GATA2 promotes hematopoietic development and represses cardiac differentiation of human mesoderm

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.The authors thank Dr Catherine Porcher (University of Oxford) for the SCL antibody, Olalla Iglesias, Anna Duarri, and Yvonne Richaud for help with cell differentiation, and core of CMRB for technical assistance. A.G. is supported by Ramón y Cajal Program (RyC-2013-13221) and MINECO (SAF2016-80205-R). C.B. is supported by the FIS/ISCIII (PI14/01191), Spanish Cancer Association (CI15152720BUEN). J.L.M. is supported by ISCIII (CA18/00045) and by the European Social Fund (ESF). M.R. is supported by MINECO (SAF2015-73226-JIN). P.M. is funded by the PERIS Program of the Generalitat de Catalunya and by the Obra Social la Caixa-Fundacion Josep Carreras. H.H. is supported by Miguel Servet (CP14/00229). CNAG-CRG Core funding is from the ISCIII, and the Generalitat de Catalunya. 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. Additional funding came from Generalitat de Catalunya (2014-SGR-1460 and PERIS SLT002/16/00234); MINECO (SAF2015-69706-R); ISCIII/FEDER (RD16/0011/0024); ACCIÓ/FEDER (AdvanceCat); Fundació la Marató de TV3 (201534-30); and CERCA Program/Generalitat de Catalunya