Serotonylation of histone H3Q5 (H3Q5ser) is a recently identified posttranslational modification of histones that acts as a permissive marker for gene activation in synergy with H3K4me3 during neuronal cell differentiation. However, any proteins that specifically recognize H3Q5ser remain unknown. Here, we found that WDR5 interacts with the N-terminal tail of histone H3 and functions as a “reader” for H3Q5ser. Crystal structures of WDR5 in complex with H3Q5ser and H3K4me3Q5ser peptides revealed that the serotonyl group is accommodated in a shallow surface pocket of WDR5. Experiments in neuroblastoma cells demonstrate that H3K4me3 modification is hampered upon disruption of WDR5-H3Q5ser interaction. WDR5 colocalizes with H3Q5ser in the promoter regions of cancer-promoting genes in neuroblastoma cells, where it promotes gene transcription to induce cell proliferation. Thus, beyond revealing a previously unknown mechanism through which WDR5 reads H3Q5ser to activate transcription, our study suggests that this WDR5-H3Q5ser–mediated epigenetic regulation apparently promotes tumorigenesis.

组蛋白 H3Q5 (H3Q5ser) 的血清素化是最近发现的组蛋白翻译后修饰，在神经元细胞分化过程中可作为基因激活的许可标记，与 H3K4me3 协同作用。然而，任何特异性识别 H3Q5ser 的蛋白质仍然未知。在这里，我们发现 WDR5 与组蛋白 H3 的 N 末端尾部相互作用，并充当 H3Q5ser 的“阅读器”。与 H3Q5ser 和 H3K4me3Q5ser 肽复合的 WDR5 的晶体结构显示血清素基团位于 WDR5 的浅表面袋中。在神经母细胞瘤细胞中进行的实验表明，H3K4me3 修饰在 WDR5-H3Q5ser 相互作用中断时受到阻碍。WDR5 在神经母细胞瘤细胞中促癌基因的启动子区域与 H3Q5ser 共定位，它促进基因转录以诱导细胞增殖。因此，除了揭示 WDR5 读取 H3Q5ser 以激活转录的先前未知机制外，我们的研究表明，这种 WDR5-H3Q5ser 介导的表观遗传调控显然促进了肿瘤发生。