Deciphering Molecular Control of VEGFR2 Regulation in Hematopoietic Progenitors: GATA1-Mediated Repression of VEGFR2 Promotes Optimum Erythropoiesis

Abstract VEGFR2 (also known as Flk1) is expressed in hemetopoietic precursors and is essential for both hematopoietic and vascular development. Interestingly, development of differentiated hematopoietic cell from hematopoietic stem cells (HSCs) is associated with VEGFR2 repression, whereas VEGFR2 expression is maintained throughout endothelial development. This differential regulation of VEGFR2 has been implicated as a key step to successfully branch out hematopoietic vs. endothelial development. However, molecular mechanisms that regulate transcriptionally active vs. repressive Vegfr2 chromatin domains in hematopoietic stem/progenitor cells (HSPCs) vs. differentiated hematopoietic cells are incompletely understood. Here, we report that transcription factor GATA1, a master-regulator of erythroid differentiation, is essential to repress VEGFR2 expression in erythroid progenitors. Genetic complementation analysis demonstrated that VEGFR2 expression in maintained in GATA1-null erythroid progenitors and rescue of GATA1-function induces VEGFR2 repression. Mechanistic studies in primary hematopoietic progenitors from mouse fetal liver and differentiating mouse embryonic stem cells (ESCs) identified a repressor element at the (-)88 kb region of the Vegfr2 locus from which GATA1 represses Vegfr2 transcription in erythroid progenitors. Furthermore, CRISPR/Cas9-mediated deletion of the Vegfr2(-)88 kb region results in reduced erythroid differentiation during fetal liver hematopoiesis. These results indicate that GATA1-mediated repression of VEGFR2 could be a determinant of optimum erythropoiesis. Disclosures No relevant conflicts of interest to declare.