Pax5 controls the identity and development of B cells by repressing lineage-inappropriate genes and activating B-cell-specific genes. Here, we used genome-wide approaches to identify Pax5 target genes in pro-B and mature B cells. In these cell types, Pax5 bound to 40% of the cisregulatory elements defined by mapping DNase I hypersensitive (DHS) sites, transcription start sites and histone modifications. Although Pax5 bound to 8000 target genes, it regulated only 4% of them in pro-B and mature B cells by inducing enhancers at activated genes and eliminating DHS sites at repressed genes. Pax5-regulated genes in pro-B cells account for 23% of all expression changes occurring between common lymphoid progenitors and committed pro-B cells, which identifies Pax5 as an important regulator of this developmental transition. Regulated Pax5 target genes minimally overlap in pro-B and mature B cells, which reflects massive expression changes between these cell types. Hence, Pax5 controls B-cell identity and function by regulating distinct target genes in early and late B lymphopoiesis. The EMBO Journal (2012) (Nutt and Kee, 2007). The helix-loop-helix protein E2A and the early B-cell factor EBF1 specify the B-cell lineage by activating the expression of B-lymphoid genes in pre-pro-B cells Treiber et al, 2010). Pax5 subsequently controls B-cell commitment at the transition to the pro-B cell stage by restricting the developmental potential of lymphoid progenitors to the B-cell lineage, as shown by the fact that Pax5-deficient pro-B cells are still able to differentiate into most hematopoietic cell types in vitro and in vivo (Nutt et al, 1999;Medvedovic et al, 2011). At the molecular level, Pax5 fulfills a dual role by repressing B-lineage-inappropriate genes to suppress alternative lineage options and by simultaneously activating B-cell-specific genes to promote B-cell development (Nutt et al, 1999;Medvedovic et al, 2011). Gene expression analyses of wild-type and Pax5-deficient pro-B cells identified 110 Pax5-repressed and 170 Pax5-activated genes, which code for key regulatory and structural proteins involved in transcriptional control, receptor signalling, adhesion, migration and immune function (Delogu et al, 2006;Schebesta et al, 2007;Pridans et al, 2008). Pax5 regulates these gene expression changes by inducing active chromatin at activated target genes and eliminating active chromatin at repressed genes in pro-B cells . Notably, Pax5 induces these chromatin and transcription changes by recruiting chromatin-remodelling, histone-modifying and basal transcription factor complexes to its target genes, which identifies Pax5 as an epigenetic regulator of B-cell commitment .Pax5 is expressed throughout B-cell development from pro-B cells in the bone marrow to mature B cells in peripheral lymphoid organs (Fuxa and Busslinger, 2007), where it plays an important role in the generation and function of distinct mature B-cell types (Horcher et al, 2001;Medvedovic et al, 2011). Pax5 is essential for maintaining the B-cell gene exp...

Innate-like B-1a cells provide a first line of defense against pathogens, yet little is known about their transcriptional control. Here we identified an essential role of the transcription factor Bhlhe41, with a lesser contribution of Bhlhe40, in controlling late stages of B-1a cell differentiation. Bhlhe41–/–Bhlhe40–/– B-1a cells were severely reduced as compared to their wild-type counterparts. Mutant B-1a cells exhibited an abnormal cell-surface phenotype and altered B-cell receptor (BCR) repertoire exemplified by loss of the phosphatidylcholine-specific VH12/Vκ4 BCR. Expression of a pre-rearranged VH12/Vκ4 BCR failed to rescue the mutant phenotype and revealed enhanced proliferation accompanied with increased cell death. Bhlhe41 directly repressed the expression of cell cycle regulators and inhibitors of BCR signaling, while enabling pro-survival cytokine signaling. Thus, Bhlhe41 controls the development, BCR repertoire and self-renewal of B-1a cells.