B-lineage commitment is dependent on a reversible epigenetic switch.

To increase our understanding of the interplay between transcription factor networks and the epigenetic landscape in early B-lymphoid development, we conducted combined SC-RNA/ATAC-seq analyses of bone marrow progenitor populations. Based on changes in DNA accessibility, we created a high-resolution model for B-cell development. Trend change analysis identified a rapid shift in DNA accessibility, resulting in the loss of T-lineage priming and the acquisition of the epigenetic landscape of B-lymphocytes in association with the activation of the B-lineage program. The epigenetic switch correlated strongly with the initiation of Ebf1 and Pax5 transcription, as well as their functional activities. The importance of epigenetic silencing for the preservation of B-cell fate is supported by our finding that inhibition of the histone methylases EZH1 and EZH2 in pro-B cells allows for the activation of T-lineage genes and the generation of T-cell progenitors in response to Notch signaling. Our data reveal that B-lymphoid commitment is associated with a transcription factor-mediated, dose-dependent epigenetic switch, suppressing an inherent T-lineage potential in early lymphoid progenitors.