Collectively, the MYC family of oncoprotein transcription factors is overexpressed in more than half of all malignancies. The ability of MYC proteins to access chromatin is fundamental to their role in promoting oncogenic gene expression programs in cancer and this function depends on MYC–cofactor interactions. One such cofactor is the chromatin regulator WDR5, which in models of Burkitt lymphoma facilitates recruitment of the c-MYC protein to chromatin at genes associated with protein synthesis, allowing for tumor progression and maintenance. However, beyond Burkitt lymphoma, it is unknown whether these observations extend to other cancers or MYC family members, and whether WDR5 can be deemed as a “universal” MYC recruiter. Here, we focus on N-MYC amplified neuroblastoma to determine the extent of colocalization between N-MYC and WDR5 on chromatin while also demonstrating that like c-MYC, WDR5 can facilitate the recruitment of N-MYC to conserved WDR5-bound genes. We conclude based on this analysis that N-MYC and WDR5 colocalize invariantly across cell lines at predicted sites of facilitated recruitment associated with protein synthesis genes. Surprisingly, we also identify N-MYC-WDR5 cobound genes that are associated with DNA repair and cell cycle processes. Dissection of chromatin binding characteristics for N-MYC and WDR5 at all cobound genes reveals that sites of facilitated recruitment are inherently different than most N-MYC-WDR5 cobound sites. Our data reveals that WDR5 acts as a universal MYC recruiter at a small cohort of previously identified genes and highlights novel biological functions that may be coregulated by N-MYC and WDR5 to sustain the neuroblastoma state.

总的来说，癌蛋白转录因子 MYC 家族在超过一半的恶性肿瘤中过度表达。MYC 蛋白接触染色质的能力对于其在癌症中促进致癌基因表达程序的作用至关重要，并且该功能取决于 MYC-辅因子的相互作用。其中一种辅助因子是染色质调节因子 WDR5，它在伯基特淋巴瘤模型中促进 c-MYC 蛋白募集到与蛋白质合成相关的基因处的染色质，从而允许肿瘤进展和维持。然而，除了伯基特淋巴瘤之外，尚不清楚这些观察结果是否扩展到其他癌症或 MYC 家族成员，以及 WDR5 是否可以被视为“通用”MYC 募集剂。在这里，我们重点关注 N-MYC 扩增的神经母细胞瘤，以确定 N-MYC 和 WDR5 在染色质上的共定位程度，同时也证明与 c-MYC 一样，WDR5 可以促进 N-MYC 招募到保守的 WDR5 结合基因。基于此分析，我们得出结论，N-MYC 和 WDR5 在细胞系中不变地共定位于与蛋白质合成基因相关的促进招募的预测位点。令人惊讶的是，我们还鉴定了与 DNA 修复和细胞周期过程相关的 N-MYC-WDR5 共结合基因。对所有共结合基因上 N-MYC 和 WDR5 的染色质结合特征的剖析表明，促进招募的位点本质上不同于大多数 N-MYC-WDR5 共结合位点。我们的数据显示，WDR5 在一小群先前鉴定的基因中充当通用 MYC 募集者，并强调了可能由 N-MYC 和 WDR5 共同调节以维持神经母细胞瘤状态的新生物功能。