Alternative splicing (AS) leads to transcriptome diversity in eukaryotic cells and is one of the key regulators driving cellular differentiation. Although AS is of crucial importance for normal hematopoiesis and hematopoietic malignancies, its role in early hematopoietic development is still largely unknown. Here, by using high‐throughput transcriptomic analyses, we show that pervasive and dynamic AS takes place during hematopoietic development of human pluripotent stem cells (hPSCs). We identify a splicing factor switch that occurs during the differentiation of mesodermal cells to endothelial progenitor cells (EPCs). Perturbation of this switch selectively impairs the emergence of EPCs and hemogenic endothelial progenitor cells (HEPs). Mechanistically, an EPC‐induced alternative spliced isoform of NUMB dictates EPC specification by controlling NOTCH signaling. Furthermore, we demonstrate that the splicing factor SRSF2 regulates splicing of the EPC‐induced NUMB isoform, and the SRSF2‐NUMB‐NOTCH splicing axis regulates EPC generation. The identification of this splicing factor switch provides a new molecular mechanism to control cell fate and lineage specification.

中文翻译：

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剪接因子开关控制多能干细胞的造血谱系规范

可变剪接 (AS) 导致真核细胞中的转录组多样性，并且是驱动细胞分化的关键调节因子之一。尽管 AS 对正常造血和造血恶性肿瘤至关重要，但其在早期造血发育中的作用仍然很大程度上未知。在这里，通过使用高通量转录组学分析，我们表明在人类多能干细胞 (hPSC) 的造血发育过程中会发生普遍和动态的 AS。我们确定了在中胚层细胞分化为内皮祖细胞 (EPC) 期间发生的剪接因子转换。这种开关的扰动选择性地损害 EPC 和造血内皮祖细胞 (HEP) 的出现。机械地，EPC 诱导的 NUMB 可变剪接异构体通过控制 NOTCH 信号来决定 EPC 规范。此外，我们证明了剪接因子 SRSF2 调节 EPC 诱导的 NUMB 异构体的剪接，而 SRSF2-NUMB-NOTCH 剪接轴调节 EPC 的产生。这种剪接因子开关的鉴定为控制细胞命运和谱系规范提供了一种新的分子机制。