Genetic and epigenetic regulation of vascular smooth muscle cell phenotype and contractility

Summary
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.
During the previous funding period we used high throughput sequencing and computational biology to study
chromatin structure and transcription factor binding in human aortic SMCs on a genome-wide level. Our work
has led to the identification of previously unrecognized SMC-selective proteins, to the characterization of
genetic mechanisms that regulate SMC contractility and blood pressure, and to novel transcription
mechanisms that regulate SMC-specific gene expression. Using mass spec approaches we recently identified
the SMC-selective methyltransferase, PRDM6, as a myocardin factor interacting protein and have cell culture
and in vivo data that PRDM6 is required for the maintenance of SMC differentiation and blood pressure.
Importantly recent human genetic study described PRDM6 coding mutations that cause patent ductus
arteriosis, and GWAS have identified a locus in PRDM that was associated with BP regulation and intracranial
aneurysm. In Aim 1 we will identify the transcription mechanisms and human genetic variations that regulate
PRDM6 the SMC-specific expression of PRDM6. Since the mechanisms by which PRDM6 regulates gene
expression are completely unknown, in Aim2 we will use genome-wide approaches to identify direct PRDM6
targets, and we will test whether PRDM6 regulates MRTF-A activity by direct methylation. In Aim 3 we will
continue to evaluate the contributions of PRDM6 to the regulation of blood pressure and SMC phenotype in
vivo using our conditional SMC-specific PRDM6 knockout mice. We have also established collaborations with
clinical cardiovascular research teams at the University of North Carolina to begin to examine the correlation
between PRDM6 genotype and hypertension in local populations.