The interplay between transcription factors of the E protein family and their antagonists, the Id proteins, is important for the regulation of lymphocyte development and differentiation. In the B cell lineage, E2A in particular is essential for early B cell commitment. However, despite being expressed at high levels throughout B cell development, E2A is dispensable for the maintenance of mature B cells and the generation of plasma cells in peripheral lymphoid organs.
Using a number of genetic approaches we have now further examined the role of E and Id proteins in B cells. We have found that Id3 was expressed at high levels in resting B cells and was downregulated in a division dependent manner after B cell activation. This suggested that tight Id3-mediated regulation of E protein activity might be important for B cell activation or antigen-induced differentiation. Transcriptional profiling of dividing B cells revealed that in addition to E2A, the related E2-2 was expressed at high levels in activated B cells. Using a number of genetic approaches, including mice that lack Id3 and mice lacking E2-2 and/or E2A specifically in B cells, we have uncovered that E protein activity was essential for germinal centre formation and plasma cell differentiation. Thus, mice deficient in both E2-2 and E2A lacked any humoral immune response. Applying RNA-seq and ChIP-seq technologies we have identified crucial target genes of E protein activity in B cells and uncovered a new layer of the gene regulatory network, which controls B cell responses.