We are exploring the role of protein acetylation in three different biological systems:
1. Transcriptional regulation of HIV expression. We have established that the chromatin organization of the HIV genome and the level of acetylation of its histones play a critical role in its transcriptional activity. We are currently focusing our effort on the Brg-1 and Brd4 proteins. Both factors contain bromodomains, an acetyl recognition motif, and are part of distinct multiprotein complexes that regulate HIV transcription. We have also established a new in vitro model for HIV latency and are identifying the cellular factors that contribute to the establishment of latency (transcriptional silencing) and to the reactivation of latency.
2. Mechanism of of positive and negative selection during thymocyte development. We are studying the role of histone deacetylase 7, which is highly expressed and regulated in double positive (CD4 and CD8) developing T cells. We found that HDAC7 regulates the expression of a cassette of genes that play a critical role in the process of positive and negative selection. We are studying the regulation of HDAC7 nucleo-cytoplasmic shuttling in response to TCR activation, We are currently developing knockout mice for HDAC7 and will be exploring its biological role in the mouse immune system.
3. Role of mitochondrial protein deacylases. We are interested in how post-translational acylation of mitochondrial proteins links cellular metabolism to protein function and disease. We are most focused on the mitochondrial deacetylase, SIRT3, and have identified a wife variety of deacetylation targets by which SIRT3 regulates lipid oxidation and ketone body metabolism, among other pathways. We also study SIRT5, a desuccinylase and demalonylase, as well as the less-understood SIRT4. Finally, we have shown that the ketone body beta-hydroxybutyrate is a histone deacetylase inhibitor, providing a mechanism by which mitochondrial metabolism can affect nuclear gene expression.