Dynamic rewiring of transcription factor networks during smooth muscle cell phenotypic modulation (ATAC-Seq 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（smooth muscle cells, SMC）的表型调控是血管疾病的标志性特征，亦是细胞核内汇聚信号整合所介导的经典细胞状态转化过程。本研究采用血小板衍生生长因子（platelet-derived growth factor, PDGF）介导的SMC激活模型，首次报道了细胞状态转变过程中的动态活性染色质响应与全基因组转录重编程。研究发现，PDGF刺激可诱导全基因组转录扩增与合成代谢过程，同时伴随细胞增殖与迁移能力的显著增强。通过动态基因表达谱与Brd4染色质共激活因子结合占据分析，本研究揭示了由即刻早期（Jun/Fos）响应所塑造的、受转录因子（transcription factor, TF）调控的增强子重编程过程，后续伴随依赖于Rev-erbα的核激素受体转录信号通路的激活增强。通过Brd4抑制剂阻断增强子与转录之间的信号传导，可抑制PDGF刺激所诱导的典型细胞表型特征；而在体内给予Brd4抑制剂，则可有效消除血管损伤应答反应。本研究数据绘制了SMC表型调控过程中TF介导的染色质重塑全景图谱，并阐明了血管疾病中转录抑制疗法的关键作用机制。