Project 2: Investigating regulation of transcriptional condensates in multiple myeloma

项目 2：研究多发性骨髓瘤中转录缩合物的调控

• 批准号: 10555732
• 负责人: RICHARD YOUNG
• 金额: $ 30.88万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-12-01 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10555732
• 关键词: Antineoplastic Agents; Behavior; Binding; Biochemical; Cell physiology; Cells; Chemicals; Chemistry; Chromosome Mapping; Cisplatin; DNA Binding Domain; DNA Repair; DNA-Directed RNA Polymerase; Development; Drug Targeting; Enhancers; Environment; Epigenetic Process; Feedback; Funding; Gene Expression; Gene Expression Regulation; Genes; Genetic Transcription; Goals; Maintenance; Mediating; Membrane; Modeling; Multiple Myeloma; Nucleic Acids; Oncogenes; Oncogenic; Organelles; Pharmaceutical Preparations; Physical condensation; Physiological Processes; Process; Property; Proteins; RNA; RNA Binding; RNA Recognition Motif; Regulation; Role; Site; Specificity; Tamoxifen; Testing; Therapeutic; Toxic effect; Transcriptional Activation Domain; Transcriptional Regulation; YY1 Transcription Factor; cancer genomics; chemical property; cofactor; epigenetic regulation; improved; insight; neoplastic cell; novel therapeutics; pharmacologic; programs; promoter; small molecule; therapeutic development; transcription factor

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.

项目概要-项目2麻省理工学院怀特黑德研究所 在我们对细胞状态的转录控制以及如何控制细胞状态的理解方面， 它们在肿瘤细胞中失调。在研究多个基因的转录和表观遗传调控时， 骨髓瘤（MM）细胞在前一个资助期，我们的研究导致了一个新的模型，转录控制的 细胞状态，一个转录和表观遗传装置成为生物分子区室化的状态。 浓缩并由生物分子以基因的典型模型所未预期的方式调节 法规（图1）。我们发现驱动癌基因的超级增强子形成了大的浓缩物 其将主转录因子（TF）、表观遗传装置、调节RNA分子和 大量的RNA聚合酶分子使癌基因转录的高速率。而且我们 发现新转录的RNA分子对局部基因调控做出了深远的贡献， 直接与TF结合并通过改变超级增强子缩合物的寿命。重要的是，我们还 发现这些转录浓缩物具有化学性质， 药物的药理学性质在药物中发生改变， 药物的目标附近。对凝析油物理化学的进一步了解应有助于开发 具有改善的功效和降低的毒性的治疗分子。基于这些研究，我们建议 推进我们的理解，在MM细胞中，转录缩合物的调节和生物化学 这些冷凝物中的环境影响药物行为。为了实现这些目标，将 目的：1）研究MM细胞状态下主转录因子与RNA结合的作用，2） 研究RNA在调节致癌转录缩合物和DNA损伤修复中的作用 MM中的冷凝物，以及3）研究冷凝物化学的特征，提供特定的化学物质 用于增强剂相关装置和浓缩药物环境。这些拟议 这些研究将促进我们对转录浓缩物调控和生物化学调控的理解。 这些冷凝物中的环境，并且因此可以使得能够开发新的治疗分子， 提高功效并降低毒性。