Transcription factor Ebf1 regulates differentiation stage-specific signaling, proliferation, and survival of B cells
- Ildiko Györy1,3,
- Sören Boller1,3,
- Robert Nechanitzky1,3,
- Elizabeth Mandel1,
- Sebastian Pott2,
- Edison Liu2 and
- Rudolf Grosschedl1,4
- 1Department of Cellular and Molecular Immunology, Max Planck Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany;
- 2Cancer Biology and Pharmacology, Genome Institute of Singapore, 138672 Singapore
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↵3 These authors contributed equally to this work.
Abstract
The transcription factor Ebf1 is an important determinant of early B lymphopoiesis. To gain insight into the functions of Ebf1 at distinct stages of differentiation, we conditionally inactivated Ebf1. We found that Ebf1 is required for the proliferation, survival, and signaling of pro-B cells and peripheral B-cell subsets, including B1 cells and marginal zone B cells. The proliferation defect of Ebf1-deficient pro-B cells and the impaired expression of multiple cell cycle regulators are overcome by transformation with v-Abl. The survival defect of transformed Ebf1fl/fl pro-B cells can be rescued by the forced expression of the Ebf1 targets c-Myb or Bcl-xL. In mature B cells, Ebf1 deficiency interferes with signaling via the B-cell-activating factor receptor (BAFF-R)- and B-cell receptor (BCR)-dependent Akt pathways. Moreover, Ebf1 is required for germinal center formation and class switch recombination. Genome-wide analyses of Ebf1-mediated gene expression and chromatin binding indicate that Ebf1 regulates both common and distinct sets of genes in early and late stage B cells. By regulating important components of transcription factor and signaling networks, Ebf1 appears to be involved in the coordination of cell proliferation, survival, and differentiation at multiple stages of B lymphopoiesis.
Keywords
- Ebf1
- c-Myb
- B-cell differentiation
- BCR signaling
- Ig class switch recombination
- germinal center B cells
Footnotes
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↵4 Corresponding author.
E-mail grosschedl{at}ie-freiburg.mpg.de.
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Supplemental material is available for this article.
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Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.187328.112.
- Received January 13, 2012.
- Accepted February 23, 2012.
- Copyright © 2012 by Cold Spring Harbor Laboratory Press
Freely available online through the Genes & Development Open Access option.