The regulatory network of B-cell differentiation: a focused view of early B-cell factor 1 function

During the last decades, many studies have investigated the transcriptional and epigenetic regulation of lineage decision in the hematopoietic system. These efforts led to a model in which extrinsic signals and intrinsic cues establish a permissive chromatin context upon which a regulatory network of transcription factors and epigenetic modifiers act to guide the differentiation of hematopoietic lineages. These networks include lineage‐specific factors that further modify the epigenetic landscape and promote the generation of specific cell types. The process of B lymphopoiesis requires a set of transcription factors, including Ikaros, PU.1, E2A, and FoxO1 to ‘prime’ cis‐regulatory regions for subsequent activation by the B‐lineage‐specific transcription factors EBF1 and Pax‐5. The expression of EBF1 is initiated by the combined action of E2A and FoxO1, and it is further enhanced and maintained by several positive feedback loops that include Pax‐5 and IL‐7 signaling. EBF1 acts in concert with Ikaros, PU.1, Runx1, E2A, FoxO1, and Pax‐5 to establish the B cell‐specific transcription profile. EBF1 and Pax‐5 also collaborate to repress alternative cell fates and lock cells into the B‐lineage fate. In addition to the functions of EBF1 in establishing and maintaining B‐cell identity, EBF1 is required to coordinate differentiation with cell proliferation and survival.