GSE103260
Pax5 regulates B cell immunity by promoting PI3K signaling via PTEN downregulation
The transcription factor Pax5 is known to control B-cell development, but its role in mature B- cells is largely enigmatic. Here, we demonstrate by conditional mutagenesis in peripheral B- lymphocytes that B-1a, marginal zone (MZ) and germinal center B-cells as well as plasma cells are not generated upon loss of Pax5. Follicular (FO) B-cells tolerate the loss of Pax5 but have a shortened half-life. The Pax5-deficient FO B-cells fail to proliferate upon B-cell receptor or Toll- like receptor stimulation due to impaired PI3K-AKT signaling, which is caused by increased expression of PTEN, a negative regulator of the PI3K pathway. Pax5 restrains PTEN protein expression at the posttranscriptional level, likely involving Pten-targeting microRNAs. Additional PTEN loss in Pten,Pax5 double-mutant mice rescues FO B-cell numbers and the development of MZ B-cells. Hence, the posttranscriptional downregulation of PTEN expression is a dominant function of Pax5 that facilitates the differentiation and survival of mature B cells, thereby promoting humoral immunity. Overall design: 25 samples in total: A) 3 ChIP-seq in 1 cell type: stimulated B cell (H3K4me2, 2 genotypes, 1 replicate each; Pax5 Bio-ChIP, 1 genotype, 1 replicate) B) 12 RNA-seq samples in 2 cell types: lymph node mature B cells (2 genotypes, 2 replicates each) stimulated B cells (2 genotypes, 2 stimulations, 2 replicates each) C) 8 miRNA-seq samples (2 genotypes, 2 cell types, 2 replicates each) D) 2 DHS-seq samples in 1 cell type: stimulated B cell (2 genotypes, 1 stimulation, 1 replicate each)