Despite being the focus of intense research in recent years, the precise mechanisms that regulate the development of haematopoietic stem and progenitor cells (HSPCs), which give rise to all differentiated blood cells, remain unclear. In particular, it is not clear how various transcription factors function together to drive the emergence of HSPCs from haemogenic endothelium (HE) during development. In this issue, two papers attempt to tackle this problem.
In the first paper (p. 4341), Valerie Kouskoff and co-workers examine how SOX7 and RUNX1 regulate haemogenic fate in the yolk sac of mouse embryos. These two factors are thought to play opposing roles: RUNX1 acts as a master regulator of endothelial-to-haemogenic transition (EHT) while SOX7 downregulation is needed for this event. Now, the authors report that, when overexpressed in ESC-derived HE, SOX7 inhibits the expression of RUNX1 target genes but has no effect on the expression of RUNX1 itself. They further reveal that SOX7 and RUNX1 are co-expressed in the yolk sac and dorsal aorta HE of mouse embryos and, importantly, can physically interact with each other via their respective HMG and RUNT domains. This interaction, the authors report, inhibits the transcriptional activity of RUNX1; the binding of SOX7 to RUNX1 prevents RUNX1 from interacting with its co-factor CBFβ and with its target DNA sites. Together, these findings highlight how direct protein-protein interactions between endothelial and haematopoietic transcription factors can regulate cell differentiation programmes during development.
In a second paper (p. 4324), Nadine Obier, Constanze Bonifer and colleagues investigate how AP-1 transcription factors regulate cell fate during the differentiation of mouse embryonic stem cells (ESCs) into haematopoietic cells. They demonstrate that the global inhibition of AP-1 factors (using inducible overexpression of a dominant-negative FOS peptide) affects various stages of ESC differentiation, as cells transition from haemangioblasts (HB) into haemogenic endothelium (HE) and haematopoietic cells. In particular, inhibition at the HB stage enhances cell proliferation and affects the balance between smooth muscle and blood cells, shifting cells towards a blood cell fate. Finally, the authors reveal that AP-1 factors bind to target genes involved in vasculogenesis; these target sites colocalize with binding motifs for TEAD transcription factors, and the authors further show that AP-1 factors are required for the de novo binding of TEAD4 to these genes. In summary, these results suggest that cis-regulatory elements that bind both AP-1 and TEAD4 act as ‘hubs’ that integrate multiple signals to regulate specific gene expression programmes during haematopoiesis.
