An atheroprotective transcriptome induced by JQ1 (a BRD4 inhibitor) in human endothelial cells

The bromodomain and extra terminal domain (BET) family of proteins, including BRD2, BRD3, and BRD4, play a key role in many cellular processes, including inflammatory gene expression, mitosis, and viral/host interaction by controlling the assembly of histone acetylation-dependent chromatin complexes. Previous studies have shown that multiple BET inhibitors (BETi), including JQ1, have therapeutic effects in cancer and cardiovascular diseases. Some BETi have entered different phases of clinical trials. Pharmacologically, JQ1 functions by displacing BET proteins from chromatin by competitively binding to the acetyl-lysine recognition pocket of BET bromodomains. JQ1 has been used as a chemical probe to investigate the role of BET bromodomains in the transcriptional regulation of cardiovascular diseases. For example, JQ1 has been shown to attenuates inflammation and experimental atherosclerosis (Mol Cell. 2014 Oct 23; 56(2): 219–231.). JQ1 has also recently been shown to reduce EndoMT and cardiac fibrosis (J Mol Cell Cardiol. 2019 Feb;127:83-96.). However, the molecular targets of JQ1 dependent or independent of BRD4 remains unknown. To depict the transcriptomic signature of JQ1 in human endothelial cells, we observed a vasoprotective and atheroprotective transcriptome by JQ1 treatment using genome-wide RNA-seq based transcriptomic profiling. JQ1 is a magic bullet in cardiovascular disease prevention. Further elucidation of new molecular targets of JQ1 will lead to the identification of potentially new therapeutic targets to treat cardiovascular diseases.

溴结构域与额外末端结构域（bromodomain and extra terminal domain, BET）蛋白家族（涵盖BRD2、BRD3与BRD4）通过调控组蛋白乙酰化依赖的染色质复合物组装，广泛参与诸多细胞生物学过程，包括炎症基因表达、有丝分裂以及病毒-宿主相互作用。既往研究表明，包括JQ1在内的多种BET抑制剂（BETi）在癌症与心血管疾病中具有治疗效应，部分BET抑制剂已进入不同阶段的临床试验。从药理学机制来看，JQ1通过竞争性结合BET溴结构域的乙酰赖氨酸识别口袋，将BET蛋白从染色质上置换下来，从而发挥生物学功能。JQ1已作为化学探针，被用于探究BET溴结构域在心血管疾病转录调控中的作用。例如，已有研究证实JQ1可减轻炎症反应并改善实验性动脉粥样硬化（《分子细胞》（Mol Cell）, 2014年10月23日; 56(2): 219–231.）。近期还有研究显示，JQ1可抑制内皮间质转化（EndoMT）与心肌纤维化（《分子与细胞心脏病学杂志》（J Mol Cell Cardiol）, 2019年2月; 127: 83–96.）。然而，JQ1依赖或不依赖BRD4的分子靶点仍未明确。为解析JQ1在人内皮细胞中的转录组特征，本研究采用基于全基因组RNA测序（RNA-seq）的转录组分析方法，经JQ1处理后观察到其可诱导产生兼具血管保护与抗动脉粥样硬化活性的转录组特征。JQ1堪称心血管疾病预防领域的精准靶向治疗药物。进一步阐明JQ1的新型分子靶点，将有助于发现用于治疗心血管疾病的潜在全新治疗靶点。