Facilitated recruitment of MYC to chromatin by interaction with WDR5

 描述(申请人提供)：MYC是一种癌蛋白转录因子，在癌症中占有重要地位。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，已被证实是抑制癌细胞MYC功能的有效点。这个项目探索了MYC通过一条涉及普遍存在的染色质调节因子WDR5的途径重新募集到染色质的机制和意义。初步数据：(I)确定WDR5是MYC-相互作用的直接伙伴，(Ii)确定MYC如何与WDR5相互作用，以及(Iii)表明干扰与WDR5的相互作用会减弱MYC结合染色质和推动肿瘤发生的能力。总之，这些数据支持一种模型，在该模型中，MYC和WDR5的相互作用是在染色质背景下识别其目标基因所必需的。重要的是，MYC-WDR5复合体的结构表明，这两种蛋白质通过一种易于发现小分子抑制剂的界面相互作用，这增加了MYC-WDR5网络可能通过阻断MYC功能打开治疗癌症的新方法的可能性。本项目的目的是描述WDR5如何将MYC招募到染色质中，并揭示这一机制对MYC的基本生物学和致癌特性的贡献。目标1将使用生化、蛋白质组和基因组学方法相结合的方法来描述MYC-WDR5共复合体的成员，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-WDR5共结合基因是如何被选择和建立的，WDR5本身是如何被招募到这些位置的，并很可能很好地识别WDR5上可以被靶向抑制癌细胞的其他相互作用表面。AIM 2将结合精确的转录分析与基于细胞和动物的系统来揭示通过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连接进行调控，定义由这种连接控制的关键通路，并为了解可能使癌细胞容易受到MYC-WDR5相互作用的小分子扰动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，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类药物分子。

 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.