Dynamic rewiring of transcription factor networks during smooth muscle cell phenotypic modulation (ChIP-Rx data sets)

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.平滑肌细胞（SMC）的表型调控是血管疾病的标志性特征，也是细胞核内整合性信号转导介导的经典细胞状态转化过程。本研究以血小板衍生生长因子（PDGF）介导的SMC激活为模型，首次报道了细胞状态转换过程中的动态活性染色质应答与全局转录重塑图谱。研究发现，PDGF刺激可驱动全局转录扩增与合成代谢，同时伴随细胞增殖与迁移能力增强。动态基因表达与Brd4染色质共激活因子结合占有率分析显示，转录因子（TF）介导的增强子重编程由即刻早期（Jun/Fos）应答所塑造，后续伴随依赖于Rev-erbα的核受体转录信号通路激活。通过Brd4抑制阻断增强子与转录间的信号传导，可抑制PDGF刺激诱导的典型细胞表型变化；而体内Brd4抑制可有效阻断血管损伤应答。本研究绘制了SMC表型调控过程中TF介导的染色质重塑全局图谱，并阐明了转录抑制在血管疾病中的关键治疗机制。