Facilitated recruitment of MYC to chromatin by interaction with WDR5

 描述（由申请人提供）：MYC是一种癌蛋白转录因子，在癌症中具有显著特征。作为转录因子，MYC与靶基因染色质稳定结合的能力对其活性至关重要，并且已被验证为癌细胞中抑制MYC功能的有效点。该项目探讨了MYC通过一条涉及普遍的染色质调节因子WDR 5的途径招募到染色质的机制和意义。初步数据：（i）鉴定WDR 5作为直接MYC相互作用伴侣，（ii）定义MYC如何与WDR 5相互作用，和（iii）证明破坏与WDR 5的相互作用减弱MYC结合染色质和驱动肿瘤发生的能力。总之，这些数据支持一个模型，其中MYC与WDR 5的相互作用是在染色质背景下识别其靶基因所必需的。重要的是，MYC-WDR 5复合物的结构揭示了这两种蛋白质通过适合于发现小分子抑制剂的界面相互作用，提高了MYC-WDR 5关系可以通过阻断MYC功能打开治疗癌症的新方法的前景。 该项目的目标是描述WDR 5如何将MYC招募到染色质中，并揭示这种机制对MYC的基本生物学和致瘤特性的贡献。目标1将使用生物化学，蛋白质组学和基因组学方法的组合来描绘MYC-WDR 5共复合物的成员，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MYC-WDR 5共结合基因是如何被选择和建立的，WDR 5本身是如何被招募到这些位点的，并且可以很好地识别WDR 5上可以靶向抑制癌细胞的其他相互作用表面。目标2将联合收割机与细胞和动物为基础的系统相结合的精确转录组学分析，揭示直接通过MYC-WDR 5相互作用控制的转录事件和这些事件的淋巴瘤发生的贡献。这些研究将确定哪些基因依赖于MYC-WDR 5连接进行调节，定义由这种连接控制的关键途径，并为理解可能使癌细胞对MYC-WDR 5相互作用的小分子干扰敏感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一个新的范例，并开发新的机会来发现和验证通过抑制MYC与染色质的相互作用靶向癌细胞的药物样分子。

 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.