Yolk sac (YS) hematopoiesis is critical for the survival of the embryo and a major source of tissue-resident macrophages that persist into adulthood. Yet, the transcriptional and epigenetic regulation of YS hematopoiesis remains poorly characterized. Here we report that the epigenetic regulator Ezh2 is essential for YS hematopoiesis but dispensable for subsequent aorta–gonad–mesonephros (AGM) blood development. Loss of EZH2 activity in hemogenic endothelium (HE) leads to the generation of phenotypically intact but functionally deficient erythro-myeloid progenitors (EMPs), while the generation of primitive erythroid cells is not affected. EZH2 activity is critical for the generation of functional EMPs at the onset of the endothelial-to-hematopoietic transition but subsequently dispensable. We identify a lack of Wnt signaling downregulation as the primary reason for the production of non-functional EMPs. Together, our findings demonstrate a critical and stage-specific role of Ezh2 in modulating Wnt signaling during the generation of EMPs from YS HE.

卵黄囊 (YS) 造血对于胚胎的存活至关重要，也是持续到成年的组织驻留巨噬细胞的主要来源。然而，YS 造血的转录和表观遗传调控仍然知之甚少。在这里，我们报道表观遗传调节因子 Ezh2 对于 YS 造血至关重要，但对于随后的主动脉-性腺-中肾 (AGM) 血液发育来说是可有可无的。造血内皮 (HE) 中 EZH2 活性的丧失会导致表型完整但功能缺陷的红系骨髓祖细胞 (EMP) 的生成，而原始红系细胞的生成不受影响。 EZH2 活性在内皮向造血转变开始时对于功能性 EMP 的生成至关重要，但随后就变得可有可无。我们认为缺乏 Wnt 信号下调是产生非功能性 EMP 的主要原因。总之，我们的研究结果证明了 Ezh2 在 YS HE 产生 EMP 过程中调节 Wnt 信号传导中的关键和特定阶段的作用。