Abstract
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.
Highlights
Yolk sac (YS) hematopoiesis is critical for the survival of the embryo and a major source of tissue-resident macrophages that persist into adulthood
We previously demonstrated that Tie2-Ezh2-KO results in lethality around E13.517
The early lethality in Tie2-Ezh2-KO embryos, associated with severe anemia, prompted us to investigate the potential defects in YS hematopoiesis
Summary
Yolk sac (YS) hematopoiesis is critical for the survival of the embryo and a major source of tissue-resident macrophages that persist into adulthood. Defect in primitive hematopoiesis results in early lethality before E10.54, a lack of EMP causes lethal embryonic anemia around E13.5, while the absence of HSC leads to perinatal lethality[5,6,7] Both YS-derived primitive erythroid, YS-derived EMP and AGM HSC arise from a similar transient subpopulation of endothelial cells called hemogenic endothelium (HE) through a process of endothelial-to-hematopoietic transition (EHT)[8,9,10,11,12]. Tie2-Ezh2-KO embryos, in which deletion is activated at the endothelial stage[23], die around E13.5 from severe anemia[17] While this severe anemia may partly involve cell-extrinsic mechanisms[17], the development of lethal embryonic anemia at E13.5 in Tie2-Ezh2-KO embryos suggests a possible defect of YS EMP6,7. Our results reveal an essential role of Ezh[2] in the temporal epigenetic regulation of YS EMPs generation
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