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There is clear evidence that phenotypic switching of smooth muscle cells (SMC) plays a critical role in development of atherosclerotic disease, and end stage clinical consequences such as plaque rupture/thrombosis. A long-term goal of our lab has been to elucidate cellular and molecular mechanisms that control the growth and differentiation of SMC during vascular development, and to determine how these control processes are altered in disease states. The focus of this presentation will be to review recent studies in our laboratory examining fundamental mechanisms that regulate early determination events in vascular SMC with a particular emphasis on identification of genes that control this process, and elucidation of the role of cell-type and gene-selective changes in chromatin structure (i.e. epigenetic controls) in this process. To this end, our laboratory has developed novel methods for production of purified populations of SMC or SMC progenitor cells derived from various stem cell populations, and using genomic screening methods have identified >350 genes that show at least a 2-fold difference in expression level in SMC progenitor cells as compared to the parental stem cell population from which they were derived. Moreover, results of quantitative chromatin immunoprecipitation (CHIP) assays have shown that SMC progenitor cells and differentiated SMC exhibit a unique pattern of histone modifications, and transcription factor binding to the promoter regions of SMC marker gene loci that are distinct from that observed at these same gene loci in non-SMC. Of major interest, these SMC selective histone modifications precede actual differentation of SMC progenitor cells during development, and are predicted to make these gene loci permissive for subsequent transcriptional activation. In addition, we found that a select subset of these histone modifications persist during reversible phenotypic switching of SMC in response to PDGF BB, thus providing a potential mechanism for cell lineage “memory”. That is, a mechanism that allows cells to re-express appropriate SMC markers upon re-establishment of appropriate environmental cues necessary for SMC differentiation. In summary, we have identified what we believe is a fundamental mechanism for controlling SMC lineage determination and reversible phenotypic switching in response to vascular injury or disease. In addition, we will present evidence suggesting that similar epigenetic controls likely play a key role in control of cell lineage determination in most if not all mammalian cells. [Supported by NIH grants HL P01 HL19242, R01 HL38854, and R37 HL57353]
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J. Vasc. Biol. 42, Sup:2 (2005) pp25-26