Enforced expression of the transcriptional coactivator OBF1 impairs B cell differentiation at the earliest stage of development.
OBF1, also known as Bob.1 or OCA-B, is a B lymphocyte-specific transcription factor which coactivates Oct1 and Oct2 on B cell specific promoters. So far, the function of OBF1 has been mainly identified in late stage B cell populations. The central defect of OBF1 deficient mice is a severely reduced immune response to T cell-dependent antigens and a lack of germinal center formation in the spleen. Relatively little is known about a potential function of OBF1 in developing B cells. Here we have generated transgenic mice overexpressing OBF1 in B cells under the control of the immunoglobulin heavy chain promoter and enhancer. Surprisingly, these mice have greatly reduced numbers of follicular B cells in the periphery and have a compromised immune response. Furthermore, B cell differentiation is impaired at an early stage in the bone marrow: a first block is observed during B cell commitment and a second differentiation block is seen at the large preB2 cell stage. The cells that succeed to escape the block and to differentiate into mature B cells have post-translationally downregulated the expression of transgene, indicating that expression of OBF1 beyond the normal level early in B cell development is deleterious. Transcriptome analysis identified genes deregulated in these mice and Id2 and Id3, two known negative regulators of B cell differentiation, were found to be upregulated in the EPLM and preB cells of the transgenic mice. Furthermore, the Id2 and Id3 promoters contain octamer-like sites, to which OBF1 can bind. These results provide evidence that tight regulation of OBF1 expression in early B cells is essential to allow efficient B lymphocyte differentiation.
Bordon
Alain
A
Friedrich Miescher Institute for Biomedical Research, Novartis Research Foundation, Basel, Switzerland.
Bosco
Nabil
N
Du Roure
Camille
C
Bartholdy
Boris
B
Kohler
Hubertus
H
Matthias
Gabriele
G
Rolink
Antonius G
AG
Matthias
Patrick
P
D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D002454:Cell Differentiation / Q000235:genetics*; D002478:Cells, Cultured; D047108:Embryonic Development / Q000235:genetics / Q000276:immunology*; D018507:Gene Expression Regulation, Developmental; D006411:Hematopoiesis, Extramedullary / Q000235:genetics; D018655:Lymphocyte Count; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000502:physiology; D013997:Time Factors; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D014162:Transfection; D015854:Up-Regulation / Q000235:genetics / Q000502:physiology
C490424:Pou2af1 protein, mouse; D015534:Trans-Activators