Ancient Synteny Links Metabolism with Erythroid Development

Development of red blood cells from progenitors requires profound reshaping of both gene expression and metabolism. How these processes are coupled is unclear. Nprl3, an inhibitor of mTORC1, has remained in synteny with α-globin for >500 million years, and harbours α-globin enhancers. We show that Nprl3 promoter-deleted mice, which retain all enhancers, exhibit severe erythropoietic-specific developmental defects. Loss of Nprl3 disrupts autophagy, glycolysis and redox control, which are all required to complete erythropoiesis. Human NPRL3-knockout erythroid progenitors exhibit dysfunctional mTORC1 signalling in response to iron, amino acids and erythropoietin. We show that Nprl3 is also regulated by the α-globin enhancers, and that enhanced Nprl3 expression enables optimal erythropoiesis independently of α-globin regulation. Therefore, obligate enhancer sharing between genes of disparate function is required to support maturation of one cell lineage. The locus containing Nprl3, α-globin and their enhancers allows environmental sensing, and unites metabolic and developmental regulation of erythropoiesis.