The establishment of B versus T cell identity

•Transcriptional regulatory networks establish lymphocyte lineage decisions.•E-protein transcription factors are crucial for establishing both B and T cell identities.•E-proteins also define nuclear architecture via enhancer–promoter interactions.•Stochastic nuclear positioning of Ebf1 may determine B versus T lineage choice.

In B cell progenitors, E-proteins E2A and HEB (HeLa E-box binding protein) are crucial for the induction of a B lineage-specific program of gene expression and for orchestrating the assembly of the immunoglobulin loci. In the thymus E2A and HEB act differently, activating the expression of genes closely associated with the establishment of T cell identity and promoting the rearrangement of T cell receptor (TCR) loci. These findings have raised the question as to how E-proteins exert these different activities. We review here the distinct regulatory networks that establish B versus T cell identity, and how genomic architecture and location of genes is modulated in these lineage decisions. We conclude by proposing a model wherein stochasticity in the nuclear location of the early B cell factor 1 (Ebf1) locus in multipotent progenitors determines this lineage choice.