WDR5 is a highly-conserved nuclear protein that performs multiple scaffolding functions in the context of chromatin. WDR5 is also a promising target for pharmacological inhibition in cancer, with small molecule inhibitors of an arginine-binding pocket of WDR5 (the 'WIN' site) showing efficacy against a range of cancer cell lines in vitro. Efforts to understand WDR5, or establish the mechanism of action of WIN site inhibitors, however, are stymied by its many functions in the nucleus, and a lack of knowledge of the conserved gene networks-if any-that are under its control. Here, we have performed comparative genomic analyses to identify the conserved sites of WDR5 binding to chromatin, and the conserved genes regulated by WDR5, across a diverse panel of cancer cell lines. We show that a specific cohort of protein synthesis genes (PSGs) are invariantly bound by WDR5, demonstrate that the WIN site anchors WDR5 to chromatin at these sites, and establish that PSGs are bona fide, acute, and persistent targets of WIN site blockade. Together, these data reveal that WDR5 plays a predominant transcriptional role in biomass accumulation and provide further evidence that WIN site inhibitors act to repress gene networks linked to protein synthesis homeostasis.

中文翻译：

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WDR5 是蛋白质合成基因表达的保守调节因子。


WDR5 是一种高度保守的核蛋白，在染色质环境中执行多种支架功能。 WDR5 也是癌症药物抑制的一个有前景的靶标，WDR5 精氨酸结合口袋（“WIN”位点）的小分子抑制剂在体外显示出针对一系列癌细胞系的功效。然而，了解 WDR5 或建立 WIN 位点抑制剂作用机制的努力受到其在细胞核中的许多功能以及对其控制下的保守基因网络（如果有的话）缺乏了解的阻碍。在这里，我们进行了比较基因组分析，以确定 WDR5 与染色质结合的保守位点，以及在不同的癌细胞系中受 WDR5 调控的保守基因。我们证明了一组特定的蛋白质合成基因 (PSG) 总是与 WDR5 结合，证明 WIN 位点将 WDR5 锚定在这些位点的染色质上，并确定 PSG 是 WIN 位点封锁的真正、急性和持久的目标。总之，这些数据揭示了 WDR5 在生物量积累中发挥着主要的转录作用，并提供了进一步的证据，证明 WIN 位点抑制剂可抑制与蛋白质合成稳态相关的基因网络。