Project 2: Investigating regulation of transcriptional condensates in multiple myeloma

项目摘要-麻省理工学院怀特黑德研究所项目2 我们对细胞状态的转录控制以及如何控制的理解已经取得了实质性的进展。 它们在肿瘤细胞中的调节失调。在研究多个基因的转录和表观遗传调控时 骨髓瘤(MM)细胞，我们的研究导致了一种新的转录调控模型 细胞状态，在这种状态下，转录和表观遗传装置在生物分子中变得分区化 生物分子以一种基因规范模型没有预料到的方式凝聚和调节 法规(图1)。我们发现，驱动癌基因的超级增强剂形成了巨大的凝聚体 它将主要转录因子(TF)、表观遗传器、调节RNA分子和 大量的RNA聚合酶分子使癌基因的高转录成为可能。此外，我们 发现新转录的RNA分子对局部基因调控做出了深远的贡献，包括 直接与TF结合，并通过改变超级增强剂冷凝物的寿命。重要的是，我们还 发现这些转录缩合物具有浓缩受试者的化学性质 抗肿瘤药物超过100倍，以至于药物的药理特性在 在毒品目标附近。对凝析油物理化学的进一步了解应该能够使 疗效更好、毒性更低的治疗分子。基于这些研究，我们建议 增进我们对多发性骨髓瘤细胞中转录缩合物和生化调节的理解 这些冷凝物中影响药物行为的环境。为了实现这些目标，将实现以下目标 1)研究主要转录因子结合RNA在多发性骨髓瘤细胞状态中的作用；2) 研究RNA在致癌转录缩合物调控和DNA损伤修复中的作用 MM中的凝析油，以及3)研究提供特定化学物质的凝析油化学特征 增强剂相关设备和浓缩抗肿瘤药物的环境。这些建议 研究将促进我们对转录缩合物和生化的调节的理解 在这些冷凝物中的环境，并因此可能使开发具有 提高疗效，降低毒性。

Project Summary – Project 2 Whitehead Institute at MIT There have been substantial advances in our understanding of the transcriptional control of cell states and how they are dysregulated in tumor cells. While investigating the transcriptional and epigenetic regulation of multiple myeloma (MM) cells in the previous funding period, our studies led to a new model for transcriptional control of cell state, one where the transcriptional and epigenetic apparatus becomes compartmentalized in biomolecular condensates and is regulated by biomolecules in a manner not anticipated by the canonical models of gene regulation (Figure 1). We discovered that the super-enhancers that drive oncogenes form large condensates that compartmentalize master transcription factors (TFs), epigenetic apparatus, regulatory RNA molecules and large numbers of RNA polymerase molecules to enable high rates of oncogene transcription. Furthermore, we found that newly transcribed RNA molecules make a profound contribution to local gene regulation both by directly binding to TFs and by altering the lifetime of the super-enhancer condensates. Importantly, we also discovered that these transcriptional condensates have chemical properties that concentrate the tested antineoplastic drugs over a hundred-fold, such that the pharmacological properties of the drug are altered in the vicinity of the drug’s target. Further insights into condensate physicochemistry should enable development of therapeutic molecules with improved efficacy and reduced toxicity. Based on these studies we propose to advance our understanding, in MM cells, of the regulation of transcriptional condensates and the biochemical environment in these condensates that influences drug behavior. To achieve these goals, the following Aims will be pursued: 1) To investigate the role of RNA binding by master transcription factors in MM cell state, 2) To investigate the role of RNA in regulation of oncogenic transcriptional condensates and DNA damage repair condensates in MM, and 3) To investigate the features of condensate chemistry that provide a specific chemical environment for enhancer-associated apparatus and that concentrate antineoplastic drugs. These proposed studies will advance our understanding of the regulation of transcriptional condensates and the biochemical environment in these condensates, and may thus enable development of novel therapeutic molecules with improved efficacy and reduced toxicity.