The transcription factors E2A and HEB act in concert to induce the expression of FOXO1 in the common lymphoid progenitor

Abstract

Recent studies have identified a number of transcriptional regulators, including E proteins, EBF1, FOXO1, and PAX5, that act together to orchestrate the B-cell fate. However, it still remains unclear as to how they are linked at the earliest stages of B-cell development. Here, we show that lymphocyte development in HEB-ablated mice exhibits a partial developmental arrest, whereas B-cell development in E2A +/− HEB −/− mice is completely blocked at the LY6D − common lymphoid progenitor stage. We show that the transcription signatures of E2A-and HEB-ablated common lymphoid progenitors significantly overlap. Notably, we found that Foxo1 expression was substantially reduced in the LY6D− HEBand E2A-deficient cells. Finally, we show that E2A binds to enhancer elements across the FOXO1 locus to activate Foxo1 expression, linking E2A and FOXO1 directly in a common pathway. In summary, the data indicate that the earliest event in B-cell specification involves the induction of FOXO1 expression and requires the combined activities of E2A and HEB.

The making of a lymphocyte: the choice among disparate cell fates and the IKAROS enigma

“…Key components of the pre-T-cell receptor (pre-TCR) and pre-B-cell receptor (pre-BCR) signaling pathways (recombination factors) as well as transcription and recombination at the antigen receptor loci (Igh and Tcrb) are examples of genes whose transcription is supported by these early T-cell and B-cell transcription factor networks (Schebesta et al 2007;Treiber et al 2010;Welinder et al 2011;Mansson et al 2012).…”

“…In a parallel process in the bone marrow, a subset of CLPs (also known as B lineage-restricted progenitors [BLPs]) under the influence of IL-7R signaling, E2A, and HEB induce expression of FOXO1 and EBF1 (Inlay et al 2009;Lin et al 2010;Welinder et al 2011). These factors set up a self-promoting feed-forward loop that establishes B-cell identity while eliminating differentiation into other affiliated cell lineages Rolink et al 1999;Pongubala et al 2008;Lin et al 2010;Treiber et al 2010;Nechanitzky et al 2013;Boller et al 2016).…”

Positive intergenic feedback circuitry, involving EBF1 and FOXO1, orchestrates B-cell fate

“…E2A-deficient mice exhibit a complete block before the expression of LY6D in the CLP compartment (4,7,8). In the CLP compartment, the E2A proteins act in concert with HEB to induce the expression of forkhead box O1 (Foxo1) (8). Although it is well established that Foxo1 is critical for normal B-cell development, the dynamic regulation of Foxo1 expression in the CLP compartment suggested roles for Foxo1 at the earliest progenitor cell stage (5,(9)(10)(11)(12).…”

“…Prominent among those are E2A, early B-cell factor 1 (EBF1), and paired box gene 5 (PAX5), as well as effectors acting downstream of the IL7-signaling cascade (6). E2A-deficient mice exhibit a complete block before the expression of LY6D in the CLP compartment (4,7,8). In the CLP compartment, the E2A proteins act in concert with HEB to induce the expression of forkhead box O1 (Foxo1) (8).…”

“…This analysis showed that EBF1 and FOXO1 act in a positive feedback circuitry to promote and stabilize B-cell fate. Previous studies have established that the E2A proteins directly activate Foxo1 expression in LY6D − CLPs (8). To evaluate how activation of Foxo1 expression relates to B-cell specification, we compared Foxo1 mRNA abundance in sorted LY6D − and LY6D + CLPs.…”