Epigenetic control of coordinated hematopoietic and cardiovascular development by Rnf2 in zebrafish

Early embryogenesis requires the coordinated development of cardiovascular and hematopoietic lineages. However, the underlying cellular and genetic mechanisms are poorly understood. Here, we show that Rnf2, the core enzymatic component of Polycomb repressive complex 1 (PRC1), plays an important role in the control of cardiovascular and hematopoietic development and differentiation via suppressing the master hematoendothelial progenitor genes in zebrafish. In the absence of Rnf2, a group of transcription factor (TF) genes crucial for hematoendothelial specification such as etv2, gata2, lmo2 and tal1 are significantly up-regulated, which causes an expansion of hematopoietic and endothelial progenitors at the expense of myocardial differentiation, resulting in severe defects in both cardiogenesis and hematopoiesis. Although the number of hematopoietic stem cells (HSCs) is increased, both primitive and definitive waves of hematopoiesis are severely compromised in rnf2 mutant embryos, suggesting that Rnf2 is required for differentiation of blood progenitor cells. Combined ChIP-seq and RNA-seq analysis shows that Rnf2 directly binds to key hematoendothelial progenitor genes and represses its expression. We further show that Rnf2-mediated gene repression depends on its H2Aub1 catalytic activity. We propose that PRC1/Rnf2-mediated epigenetic mechanism plays a key role in coordinated development of cardiovascular and hematopoietic lineages by repressing key hematoendothelial progenitor genes. HighlightsO_LIRnf2 is required for suppressing the expression of key hematoendothelial TF genes in precursors and its differentiated descendants. C_LIO_LIRnf2 mutant zebrafish embryos display defective hematopoiesis and cardiogenesis. C_LIO_LILoss of Rnf2 results in increased HSC numbers and arrested differentiation, hallmarks of leukemia. C_LIO_LIRnf2 suppresses hematoendothelial progenitor genes via depositing H2Aub1. C_LI