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.

Castaño J ，Aranda S ，Bueno C ，Calero-Nieto FJ ，Mejia-Ramirez E ，Mosquera JL ，Blanco E ，Wang X ，Prieto C ，Zabaleta L ，Mereu E ，Rovira M ，Jiménez-Delgado S ，Matson DR ，Heyn H ，Bresnick EH ，Göttgens B ，Di Croce L ，Menendez P ，Raya A ，Giorgetti A ... -  《Stem Cell Reports》

GATA2 Is Dispensable for Specification of Hemogenic Endothelium but Promotes Endothelial-to-Hematopoietic Transition.

The transcriptional factor GATA2 is required for blood and hematopoietic stem cell formation during the hemogenic endothelium (HE) stage of development in the embryo. However, it is unclear if GATA2 controls HE lineage specification or if it solely regulates endothelial-to-hematopoietic transition (EHT). To address this problem, we innovated a unique system, which involved generating GATA2 knockout human embryonic stem cell (hESC) lines with conditional GATA2 expression (iG2-/- hESCs). We demonstrated that GATA2 activity is not required for VE-cadherin+CD43-CD73+ non-HE or VE-cadherin+CD43-CD73- HE generation and subsequent HE diversification into DLL4+ arterial and DLL4- non-arterial lineages. However, GATA2 is primarily needed for HE to undergo EHT. Forced expression of GATA2 in non-HE failed to induce blood formation. The lack of GATA2 requirement for generation of HE and non-HE indicates the critical role of GATA2-independent pathways in specification of these two distinct endothelial lineages.

Kang H ，Mesquitta WT ，Jung HS ，Moskvin OV ，Thomson JA ，Slukvin II ... -  《Stem Cell Reports》

GATA2 deficiency and human hematopoietic development modeled using induced pluripotent stem cells.

Jung M ，Cordes S ，Zou J ，Yu SJ ，Guitart X ，Hong SG ，Dang V ，Kang E ，Donaires FS ，Hassan SA ，Albitar M ，Hsu AP ，Holland SM ，Hickstein DD ，Townsley D ，Dunbar CE ，Winkler T ... -  《-》

Cooperative Transcription Factor Induction Mediates Hemogenic Reprogramming.

During development, hematopoietic stem and progenitor cells (HSPCs) arise from specialized endothelial cells by a process termed endothelial-to-hematopoietic transition (EHT). The genetic program driving human HSPC emergence remains largely unknown. We previously reported that the generation of hemogenic precursor cells from mouse fibroblasts recapitulates developmental hematopoiesis. Here, we demonstrate that human fibroblasts can be reprogrammed into hemogenic cells by the same transcription factors. Induced cells display dynamic EHT transcriptional programs, generate hematopoietic progeny, possess HSPC cell surface phenotype, and repopulate immunodeficient mice for 3 months. Mechanistically, GATA2 and GFI1B interact and co-occupy a cohort of targets. This cooperative binding is reflected by engagement of open enhancers and promoters, initiating silencing of fibroblast genes and activating the hemogenic program. However, GATA2 displays dominant and independent targeting activity during the early phases of reprogramming. These findings shed light on the processes controlling human HSC specification and support generation of reprogrammed HSCs for clinical applications.

Gomes AM ，Kurochkin I ，Chang B ，Daniel M ，Law K ，Satija N ，Lachmann A ，Wang Z ，Ferreira L ，Ma'ayan A ，Chen BK ，Papatsenko D ，Lemischka IR ，Moore KA ，Pereira CF ... -  《Cell Reports》

Polycomb group protein Bmi1 promotes hematopoietic cell development from embryonic stem cells.

Ding X ，Lin Q ，Ensenat-Waser R ，Rose-John S ，Zenke M ... -  《-》