EBF1 primes B-lymphoid enhancers and limits the myeloid bias in murine multipotent progenitors

Haematopoietic stem cells (HSC) and multipotent progenitors (MPP) generate all cells of the blood system. Despite their multipotency, MPPs display poorly understood lineage bias. Here, we examine whether lineage-specifying transcription factors, such as the B-lineage determinant EBF1, regulate lineage preference in early progenitors. We detect low level EBF1 expression in myeloid-biased MPP3 and lymphoid-biased MPP4 cells, coinciding with expression of the myeloid determinant C/EBPα. Hematopoietic deletion of <em>Ebf1</em> results in enhanced myelopoiesis and reduced HSC repopulation capacity. <em>Ebf1</em>-deficient MPP3 and MPP4 cells exhibit augmented myeloid differentiation potential and a myeloid-enriched transcriptome that is inversely correlated with <em>Cebpa</em>-deficient progenitors. Correspondingly, EBF1 binds the <em>Cebpa</em> enhancer and <em>Ebf1</em>-deficient MPP3 and MPP4 cells upregulate <em>Cebpa </em>expression. In addition, EBF1 primes the chromatin of B-lymphoid enhancers specifically in MPP3 cells. Thus, our study implicates EBF1 in regulating myeloid/lymphoid fate bias in MPPs by constraining C/EBPα -driven myelopoiesis and priming the B-lymphoid fate.