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A global network of transcription factors, involving E2A, EBF1 and Foxo1, that orchestrates B cell fate
- Yin C Lin1 na1,
- Suchit Jhunjhunwala1 na1,
- Christopher Benner2,
- Sven Heinz2,
- Eva Welinder1,3,
- Robert Mansson1,
- Mikael Sigvardsson4,
- James Hagman5,
- Celso A Espinoza6,
- Janusz Dutkowski7,8,
- Trey Ideker7,8,
- Christopher K Glass2 &
- …
- Cornelis Murre1
Nature Immunologyvolume 11, pages635–643 (2010)Cite this article
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Abstract
It is now established that the transcription factors E2A, EBF1 and Foxo1 have critical roles in B cell development. Here we show that E2A and EBF1 bound regulatory elements present in theFoxo1 locus. E2A and EBF1, as well as E2A and Foxo1, in turn, were wired together by a vast spectrum ofcis-regulatory sequences. These associations were dynamic during developmental progression. Occupancy by the E2A isoform E47 directly resulted in greater abundance, as well as a pattern of monomethylation of histone H3 at lysine 4 (H3K4) across putative enhancer regions. Finally, we divided the pro-B cell epigenome into clusters of loci with occupancy by E2A, EBF and Foxo1. From this analysis we constructed a global network consisting of transcriptional regulators, signaling and survival factors that we propose orchestrates B cell fate.
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Acknowledgements
We thank G. Hardiman, C. Ludka, L. Edsall and Z. Ye for help with Solexa DNA sequencing; R. DePinho (Harvard Medical School) for Foxo1-deficient mice; J. Sprague and R. Sasik for microarray analysis; and members of the Murre laboratory for comments on the manuscript. Supported by the National Institutes of Health (1F32CA130276 to Y.C.L., P01DK074868 to C.B., F32HL083752 to S.H., CA52599 to C.K.G., AI05466 to J.H. and CA054198-20 to C.M.) and the National Science Foundation (IIS-0803937 to T.I. and BIOGEM DK063491 to the University of California, San Diego Core Facility).
Author information
Yin C Lin and Suchit Jhunjhunwala: These authors contributed equally to this work.
Authors and Affiliations
Department of Molecular Biology, University of California, San Diego, La Jolla, California, USA
Yin C Lin, Suchit Jhunjhunwala, Eva Welinder, Robert Mansson & Cornelis Murre
Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, California, USA
Christopher Benner, Sven Heinz & Christopher K Glass
Center for Stem Cell Biology and Cell Therapy, Lund University, Lund, Sweden
Eva Welinder
Department for Biomedicine and Surgery, Linkoping University, Linkoping, Sweden
Mikael Sigvardsson
Integrated Department of Immunology, National Jewish Health, Denver, Colorado, USA
James Hagman
Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, California, USA
Celso A Espinoza
Department of Bioengineering and Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, California, USA
Janusz Dutkowski & Trey Ideker
The Institute for Genomic Medicine, University of California, San Diego, La Jolla, California, USA
Janusz Dutkowski & Trey Ideker
- Yin C Lin
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- Suchit Jhunjhunwala
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- Christopher Benner
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- Sven Heinz
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- Eva Welinder
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- Robert Mansson
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- Mikael Sigvardsson
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- James Hagman
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- Celso A Espinoza
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- Janusz Dutkowski
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- Trey Ideker
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- Christopher K Glass
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- Cornelis Murre
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Contributions
Y.C.L. designed and did experiments, analyzed data and wrote the manuscript; S.J. and C.B. wrote programs and analyzed data; S.H. did CTCF ChIP-Seq and monomethylation of H3K4 in RAG-deficient pro-B cells; J.H. generated EBF-deficient pre-pro-B cells; M.S. provided anti-EBF; E.W. and R.M. analyzed E2A-Foxo1–deficient mice; C.A.E. did ChIP-Seq experiments during the initial phase of the study; J.D. and T.I. applied computational approaches to generate a global network; C.K.G. analyzed data and edited the manuscript; and C.M. designed experiments, analyzed data and wrote the manuscript.
Corresponding authors
Correspondence toChristopher K Glass orCornelis Murre.
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Lin, Y., Jhunjhunwala, S., Benner, C.et al. A global network of transcription factors, involving E2A, EBF1 and Foxo1, that orchestrates B cell fate.Nat Immunol11, 635–643 (2010). https://doi.org/10.1038/ni.1891
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