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¹ Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093
² Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037

CORRESPONDENCE Cornelis Murre: murre{at}biomail.ucsd.edu

The E2A gene products, E12 and E47, are critical regulators of B cell development. However, it remains elusive whether E12 and E47 have overlapping and/or distinct functions during B lymphopoiesis. We have generated mice deficient for either E12 or E47 and examined their roles in B cell maturation. We show that E47 is essential for developmental progression at the prepro–B cell stage, whereas E12 is dispensable for early B cell development, commitment, and maintenance. In contrast, both E12 and E47 play critical roles in pre–B and immature B cells to promote immunoglobulin (Ig) germline transcription as well as Ig VJ gene rearrangement. Furthermore, we show that E12 as well as E47 is required to promote receptor editing upon exposure to self-antigen. We demonstrate that increasing levels of E12 and E47 act to induce Ig germline transcription, promote trimethylated lysine 4 on histone 3 (H3) as well as H3 acetylation across the J region, and activate Ig VJ gene rearrangement. We propose that in the pre–B and immature B cell compartments, gradients of E12 and E47 activities are established to mechanistically regulate the sequential rearrangement of the Ig light chain genes.

Abbreviations used: BCR, B cell receptor; ChIP, chromatin immunoprecipitation; CLP, common lymphoid progenitor; EBF, early B cell factor; ES, embryonic stem; H3, histone 3; H3ac, H3 acetylation; H3K4me3, trimethylated lysine 4 on H3; HEL-Tg, hen egg lysozyme transgene; HLH, helix-loop-helix; Hprt1, hypoxanthine guanine phosphoribosyl transferase 1; HSA, heat stable antigen; HSC, hematopoietic stem cell; iE, Ig intronic enhancer; IgH, Ig heavy chain; LMPP, lymphoid-primed multipotent progenitor; RS, recombining sequence.

© 2009 Beck et al.
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