The transcription factor SOX9 is activated at the onset of endothelial-to-mesenchymal transition (EndMT) during embryonic development and in pathological conditions. Its roles in regulating these processes, however, are not clear. Using human umbilical vein endothelial cells (HUVECs) as an EndMT model, we show that SOX9 expression alone is sufficient to activate mesenchymal genes and steer endothelial cells towards a mesenchymal fate. By genome-wide mapping of the chromatin landscape, we show that SOX9 displays features of a pioneer transcription factor, such as opening of chromatin and leading to deposition of active histone modifications at silent chromatin regions, guided by SOX dimer motifs and H2A.Z enrichment. We further observe highly transient and dynamic SOX9 binding, possibly promoted through its eviction by histone phosphorylation. However, while SOX9 binding is dynamic, changes in the chromatin landscape and cell fate induced by SOX9 are persistent. Finally, our analysis of single-cell chromatin accessibility indicates that SOX9 opens chromatin to drive EndMT in atherosclerotic lesions in vivo. This study provides new insight into key molecular functions of SOX9 and mechanisms of EndMT and highlights the crucial developmental role of SOX9 and relevance to human disease.

中文翻译：

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SOX9 通过改变染色质景观重新编程内皮细胞

转录因子 SOX9 在胚胎发育和病理条件下在内皮-间质转化 (EndMT) 开始时被激活。然而，它在调节这些过程中的作用尚不清楚。我们使用人脐静脉内皮细胞 (HUVEC) 作为 EndMT 模型，表明仅 SOX9 表达就足以激活间充质基因并引导内皮细胞走向间充质命运。通过染色质景观的全基因组图谱，我们表明 SOX9 显示出先驱转录因子的特征，例如在 SOX 二聚体基序和 H2A.Z 富集的指导下，染色质的开放和导致活性组蛋白修饰在沉默染色质区域的沉积. 我们进一步观察到高度瞬态和动态的 SOX9 结合，可能通过组蛋白磷酸化对其的驱逐来促进。然而，虽然 SOX9 结合是动态的，但由 SOX9 诱导的染色质景观和细胞命运的变化是持久的。最后，我们对单细胞染色质可及性的分析表明，SOX9 打开染色质以驱动体内动脉粥样硬化病变中的 EndMT。这项研究为 SOX9 的关键分子功能和 EndMT 机制提供了新的见解，并强调了 SOX9 的关键发育作用和与人类疾病的相关性。