Upon stimulation by extrinsic stimuli, stem cells initiate a programme that enables differentiation or self-renewal. Disruption of the stem state exit has catastrophic consequences for embryogenesis and can lead to cancer. While some elements of this stem state switch are known, major regulatory mechanisms remain unclear. Here we show that this switch involves a global increase in splicing efficiency coordinated by DNA methyltransferase 3α (DNMT3A), an enzyme typically involved in DNA methylation. Proper activation of murine and human embryonic and haematopoietic stem cells depends on messenger RNA processing, influenced by DNMT3A in response to stimuli. DNMT3A coordinates splicing through recruitment of the core spliceosome protein SF3B1 to RNA polymerase and mRNA. Importantly, the DNA methylation function of DNMT3A is not required and loss of DNMT3A leads to impaired splicing during stem cell turnover. Finally, we identify the spliceosome as a potential therapeutic target in DNMT3A-mutated leukaemias. Together, our results reveal a modality through which DNMT3A and the spliceosome govern exit from the stem state towards differentiation.

在受到外部刺激的刺激后，干细胞启动一个能够分化或自我更新的程序。干状态退出的破坏会给胚胎发生带来灾难性的后果，并可能导致癌症。虽然这种干状态转换的一些要素是已知的，但主要的调节机制仍不清楚。在这里，我们表明，这种转换涉及由 DNA 甲基转移酶 3α (DNMT3A)（一种通常参与 DNA 甲基化的酶）协调的剪接效率的整体提高。小鼠和人类胚胎干细胞和造血干细胞的正确激活取决于信使 RNA 的加工，并受到 DNMT3A 对刺激的反应的影响。 DNMT3A 通过将核心剪接体蛋白 SF3B1 招募到 RNA 聚合酶和 mRNA 来协调剪接。重要的是，DNMT3A 的 DNA 甲基化功能不是必需的，DNMT3A 的丢失会导致干细胞更新过程中的剪接受损。最后，我们将剪接体确定为 DNMT3A 突变白血病的潜在治疗靶点。总之，我们的结果揭示了 DNMT3A 和剪接体控制从干状态退出到分化的模式。