Infection perturbs Bach2- and Bach1-dependent erythroid lineage ‘choice’ to cause anemia

Elucidation of how the differentiation of hematopoietic stem and progenitor cells(HSPCs) is reconfigured in response to the environment is critical for understanding the biology and disorder of hematopoiesis. Here we found that the transcription factors (TFs) Bach2 and Bach1 promoted erythropoiesisby regulating heme metabolism in committed erythroid cells to sustain erythroblastmaturation and by reinforcing erythroid commitment at the erythro– myeloidbifurcation step. Bach TFs repressed expression of the gene encoding the transcription factor C/EBPβ, as well as that of its target genes encoding molecules important for myelopoiesisand inflammation; they achieved the latter by binding to their regulatory regions also bound by C/EBPβ. Lipopolysaccharide diminished the expression of Bach TFs in progenitor cellsand promoted myeloiddifferentiation. Overexpression of Bach2 in HSPCs promoted erythroid development and inhibited myelopoiesis. Knockdown of BACH1 or BACH2 in human CD34+ HSPCs impaired erythroid differentiation in vitro. Thus, Bach TFs accelerate erythroid commitment by suppressing the myeloidprogram at steady state. Anemia of inflammation and myelodysplastic syndromemight involve reduced activity of Bach TFs.