GATA2 Promotes Hematopoietic Development and Represses Cardiac Differentiation of Human Mesoderm

Altres ajuts: A.G. is supported by Ramón y Cajal Program (RyC-2013-13221). C.B. is supported by Spanish Cancer Association (CI15152720BUEN). P.M. is funded by the PERIS Program of the Generalitat de Catalunya and by the Obra Social la Caixa-Fundacion Josep Carreras. Gottgens laboratory is supported by The Wellcome Trust, MRC, CRUK, NIH -NIDDK, and core support grants by The Wellcome Trust to the Wellcome and MRC Cambridge Stem Cell Institute. ACCIÓ /FEDER (AdvanceCat); Fundació la Marató de TV3 (201534-30).In vertebrates, GATA2 is a master regulator of hematopoiesis and is expressed throughout embryo development and in adult life. Although the essential role of GATA2 in mouse hematopoiesis is well established, its involvement during early human hematopoietic development is not clear. By combining time-controlled overexpression of GATA2 with genetic knockout experiments, we found that GATA2, at the mesoderm specification stage, promotes the generation of hemogenic endothelial progenitors and their further differentiation to hematopoietic progenitor cells, and negatively regulates cardiac differentiation. Surprisingly, genome-wide transcriptional and chromatin immunoprecipitation analysis showed that GATA2 bound to regulatory regions, and repressed the expression of cardiac development-related genes. Moreover, genes important for hematopoietic differentiation were upregulated by GATA2 in a mostly indirect manner. Collectively, our data reveal a hitherto unrecognized role of GATA2 as a repressor of cardiac fates, and highlight the importance of coordinating the specification and repression of alternative cell fates