Interaction with WDR5 recruits MYC to a small cohort of genes required for tumor onset and maintenance

The oncoprotein transcription factor MYC is overexpressed in the majority of human cancers. Key to its oncogenic activity is the ability of MYC to bind chromatin and regulate broad gene expression patterns that drive and maintain the tumorigenic state. The interaction of MYC with chromatin is absolutely dependent on interaction with MAX, but may also be facilitated by additional chromatin-resident proteins such as WDR5. If the role of these additional proteins can be understood, they could serve as novel focal points for therapeutically targeting MYC. To stringently challenge the role of WDR5 in MYC function, we developed a Burkitt's Lymphoma system that allows inducible and quantitative exchange of wild-type for mutant forms of MYC defective for interaction with WDR5 or MAX. Using this system, we show that WDR5 recruits MYC to a small cohort of genes, enriched in those encoding ribosome protein subunits, and demonstrate that disrupting the MYC-WDR5 interaction is as effective as disrupting interaction with MAX at preventing tumor initiation and promoting tumor regression in vivo. These findings show that WDR5 is connected to a central tumorigenic function of MYC and forecast that small molecule WDR5 inhibitors could be broadly effective anti-cancer agents. Overall design: ChIPseq and RNAseq in Ramos cells with engineered Myc mutations

致癌蛋白转录因子MYC在绝大多数人类癌症中呈过表达状态。其致癌活性的核心在于，MYC能够结合染色质并调控广泛的基因表达谱，这些表达谱驱动并维持肿瘤发生状态。MYC与染色质的结合完全依赖于其与MAX的相互作用，但也可通过其他染色质驻留蛋白（如WDR5）得到促进。若能阐明这类辅助蛋白的作用机制，它们可成为靶向MYC的新型治疗靶点。为严格验证WDR5在MYC功能中的作用，我们构建了伯基特淋巴瘤（Burkitt's Lymphoma）模型系统，该系统可诱导性且定量地将野生型MYC替换为无法与WDR5或MAX结合的突变型MYC。利用该模型系统，我们发现WDR5可将MYC招募至一小部分基因位点，这些位点富集编码核糖体蛋白亚基的基因；同时证实，破坏MYC与WDR5的相互作用，在预防体内肿瘤发生和促进肿瘤消退方面，其效果与破坏MYC与MAX的相互作用相当。上述研究结果表明，WDR5与MYC的核心致癌功能密切相关，并预示小分子WDR5抑制剂有望成为广谱有效的抗癌治疗药物。整体实验设计：在携带工程化Myc突变的Ramos细胞中开展染色质免疫共沉淀测序（ChIPseq）与RNA测序（RNAseq）实验。