Silencing and nuclear repositioning of the lambda5 gene locus at the pre-B cell stage requires Aiolos and OBF-1.
The chromatin regulator Aiolos and the transcriptional coactivator OBF-1 have been implicated in regulating aspects of B cell maturation and activation. Mice lacking either of these factors have a largely normal early B cell development. However, when both factors are eliminated simultaneously a block is uncovered at the transition between pre-B and immature B cells, indicating that these proteins exert a critical function in developing B lymphocytes. In mice deficient for Aiolos and OBF-1, the numbers of immature B cells are reduced, small pre-BII cells are increased and a significant impairment in immunoglobulin light chain DNA rearrangement is observed. We identified genes whose expression is deregulated in the pre-B cell compartment of these mice. In particular, we found that components of the pre-BCR, such as the surrogate light chain genes lambda5 and VpreB, fail to be efficiently silenced in double-mutant mice. Strikingly, developmentally regulated nuclear repositioning of the lambda5 gene is impaired in pre-B cells lacking OBF-1 and Aiolos. These studies uncover a novel role for OBF-1 and Aiolos in controlling the transcription and nuclear organization of genes involved in pre-BCR function.
Karnowski
Alexander
A
Friedrich Miescher Institute for Biomedical Research, Novartis Research Foundation, Basel, Switzerland.
Cao
Chun
C
Matthias
Gabriele
G
Carotta
Sebastian
S
Corcoran
Lynn M
LM
Martensson
Inga-Lill
IL
Skok
Jane A
JA
Matthias
Patrick
P
D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism / Q000502:physiology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002467:Cell Nucleus / Q000235:genetics; D002478:Cells, Cultured; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000276:immunology; D023061:Gene Order / Q000502:physiology*; D015328:Gene Rearrangement, B-Lymphocyte, Light Chain; D020868:Gene Silencing / Q000276:immunology*; D051740:Ikaros Transcription Factor; D007146:Immunoglobulin lambda-Chains / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D054448:Precursor Cells, B-Lymphoid / Q000378:metabolism* / Q000502:physiology; D015534:Trans-Activators / Q000235:genetics / Q000502:physiology*
C491396:Ikzf3 protein, mouse; D007146:Immunoglobulin lambda-Chains; C490424:Pou2af1 protein, mouse; D015534:Trans-Activators; D051740:Ikaros Transcription Factor