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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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References

  1. Cosgrove, M.S. Histone proteomics and the epigenetic regulation of nucleosome mobility. Expert Rev. Proteomics 4, 465–478 (2007).

    Article  CAS  PubMed  Google Scholar 

  2. Ruthenburg, A.J., Li, H., Patel, D.J. & Allis, C.D. Multivalent engagement of chromatin modifications by linked binding modules. Nat. Rev. Mol. Cell Biol. 8, 983–994 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Pokholok, D.K. et al. Genome-wide map of nucleosome acetylation and methylation in yeast. Cell 26, 517–527 (2005).

    Article  Google Scholar 

  4. Heintzman, N.D. et al. Distinct and predictive chromatin signatures of transcriptional promoters and enhancers in the human genome. Nat. Genet. 39, 311–318 (2007).

    Article  CAS  PubMed  Google Scholar 

  5. Kee, B.L. & Murre, C. Induction of EBF and multiple B lineage genes by the helix-loop-helix protein E12. J. Exp. Med. 188, 699–713 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Ikawa, T., Kawamoto, H., Wright, L.Y. & Murre, C. Long-term cultured E2A-deficient hematopoietic progenitor cells are pluripotent. Immunity 20, 349–360 (2004).

    Article  CAS  PubMed  Google Scholar 

  7. Inlay, M.A. et al. Ly6d marks the earliest stage of B-cell specification and identifies the branchpoint between B-cell and T-cell development. Genes Dev. 23, 2376–2381 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Beck, K., Peak, M.M., Ota, T., Nemazee, D. & Murre, C. Distinct roles for E12 and E47 in B cell specification and the sequential rearrangement of immunoglobulin light chain loci. J. Exp. Med. 206, 2271–2284 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Decker, T. et al. Stepwise activation of enhancer and promoter regions of the B cell commitment gene Pax5 in early lymphopoiesis. Immunity 30, 508–520 (2009).

    Article  CAS  PubMed  Google Scholar 

  10. Roessler, S. et al. Distinct promoters mediate the regulation of Ebf1 gene expression by interleukin-7 and Pax5. Mol. Cell. Biol. 2, 579–594 (2007).

    Article  Google Scholar 

  11. O'Riordan, M. & Grosschedl, R. Coordinate regulation of B cell differentiation by the transcription factors E2A and EBF. Immunity 11, 21–31 (1999).

    Article  CAS  PubMed  Google Scholar 

  12. Liu, P. et al. Bcl11a is essential for normal lymphoid development. Nat. Immunol. 4, 525–531 (2003).

    Article  CAS  PubMed  Google Scholar 

  13. Dengler, H.S. et al. Distinct functions for the transcription factor Foxo1 at various stages of B cell differentiation. Nat. Immunol. 9, 1388–1398 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Amin, R.H. & Schlissel, M.S. Foxo1 directly regulates the transcription of recombination-activating genes during B cell development. Nat. Immunol. 9, 396–404 (2008).

    Article  Google Scholar 

  15. Nutt, S.L., Heavey, B., Rolink, A.G. & Busslinger, M. Commitment to the B-lymphoid lineage depends on the transcription factor Pax5. Nature 401, 556–572 (1999).

    Article  CAS  PubMed  Google Scholar 

  16. Pongubala, J.M. et al. Transcription factor EBF restricts alternative lineage options and promotes B cell fate commitment independently of Pax5. Nat. Immunol. 9, 203–215 (2008).

    Article  CAS  PubMed  Google Scholar 

  17. Murre, C. Developmental trajectories in early hematopoiesis. Genes Dev. 15, 2366–2370 (2009).

    Article  Google Scholar 

  18. Cui, K. et al. Chromatin signatures in multipotent human hematopoietic stem cells indicate the fate of bivalent genes during differentiation. Cell Stem Cell 4, 80–93 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Visel, A. et al. ChIP-Seq accurately predicts tissue-specific activity of enhancers. Nature 12, 854–858 (2009).

    Article  Google Scholar 

  20. Heintzman, N. et al. Histone modifications at human enhancers reflect global cell-type specific gene expression. Nature 459, 108–112 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Agata, Y. et al. Regulation of T cell receptor beta gene rearrangements and allelic exclusion by the helix-loop-helix protein, E47. Immunity 27, 871–884 (2007).

    Article  CAS  PubMed  Google Scholar 

  22. Barski, A. et al. High resolution profiling of histone methylations in the human genome. Cell 129, 823–837 (2007).

    Article  CAS  PubMed  Google Scholar 

  23. Ward, J.H. Hierarchical grouping to optimize an objective function. J. Am. Stat. Assoc. 58, 236–242 (1963).

    Article  Google Scholar 

  24. Shannon, P. et al. Cytoscape a software environment for integrated models of biomolecular interaction networks. Genome Res. 13, 2498–2504 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Maere, S., Heymans, K. & Kuiper, M. Bingo: a Cytoscape plugin to assess overrepresentation of Gene Ontology categories in biological networks. Bioinformatics 21, 3448–3449 (2005).

    Article  CAS  PubMed  Google Scholar 

  26. Medina, K.L. et al. Assembling a gene regulatory network for specification of the B cell fate. Dev. Cell 7, 607–617 (2004).

    Article  CAS  PubMed  Google Scholar 

  27. Ikawa, T., Kawamoto, H., Goldrath, A.W. & Murre, C. E proteins and Notch signaling cooperate T lineage specific progression and commitment. J. Exp. Med. 15, 1329–1342 (2006).

    Article  Google Scholar 

  28. Tothova, Z. et al. FoxOs are critical mediators of hematopoietic stem cell resistance to physiologic oxidative stress. Cell 128, 325–339 (2007).

    Article  CAS  PubMed  Google Scholar 

  29. Yang, Q. et al. E47 controls the developmental integrity and cell cycle quiescence of multipotential hematopoietic progenitors. J. Immunol. 181, 5885–5894 (2008).

    Article  CAS  PubMed  Google Scholar 

  30. Dias, S., Mansson, R., Gurbuxani, S., Sigvardsson, M. & Kee, B.L. E2A proteins promote development of lymphoid-primed multipotent progenitors. Immunity 29, 217–227 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Semerad, C.L., Mercer, E.M., Inlay, M.A., Weissman, I.L. & Murre, C. E2A proteins maintain the hematopoietic stem cell pool and promote the maturation of myelolymphid and myeloerythorid progenitors. Proc. Natl. Acad. USA 106, 1930–1935 (2009).

    Article  CAS  Google Scholar 

  32. Bain, G. et al. Both E12 and E47 allow commitment to the B cell lineage. Immunity 6, 145–154 (1997b).

    Article  CAS  PubMed  Google Scholar 

  33. Llorian, M., Stamataki, Z., Hill, S., Turner, M. & Martensson, I.L. The PI3K p110δ is required for down-regulation of RAG expression in immature B cells. J. Immunol. 178, 1981–1985 (2007).

    Article  CAS  PubMed  Google Scholar 

  34. Quong, M.W. et al. Receptor editing and marginal zone B cell development are regulated by the helix-loop-helix protein, E2A. J. Exp. Med. 199, 1101–1112 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Anzelon, A.N., Wu, H. & Rickert, R.C. Pten inactivation alters peripheral B lymphocyte fate and reconstitutes CD19 function. Nat. Immunol. 4, 287–294 (2003).

    Article  CAS  PubMed  Google Scholar 

  36. Sayegh, C.E., Quong, M.W., Agata, Y. & Murre, C. E-proteins directly regulate expression of activation-induced deaminase in mature B cells. Nat. Immunol. 4, 586–593 (2003).

    Article  CAS  PubMed  Google Scholar 

  37. Suzuki, A. et al. Critical roles of Pten in B cell homeostasis and immunoglobulin class switch recombination. J. Exp. Med. 197, 657–667 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Engel, I. & Murre, C. E2A proteins enforce a proliferation checkpoint in developing thymocytes. EMBO J. 23, 202–211 (2004).

    Article  CAS  PubMed  Google Scholar 

  39. Hagenbeek, T.J. et al. The loss of PTEN allows TCR αβ lineage thymocytes to bypass IL-7 and Pre-TCR-mediated signaling. J. Exp. Med. 200, 883–894 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Engel, I. & Murre, C. Disruption of pre-TCR expression accelerates lymphomagenesis in E2A-deficient mice. Proc. Natl. Acad. Sci. USA 99, 11322–11327 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Paik, J.H. et al. FoxOs are lineage-restricted redundant tumor suppressors and regulate endothelial cell homeostasis. Cell 28, 309–323 (2007).

    Article  Google Scholar 

  42. Bain, G. et al. E2A deficiency leads to abnormalities in α/β T-cell development and to rapid development of T-cell lymphomas. Mol. Cell. Biol. 17, 4782–4791 (1997a).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Reya, T.O., Riordan, M., Okamura, R., Devaney, E., Willert, K., Nusse, R. & Grosschedl, R. Wnt signaling regulates B lymphocyte proliferation through a LEF-1 dependent mechanism. Immunity 13, 15–24 (2000).

    Article  CAS  PubMed  Google Scholar 

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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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