Abstract 4147898: Bromodomain-containing protein 4 Mediates TGF-β-induced Smooth Muscle Cell Differentiation

Vascular smooth muscle cell (VSMC) differentiation is an essential component of vascular development. VSMCs are not terminally differentiated cells. They switch their phenotypes between proliferative and differentiated states, which is a major factor contributing to vascular diseases like atherosclerosis, aneurysms, hypertension, etc. Transforming growth factor-β (TGF-β) plays an essential role in VSMC differentiation. However, the detailed mechanisms remain incompletely understood. Bromodomain-containing protein 4 (BRD4) belongs to the family of bromodomain and extra-terminal domain (BET) proteins. It is an epigenetic modulator that has been implicated in different human diseases including cancer and tissue fibrosis. However, whether BRD4 mediates TGF-β-induced SMC differentiation remains unclear and was explored in this study. We found that TGF-β induced 10T1/2 cells (a mesenchymal stem cell line) to express markers of SMCs in a time dependent manner. Interestingly, the BRD4 inhibitor JQ1 and degrader ARV-825 effectively blocked the differentiation of 10T1/2 cells towards SMCs induced by TGF-β, as indicated by decreased induction of SMC markers such as SM22α and α-SMA. Knockdown of BRD4 using siRNA also significantly decreased TGF-β-induced differentiation of 10T1/2 cells towards SMCs. TAZ is a mediator of TGF-β-induced SMC maker gene expression. BRD4 inhibition attenuated TGF-β-induced TAZ expression, suggesting that BRD4 may regulate SMC differentiation through TAZ expression. In addition, BRD4 mediates the binding between TAZ and Smad3 to regulate the SMC marker gene transcription. Take together, our findings suggest that BRD4 modulates TGF-β-induced SMC differentiation and might play a role in SMC differentiation-related vascular diseases.