance in an effort to identify biomarkers that predict response to these drugs and to find other therapeutics that might synergize with KDAC inhibitors to kill resistant DLBCL cells.