E2A is an essential regulator of early B-cell development. Here we demonstrated that E2A together with E2-2 controlled germinal-center B-cell and plasma cell development. As shown by identification of regulated E2A,E2-2 targets in activated B-cells, these E-proteins directly activated genes with important functions in germinal-center B-cells and plasma cells by inducing or maintaining DNase I hypersensitive sites. Through controlling multiple enhancers in the Igh 3’ regulatory region and Aicda locus, E-proteins regulated class switching by inducing both Igh germline transcription and AID expression. By regulating 3’ Igk enhancers and a distal element at the Prdm1 (Blimp1) locus, E-proteins contributed to Igk, Igh and Prdm1 activation in plasmablasts. These data identified E2A and E2-2 as central regulators of B-cell immunity. 56 samples in total: A) 38 RNA-Seq samples in 5 cell types: Follicular B cells (FO B cell, 2 genotypes, 2 replicates each) Activated B cells (Act B cell, 2 genoytpes, 6 stimulations, 2 replicates each) Pre-Plasmablasts (Pre-PB, 1 genotype, 2 stimulations, 2 replicates each) Plasmablasts (PB, 1 genotype, 2 stimulations, 2 replicates each) Germline Center B cells (GC B cell, 1 genotype, 2 replicates); B) 13 ChIP-Seq samples in 5 cell types: FO B cell (E2A, 2 crosslinking types, 1 replicate each) Act B cell (E2A, 2 crosslinking types, 2 stimulations, 1 replicate each; H3K27ac, 1 crosslinking type, 1 stimulation, 2 genotypes, 1 replicate each) Pre-PB (E2A, 2 crosslinking types, 1 stimulation, 1 replicate each) PB (E2A, 2 crosslinking types, 1 stimulation, 1 replicate each) Mature B cell (input); C) 5 ATAC Seq samples in 2 cell types: Act B cell (2 stimulations, 2 genotypes, 1 replicate each), Pre-PB (1 stimulation, 1 genotype, 1 replicate).