Essential role of the transcription factor Bhlhe41 in regulating the self-renewal and BCR repertoire of B-1a cells. Mus musculus

The innate-like B-1a cells provide a first line of defense against pathogens, and 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 mutant B-1a cells were strongly reduced and had an abnormal cell-surface phenotype and altered B-cell receptor (BCR) repertoire, as exemplified by loss of the phosphatidylcholine-specific Vh12/Vk4 BCR. Expression of a pre-rearranged Vh12/Vk4 BCR failed to rescue the mutant phenotype and revealed enhanced proliferation accompanied with increased cell death, implicating Bhlhe41 in controlling the self-renewal of B-1a cells. Bhlhe41 directly repressed the expression of cell cycle regulators and inhibitors of BCR signaling, while activating pro-survival cytokine signaling. Overall design: 22 samples in total: A) 18 RNA-seq samples in 2 cell types: B-1a cells (WT, DKO, 6 replicates each; Vh12/Vk4 Tg, Vh12/Vk4 Tg DKO, 2 replicates each), B-1b cells (WT, DKO, 1 replicate each) B) 2 ChIP-seq samples in 2 cell types: B-1a cells (Bhlhe41, 1 replicate), pro-B cells (input) C) 2 ATAC-seq samples in 1 cell type: B-1a cells (Vh12/Vk4 Tg, Vh12/Vk4 Tg DKO, 1 replicate each)