Olajuyin Ayobami, Mandlem Venkatakirankumar, Sunil Christudas, Hou Yunzhuan, Adeyanju Oluwaseun, Petkar Sana, Li Qinying, Tucker Torry A, Idell Steven, Chen Shi-You, Guo Xia, Qian Guoqing
Department of Cellular and Molecular Biology, The University of Texas Health Science Center at Tyler, Tyler, TX 75708, USA.
Department of Surgery, School of Medicine, The University of Missouri, Columbia, MO 65211, USA.
Int J Mol Sci. 2025 Aug 21;26(16):8074. doi: 10.3390/ijms26168074.
Smooth muscle cell (SMC) differentiation plays a crucial role in angiogenesis and vasculogenesis during embryonic development. The underlying mechanisms controlling SMC differentiation, especially progenitor-specific regulation, however, remain largely unclear. In this study, we identified bromodomain-containing protein 4 (BRD4) as a novel regulator for SMC differentiation. Transforming growth factor-β (TGF-β) induces BRD4 expression in the initial phase of SMC differentiation of pluripotent murine 10T1/2 cells. BRD4 was found critical in mediating TGF-β-induced SMC differentiation. Knockdown of BRD4 with siRNA suppressed TGF-β-induced expression of SMC markers including α-SMA and SM22α. In addition, the BRD4 inhibitor JQ1 and degraders ARV-825 and dBET1 suppressed TGF-β-induced SMC marker gene expression. BRD4 regulates SMC differentiation by activating SMC marker gene transcription. BRD4 mediated SMC differentiation is independent of the phosphorylation of Smad2/3. Instead, BRD4 mediated TAZ expression induced by TGF-β. Consistent with the function of TAZ, the inhibition of BRD4 reduced nuclear retention of Smad3, thereby impairing Smad3 mediated SMC gene transcription. Myocardin is an important transcriptional modulator for SMC markers. Interestingly, the knockdown of BRD4 also attenuated the induction of myocardin due to TGF-β in 10T1/2 cells. Taken together, this study demonstrates that BRD4 is a novel modulator for SMC differentiation from mesenchymal progenitor cells through the regulation of TAZ and myocardin.
平滑肌细胞（SMC）分化在胚胎发育过程中的血管生成和血管发生中起着关键作用。然而，控制SMC分化的潜在机制，尤其是祖细胞特异性调节，在很大程度上仍不清楚。在本研究中，我们鉴定出含溴结构域蛋白4（BRD4）是SMC分化的一种新型调节因子。转化生长因子-β（TGF-β）在多能小鼠10T1/2细胞SMC分化的初始阶段诱导BRD4表达。发现BRD4在介导TGF-β诱导的SMC分化中起关键作用。用小干扰RNA（siRNA）敲低BRD4可抑制TGF-β诱导的包括α-平滑肌肌动蛋白（α-SMA）和SM22α在内的SMC标志物的表达。此外，BRD4抑制剂JQ1以及降解剂ARV-825和dBET1可抑制TGF-β诱导的SMC标志物基因表达。BRD4通过激活SMC标志物基因转录来调节SMC分化。BRD4介导的SMC分化独立于Smad2/3的磷酸化。相反，BRD4介导TGF-β诱导的转录共激活因子TAZ表达。与TAZ的功能一致，抑制BRD4可降低Smad3的核内滞留，从而损害Smad3介导的SMC基因转录。心肌素是SMC标志物的一种重要转录调节因子。有趣的是，在10T1/2细胞中敲低BRD4也减弱了TGF-β对心肌素的诱导作用。综上所述，本研究表明BRD4是一种通过调节TAZ和心肌素来介导间充质祖细胞向SMC分化的新型调节因子。
