Epigenetic Control of Smooth Muscle Cell Lineage and Phenotypic Switching

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DESCRIPTION (provided by applicant): Altered control of the differentiated state of the smooth muscle cell (SMC) or "phenotypic switching" is known to play a critical role in the development and/or progression of a number of major human diseases including atherosclerosis, asthma, and post-angioplasty restenosis. However, the mechanisms that control SMC phenotypic switching are poorly understood. The focus of this proposal is to determine mechanisms by which histone patterning of chromatin, a key epigenetic control in higher eukaryotic cells, regulates SMC differentiation in development and disease. Of major significance, during the current funding period, we completed a series of pioneering studies showing that development of SMC from embryonic stem cells (ESC) is associated with acquisition of a unique pattern of histone modifications at SMC marker gene loci that distinguish them from non-SMC, and make these loci permissive for transcriptional activation. In contrast, phenotypic switching of SMC in response to vascular injury, or PDGF BB treatment, was associated with loss of many of these SMC-selective histone modifications, as well as acquisition of histone changes associated with transcriptional silencing/chromatin condensation. However, H3K4 demethylation at SMC marker gene loci, a histone change that appears during development of SMC from ESC, was completely unchanged in all models of SMC phenotypic switching examined, suggesting that it may be relatively "fixed", and serve to preserve SMC "lineage memory" during reversible phenotypic switching. Taken together, results indicate that there is a distinct pattern of histone modifications that distinguishes SMC from non-SMC, and that these SMC- and gene locus-specific epigenetic modifications are likely to play a key role in regulating SMC differentiation marker gene expression in development and disease. The focus of this project is to test the hypothesis that development of SMC from embryonic stem cells is associated with acquisition of a unique pattern of histone modifications at SMC marker (and regulatory) gene loci and that these histone modifications play a key role in determining the permissiveness of these gene loci for transcriptional activation as well as in providing "SMC lineage memory" during reversible phenotypic switching. We will address this hypothesis by addressing the following two specific aims. Aim 1 is to determine mechanisms by which SMC selective/specific chromatin modifications regulate expression of SMC differentiation marker and regulatory genes during development of SMC lineages from multipotential stem cells. This will include the first studies to directly test the role of specific histone modifications in control of SMC lineage/differentiation, and how these histone modifications are acquired during development. Aim 2 is to define the role of epigenetic modifications in mediating reversible phenotypic switching of vascular SMC in response to vascular injury in vivo or treatment of cultured SMC with PDGF BB. Studies will define fundamental mechanisms that control differentiation of SMC, and are likely to lead to novel therapies for treatment of diseases in which SMC phenotypic switching plays a major role.