BioProject

Phenotypic modulation of smooth muscle cells (SMC) is a hallmark of vascular disease and a classic cell state transformation mediated by convergent signal-integration in the nucleus. More...

Phenotypic modulation of smooth muscle cells (SMC) is a hallmark of vascular disease and a classic cell state transformation mediated by convergent signal-integration in the nucleus. Here, using PDGF-mediated SMC activation, we describe for the first time the dynamic active chromatin response and global transcriptional remodeling of cell state. We find that PDGF stimulation drives global transcriptional amplification and anabolism concurrent with increased proliferation and motility. Kinetic gene expression and Brd4 chromatin co-activator occupancy analysis reveals transcription factor (TF) directed enhancer re-wiring shaped by an immediate-early (Jun/Fos) response followed by increased nuclear hormone receptor transcriptional signaling that is Rev-erbdependent. Interdicting signaling between enhancers and transcription via Brd4 inhibition halts canonical cellular features of PDGF stimulation, and in vivo Brd4 inhibition potently abrogates vascular injury responses. These data provide a global map of TF-directed chromatin remodeling during SMC phenotypic modulation and elucidate key therapeutic mechanisms of transcriptional inhibition in vascular disease. Overall design: ChIP-Rx in rat aortic smooth muscle cells (RASMC) for H3K27ac and input control Less...