Abstract：
Bromodomain (BRD)-containing proteins are evolutionarily conserved protein-protein interaction modules involved in many biological processes. BRDs selectively recognize and bind to acetylated lysine residues, particularly in histones, and thereby have a crucial role in the regulation of gene expression. BRD protein dysfunction has been linked to many diseases, including tumorigenesis. Previously, we reported the critical role of BRD-containing protein 9 (BRD9) in the pathogenesis of UFs. The present study aimed to extend our previous finding and further understand the role of the BRD9 in UFs. Our studies demonstrated that targeted inhibition of BRD9 with its potent inhibitor TP-472 inhibited the pathogenesis of UF through increased apoptosis and proliferation arrest and decreased extracellular matrix deposition in UF cells. High-throughput transcriptomic analysis further and extensively demonstrated that targeted inhibition of BRD9 by TP-472 impacted the biological pathways, including cell cycle progression, inflammatory response, E2F targets, ECM deposition, and m6A reprogramming. Compared with the previous study, we identified common enriched pathways induced by two BRD9 inhibitors, I-BRD9 and TP-472. Taken together, our studies further revealed the critical role of BRD9 in UF cells. We characterized the link between BRD9 and other vital pathways, as well as the connection between epigenetic and epitranscriptome involved in UF progression. Targeted inhibition of BRD proteins might provide a non-hormonal treatment strategy for this most common benign tumor in women of reproductive age.
摘要：
含溴结构域（BRD）的蛋白质是进化上保守的蛋白质-蛋白质相互作用模块，参与许多生物学过程。BRD选择性识别和结合乙酰化赖氨酸残基，特别是在组蛋白中，从而在基因表达的调控中起着至关重要的作用。BRD蛋白功能障碍与许多疾病有关,包括肿瘤发生。以前,我们报道了含BRD蛋白9(BRD9)在UFs发病机制中的关键作用.本研究旨在扩展我们先前的发现，并进一步了解BRD9在UF中的作用。我们的研究表明，靶向抑制BRD9及其有效的抑制剂TP-472通过增加UF细胞的凋亡和增殖停滞以及减少细胞外基质沉积来抑制UF的发病机理。高通量转录组分析进一步和广泛地证明了通过TP-472靶向抑制BRD9影响生物学途径,包括细胞周期进程，炎症反应，E2F目标,ECM沉积,和m6A重新编程。与以前的研究相比，我们确定了两种BRD9抑制剂诱导的常见富集途径，I-BRD9和TP-472。一起来看,我们的研究进一步揭示了BRD9在UF细胞中的关键作用。我们描述了BRD9和其他重要途径之间的联系，以及与UF进展有关的表观遗传和表观转录组之间的联系。BRD蛋白的靶向抑制可能为育龄妇女这种最常见的良性肿瘤提供非激素治疗策略。
