Facilitated recruitment of MYC to chromatin by interaction with WDR5

通过与 WDR5 相互作用促进 MYC 募集至染色质

• 批准号: 9212795
• 负责人: William Patrick Tansey
• 金额: $ 38.15万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-02-01 至 2021-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9212795
• 关键词: American; Animals; Antineoplastic Agents; Association Learning; Attention; Attenuated; Base Pairing; Binding; Biochemical; Biology; Cancer Model; Cells; Cessation of life; Chromatin; Complex; Critical Pathways; DNA; DNA Modification Process; Data; Event; Family; Foundations; Gap Junctions; Gene Targeting; Genes; Genetic Transcription; Genome; Genomic approach; Genomics; Goals; Human; Hydrophobicity; Link; Location; Lymphomagenesis; MYC Family Protein; MYC gene; Malignant Neoplasms; Membrane Proteins; Metabolism; Methods; Modeling; Molecular; Oncogenic; Oncoproteins; Oranges; Pathway interactions; Pharmaceutical Preparations; Point Mutation; Positioning Attribute; Post-Translational Protein Processing; Process; Property; Proteins; Proteomics; Recruitment Activity; Regulation; Resolution; Role; Site; Surface; System; Therapeutic; Tumorigenicity; United States; Validation; base; cancer cell; cancer therapy; cell growth; chromatin protein; drug discovery; expectation; experimental study; genome integrity; histone modification; in vivo; inhibitor/antagonist; member; mouse model; novel; overexpression; prevent; public health relevance; small molecule; small molecule inhibitor; stem; transcription factor; transcriptomics; tumor; tumorigenesis; tumorigenic

 DESCRIPTION (provided by applicant): MYC is an oncoprotein transcription factor that features prominently in cancer. As a transcription factor, the ability of MYC to stably associate with target gene chromatin is paramount to its activity, and has been validated as an effective point of inhibition of MYC function in cancer cells. This project explores the mechanisms and significance of recruitment of MYC to chromatin by a pathway that involves the prevalent chromatin regulator WDR5. Preliminary data: (i) identify WDR5 as a direct MYC-interaction partner, (ii) define how MYC interacts with WDR5, and (iii) demonstrate that disrupting interaction with WDR5 attenuates the ability of MYC to bind chromatin and to drive tumorigenesis. Together, these data support a model in which interaction of MYC with WDR5 is required for recognition of its target genes in the context of chromatin. Importantly, the structur of the MYC-WDR5 complex reveals that the two proteins interact via an interface that is amenable to discovery of small molecule inhibitors, raising the prospect that the MYC- WDR5 nexus could open the door to novel ways to treat cancer by blocking MYC function. The goal of this project is to characterize how WDR5 recruits MYC to chromatin and to reveal the contribution of this mechanism to the basic biology and tumorigenic properties of MYC. Aim 1 will use a combination of biochemical, proteomic, and genomic approaches to delineate members of the MYC-WDR5 co-complex and define at high resolution how they associate with target gene chromatin. These studies will illuminate how MYC-WDR5 co-bound genes are selected and established, how WDR5 itself is recruited to these sites, and may very-well identify additional interaction surfaces on WDR5 that can be targeted for inhibition in cancer cells. Aim 2 will combine precision transcriptomic analyses with cell- and animal-based systems to reveal the transcriptional events that are directly controlled via the MYC-WDR5 interaction and the contribution of these events to lymphomagenesis. These studies will identify which genes depend on the MYC-WDR5 connection for regulation, define critical pathways controlled by this connection, and lay the foundation for understanding molecular events that could render cancer cells susceptible to small molecule perturbation of the MYC-WDR5 interaction. Completion of these studies will establish a new paradigm for how MYC is recruited to chromatin and develop new opportunities to discover and validate drug-like molecules that target cancer cells by inhibiting the interaction of MYC with chromatin.

 描述（申请人提供）： MYC 是一种在癌症中具有显着特征的癌蛋白转录因子。 作为一种转录因子，MYC 与靶基因染色质稳定结合的能力对其活性至关重要，并且已被验证为癌症的有效点。抑制癌细胞中的 MYC 功能 该项目探讨了通过涉及普遍的染色质调节因子 WDR5 的途径将 MYC 募集至染色质的机制和意义。数据：(i) 将 WDR5 确定为直接的 MYC 相互作用伙伴，(ii) 定义 MYC 如何与 WDR5 相互作用，以及 (iii) 证明破坏与 WDR5 的相互作用会减弱 MYC 结合染色质并驱动肿瘤发生的能力，这些数据支持一个模型，其中 MYC 与 WDR5 的相互作用是在染色质背景下识别其靶基因所必需的。 MYC-WDR5 复合物揭示了这两种蛋白质通过一个易于发现小分子抑制剂的界面相互作用，从而提出了 MYC-WDR5 连接可能为通过阻断 MYC 功能来治疗癌症的新方法打开大门的前景。该项目旨在描述 WDR5 如何将 MYC 募集至染色质，并揭示该机制对 MYC 的基本生物学和致瘤特性的贡献，Aim 1 将结合使用以下技术。生物化学、蛋白质组学和基因组学方法来描述 MYC-WDR5 复合物的成员，并以高分辨率定义它们如何与靶基因染色质相关联。这些研究将阐明如何选择和建立 MYC-WDR5 共结合基因，以及如何选择和建立 WDR5。 Aim 2 本身正在招募到这些位点，并且很可能会识别 WDR5 上的其他相互作用表面，这些表面可用于抑制癌细胞。Aim 2 将结合细胞和动物系统进行精确的转录组分析。揭示通过 MYC-WDR5 相互作用直接控制的转录事件以及这些事件对淋巴瘤发生的贡献。这些研究将确定哪些基因依赖于 MYC-WDR5 连接进行调节，定义由该连接控制的关键途径，并奠定基础。为了解可能使癌细胞易受 MYC-WDR5 相互作用的小分子扰动影响的分子事件奠定基础。这些研究的完成将为 MYC 如何被招募到染色质建立新的范例，并开发新的机会。通过抑制 MYC 与染色质的相互作用来发现和验证靶向癌细胞的药物样分子。