Transcriptional control is vital to the health and development of all organisms. Transcription is regulated in part by chemical modification of histone proteins. Acetylation, one of the most important modifications, is typically associated with gene activation while deacetylation is associated with gene repression. The SIN3 histone deacetylase (HDAC) complex, which is required for viability of organisms from S. pombe to mouse, is one of two major class I HDAC complexes. Knock down of this essential Drosophila gene results in a loss of cell proliferation without changing global histone acetylation levels. This result suggests that histone deacetylation by the SIN3 complex controls proliferation by a gene- specific regulatory mechanism. The long term goal of this laboratory is to understand how modification of chromatin regulates growth and development. The objective of this project is to elucidate the molecular mechanisms by which SIN3 isoforms regulate specific gene expression to affect cell differentiation and proliferation. These experiments are based on the hypothesis that Drosophila SIN3 isoforms have unique gene regulatory functions. Experiments of Aim 1 of the proposal will test the hypothesis that SIN3 isoform specific complexes regulate cell cycle progression. This will be accomplished by determining the effect of loss or knock down of specific isoforms on Drosophila viability and cell proliferation. Experiments of Aim 2 are designed to identify the genes and genomic regions that are regulated by each isoform and to determine how each isoform and its specific components affects deacetylation and gene repression. This research is significant as the results are anticipated to elucidate the poorly understood molecular mechanisms involved in regulation of histone deacetylation. Many types of cancer result from altered gene transcription due to mutations in protein regulators of histone acetylation. While a number of HDAC inhibitors are currently being tested as anti- cancer agents in clinical trials, the molecular mechanisms behind their tumor killing properties are not well understood. Information gained from the proposed experiments is anticipated to aid in the development of the next generation of HDAC inhibitors for use as anti-tumor agents.
Multiple histone deacetylase inhibitors are currently being tested as anti-proliferative agents in clinical trials. Experiments outlined in this proposal are anticipated to elucidate mechanisms of action of the SIN3 histone deacetylase complex, an essential protein complex required for viability and cell cycle progression. Results from this proposal are anticipated to aid in refinement of deacetylase inhibitors designed to target cancer cells.
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