BRD4 is a novel therapeutic target for liver fibrosis..pptVIP

BRD4 is a novel therapeutic 摘要 摘要 We report here that JQ1, a small molecule inhibitor of bromodomain-containing protein 4 (BRD4),a member of bromodomain and extrater-minal (BET) proteins, abrogate cytokine-induced activation of HSCs. JQ1，是BRD4的小分子抑制剂，（BRD4 是BET蛋白家族的一员），抑制细胞因子诱导的HSCs活化。 摘要 Cistromic analyses reveal that BRD4 is highly enriched at enhancers associated with genes involved in multiple profibrotic pathways, where BRD4 is colocalized with profibrotic transcription factors. Furthermore, we show that JQ1 is not only protective, but can reverse the fibrotic response in carbon tetrachloride-induced fibrosis in mouse models. . JQ1不仅对纤维化有保护作用，还可以逆转四氯化碳诱导的小鼠肝纤维化的纤维化反应 摘要 Our results implicate that BRD4 can act as a global genomic regulator to direct the fibrotic response through its coordinated regulation of myofibroblast transcription. This suggests BRD4 as a potential therapeutic target for patients with fibrotic complications. 我们的研究结果表明，BRD4可以作为一个全套基因组调节器，通过协同调控纤维化反应成肌纤维细胞转录。这表明BRD4可以作为一个潜在的治疗靶点。 前言 These findings identify BRD4-mediated enhancers as critical genomic regulators of liver fibrosis and provide mechanistic insights into the intrinsic epigenetic vulnerabilities of fibrotic disease that can be exploited for pharmacological intervention. 这些调查结果确定：BRD4是肝纤维化基因调控的一个关键介导增强子，可以为药物干预和遗传缺陷提供可靠的理论机制。 结果 BRD4 Mediates a Profibrotic Response in Activated HSCs. BRD4介导活化的HSCs纤维化反应 1、 RNAi实验 2、探讨JQ1 ，I-BET-151 ， PFI-1的抑制效果 3、染色质免疫沉淀实验（ChIP） 结果：BRD4在介导纤维化基因的转录因子调控中起着至关重要的作用 BRD4 Inhibition Blocks HSC Activation into Myo-fibroblasts. （BRD4抑制HSC的活化为肌成纤维细胞。 ） 基因表达的变化（GO）：mRNA序列是静态的原代HSC进行（1天，基线）和肌成纤维细胞转化过程中（3，6天），分析确定 900上调基因在HSC的活化，其中 400是由JQ1处理抑制。 JQ1处理HSC活化过程中的肌成纤维细胞抑制的关键标志基因，COL1A1和COL1A2，DES，ACTA2 BRD4 Is a Critical Mitogenic Regulator of HSC Activation. （BRD4是HSC活化的一个关键的促有丝分裂器。） TUNEL法测定β-半乳糖苷酶的活性，我们发现JQ1可以抑制抑制细胞增殖 BRD4 Inhibition Is Protective Against Liver Fibrosis.（BRD4抑制可预防肝纤维化。） HE染色，肝组织羟脯氨酸含量测定，组织学纤维化评