Terry Fox Laboratory, BC Cancer, Vancouver, British Columbia V5Z 1L3, Canada.
Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia V6H 3N1, Canada.
Nucleic Acids Res. 2022 Aug 26;50(15):8547-8565. doi: 10.1093/nar/gkac652.
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.
转录因子 SOX9 在胚胎发育和病理条件下内皮细胞向间充质转化（EndMT）开始时被激活。然而，其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 SOX9 的单独表达足以激活间充质基因，并促使内皮细胞向间充质命运发展。通过对染色质景观的全基因组作图，我们表明 SOX9 表现出先驱转录因子的特征，例如打开染色质，并导致沉默染色质区域的活性组蛋白修饰沉积，这是由 SOX 二聚体基序和 H2A.Z 富集引导的。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的驱逐来促进。然而，虽然 SOX9 结合是动态的，但 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。本研究为 SOX9 的关键分子功能和 EndMT 的机制提供了新的见解，并强调了 SOX9 在发育中的关键作用及其与人类疾病的相关性。
