Epigenetic regulation of vascular smooth muscle cell phenotype Vascular smooth muscle cell (SMC) differentiation is a very important process during vasculogenesis and angiogenesis, and it is well recognized that alterations in SMC phenotype play a role in the progression of several prominent cardiovascular disease states including atherosclerosis, hypertension, and restenosis. Although serum response factor (SRF) and the myocardin factors are critical for SMC differentiation, recent studies from our lab and others indicate that epigenetic mechanisms are also critical for the overall pattern of SMC-specific gene expression. Indeed, we identified the histone demethylase, jmjd1a, as a myocardin factor interacting protein and have shown that jmjd1a stimulates SMC differentiation marker gene expression in aortic SMC cultures by demethylating H3K9 near the SMC-specific. A major goal of the current proposal will be to closely examine jmjd1a knock-out mice for effects on SMC phenotype, and we will characterize H3K9 methylation in several in vitro and in vivo models of SMC phenotypic modulation. H3K9 methylation is strongly associated with DNA methylation, and interestingly, the SRF binding regions within the SMC-specific promoters are embedded within CpG islands. Based on our preliminary data indicating that the SMC-specific promoters are regulated by methylation, the goal of Aim 2 is to identify the molecular mechanisms involved. Finally, in an attempt to better understand the global chromatin changes that control SMC phenotype, we have established collaborations with Jason Lieb and Terry Furrey to """"""""map"""""""" open chromatin regions in SMC using DNase hypersensitivity and Formaldehyde-Assisted Isolation of Regulatory Elements (FAIRE). We have generated a genome-wide map from human aortic SMC cultures and have identified a number of previously unexamined promoter regions as potentially important for SMC-specific gene expression. The goals of Aim 3 are to test whether these regions drive expression in vivo and to identify the chromatin modifying and transcription factors that are involved.
Vascular smooth muscle cell differentiation is a very important process during the development of blood vessels and it is well recognized that alterations in this process play a role in the progression of several prominent cardiovascular disease states including atherosclerosis, hypertension, and restenosis. Our proposal examines the molecular mechanisms that regulate smooth muscle differentiation and should help to identify therapeutic targets for the treatment of these diseases.
|Bai, Xue; Mangum, Kevin D; Dee, Rachel A et al. (2017) Blood pressure-associated polymorphism controls ARHGAP42 expression via serum response factor DNA binding. J Clin Invest 127:670-680|
|Cheng, Zhaokang; Zhu, Qiang; Dee, Rachel et al. (2017) Focal Adhesion Kinase-mediated Phosphorylation of Beclin1 Protein Suppresses Cardiomyocyte Autophagy and Initiates Hypertrophic Growth. J Biol Chem 292:2065-2079|
|Weise-Cross, Laura; Taylor, Joan M; Mack, Christopher P (2015) Inhibition of Diaphanous Formin Signaling In Vivo Impairs Cardiovascular Development and Alters Smooth Muscle Cell Phenotype. Arterioscler Thromb Vasc Biol 35:2374-83|
|Lenhart, Kaitlin C; Becherer, Abby L; Li, Jianbin et al. (2014) GRAF1 promotes ferlin-dependent myoblast fusion. Dev Biol 393:298-311|
|Cheng, Zhaokang; DiMichele, Laura A; Rojas, Mauricio et al. (2014) Focal adhesion kinase antagonizes doxorubicin cardiotoxicity via p21(Cip1.). J Mol Cell Cardiol 67:1-11|
|Rozenberg, Julian M; Tesfu, Daniel B; Musunuri, Srilaxmi et al. (2014) DNA methylation of a GC repressor element in the smooth muscle myosin heavy chain promoter facilitates binding of the Notch-associated transcription factor, RBPJ/CSL1. Arterioscler Thromb Vasc Biol 34:2624-31|
|Bai, Xue; Lenhart, Kaitlin C; Bird, Kim E et al. (2013) The smooth muscle-selective RhoGAP GRAF3 is a critical regulator of vascular tone and hypertension. Nat Commun 4:2910|