Activating transcription factor 3 coordinates differentiation of cardiac and hematopoietic progenitors by regulating glucose metabolism

Abstract

The cardiac and hematopoietic progenitors (CPs and HPs, respectively) in the mesoderm ultimately form a well-organized circulation system, but mechanisms that reconcile their development remain elusive. We found that activating transcription factor 3 (<i>atf3</i>) was highly expressed in the CPs, HPs, and mesoderm, in zebrafish. The <i>atf3</i> ^-/- mutants exhibited atrial dilated cardiomyopathy and a high ratio of immature myeloid cells. These manifestations were primarily caused by the blockade of differentiation of both CPs and HPs within the anterior lateral plate mesoderm. Mechanistically, Atf3 targets <i>cebpγ</i> to repress <i>slc2a1a</i>-mediated glucose utilization. The high rate of glucose metabolism in <i>atf3</i> ^-/- mutants inhibited the differentiation of progenitors by changing the redox state. Therefore, <i>atf3</i> could provide CPs and HPs with metabolic adaptive capacity to changes in glucose levels. Our study provides new insights into the role of <i>atf3</i> in the coordination of differentiation of CPs and HPs by regulating glucose metabolism.