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A global network of transcription factors, involving E2A, EBF1 and Foxo1, that orchestrates B cell fate

Nature Immunology volume 11, pages 635–643 (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 the Foxo1 locus. E2A and EBF1, as well as E2A and Foxo1, in turn, were wired together by a vast spectrum of cis-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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Figure 1: E2A occupancy and epigenetic marking in cultured EBF1-deficient pre-pro-B cells and RAG-1-deficient pro-B cells.
Figure 2: E2A occupancy and H3K4 methylation in cultured RAG-1-deficient pro-B cells.
Figure 3: E2A occupancy and patterns of H3K4 methylation in cultured EBF1-deficient pre-pro-B cells and RAG-1-deficient pro-B cells.
Figure 4: Distinct cis-regulatory DNA sequences associate with E2A occupancy in cultured RAG-1-deficient pro-B cells.
Figure 5: Distinct patterns of H3K4 monomethylation are associated with coordinated occupancy by E2A and EBF1 and Foxo1.
Figure 6: Coordinated binding of E2A, EBF and Foxo1 is associated with a B lineage–specific program of gene expression.
Figure 7: Binding of E47 to DNA alters the pattern of H3K4 monomethylation.
Figure 8: Regulatory network that links the activities of an ensemble of transcriptional regulators, signaling components and survival factors in developing B cells into a common pathway.

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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).

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Author notes

  1. Yin C Lin and Suchit Jhunjhunwala: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Molecular Biology, University of California, San Diego, La Jolla, California, USA

    Yin C Lin, Suchit Jhunjhunwala, Eva Welinder, Robert Mansson & Cornelis Murre

  2. Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, California, USA

    Christopher Benner, Sven Heinz & Christopher K Glass

  3. Center for Stem Cell Biology and Cell Therapy, Lund University, Lund, Sweden

    Eva Welinder

  4. Department for Biomedicine and Surgery, Linkoping University, Linkoping, Sweden

    Mikael Sigvardsson

  5. Integrated Department of Immunology, National Jewish Health, Denver, Colorado, USA

    James Hagman

  6. Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, California, USA

    Celso A Espinoza

  7. Department of Bioengineering and Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, California, USA

    Janusz Dutkowski & Trey Ideker

  8. The Institute for Genomic Medicine, University of California, San Diego, La Jolla, California, USA

    Janusz Dutkowski & Trey Ideker

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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 to Christopher K Glass or Cornelis Murre.

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The authors declare no competing financial interests.

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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 Immunol 11, 635–643 (2010). https://doi.org/10.1038/ni.1891

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