The long-term goal of this project is to understand the molecular mechanisms that regulate smooth muscle cell (SMC) phenotypic changes during smooth muscle myogenesis and in the pathogenesis of human vascular diseases. Recent extensive biochemical and genetic studies have provided substantial evidence showing that the balance of histone acetylation and deacetylation is crucial to the control of cell proliferation in cancer and cardiac hypertrophy. However, little is known about how manipulating histone acetylation controls SMC gene transcription and proliferation in human vascular diseases. The goal of this application is to determine the molecular mechanisms whereby histone modifiers, especially HDAC8, regulate SMC gene transcription both in vitro and in vivo. This study integrates innovative transgenic/knockout mice, BAG recombineering and bioinformatics tools into classic biochemical, molecular and developmental biology approaches. The results of this study will not only fill a gap in our understanding of HDACs in transcriptional regulation, but also further our knowledge of epigenetic mechanisms in regulating SMC myogenesis^ Extensive studies demonstrate that the dynamic changes of histone acetylation and deacetylation play important roles in gene transcription and cell proliferation. HDACS is a member of the class I HDAC (histone deacetylase) family, and possesses histone deacetylase activities. Our preliminary results show that HDACS, unlike other HDACs, acts as a transcriptional activator for SMC gene transcription. We hypothesize that HDACS is a pro-SMC differentiation factor that modulates SRF/Myocardin and SmadS-mediated SMC transcriptional regulatory complexes.
The specific aims are: (1) to determine whether HDACS affects histone modification at the SM22 locus in vitro, and whether the deacetylase activity of HDACS is required to enhance the pro-myogenic activities of SMC regulators; (2) to determine how HDACS interacts with the SMC transcriptional regulatory network and TGFpl signal pathway; (3) to determine whether histone deacetylase inhibitors affect atherogenesis and how HDACS modulates SMC differentiation in SMC myogenesis and in injury-induced restenosis in vivo. Given the important roles of histone modification in SMC growth and differentiation, the results of this study will contribute significantly towards developing novel therapeutical strategies targeted at the epigenetic mechanisms affecting the abnormal SMC-associated human vascular diseases. ? ? ?
