Distinct roles for E12 and E47 in B cell specification and the sequential rearrangement of immunoglobulin light chain loci.
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 lambda (Ig lambda) germline transcription as well as Ig lambda 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 lambda germline transcription, promote trimethylated lysine 4 on histone 3 (H3) as well as H3 acetylation across the J lambda region, and activate Ig lambda 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.
Beck
Kristina
K
Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
Peak
Mandy M
MM
Ota
Takayuki
T
Nemazee
David
D
Murre
Cornelis
C
D000818:Animals; D001402:B-Lymphocytes / Q000502:physiology*; D051792:Basic Helix-Loop-Helix Proteins / Q000502:physiology; D002874:Chromosome Mapping; D044127:Epigenesis, Genetic; D015322:Gene Rearrangement, B-Lymphocyte; D007146:Immunoglobulin lambda-Chains / Q000235:genetics*; D015851:Interleukin-7 / Q000502:physiology; D051379:Mice; D051820:TCF Transcription Factors / Q000235:genetics / Q000502:physiology*; D058125:Transcription Factor 7-Like 1 Protein
D051792:Basic Helix-Loop-Helix Proteins; D007146:Immunoglobulin lambda-Chains; D015851:Interleukin-7; D051820:TCF Transcription Factors; D058125:Transcription Factor 7-Like 1 Protein; C075668:Tcf3 protein, mouse; C544913:Tcf7l1 protein, mouse