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Novel ChIP-based strategies to uncover transcription factor target genes in the immune system

Nature Reviews Immunology volume 4, pages 381–386 (2004)Cite this article

Abstract

Transcription factors can have a marked effect on the fate of a cell by establishing the gene expression patterns that determine cellular function. Therefore, a great deal of effort has been invested in identifying and understanding the individual transcription factors that influence key activities. New strategies to identify transcription factor target genes based on their ability to bind to DNA in the nuclear environment have recently been developed, providing an opportunity to address many questions concerning the function of transcription factors. This article discusses the advantages and applications for these new strategies in reference to the developing immune response.

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Figure 1: Classifying transcription factor target genes.
Figure 2: Schematic representation of ChIP-based target-gene identification strategies.
Figure 3: Addressing questions using new ChIP-based target-gene approaches.

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References

  1. Szabo, S. J., Sullivan, B. M., Peng, S. L. & Glimcher, L. H. Molecular mechanisms regulating TH1 immune responses. Annu. Rev. Immunol. 21, 713–758 (2003).

    Article  CAS  PubMed  Google Scholar 

  2. Glimcher, L. H. & Murphy, K. M. Lineage commitment in the immune system: the T helper lymphocyte grows up. Genes Dev. 14, 1693–1711 (2000).

    CAS  PubMed  Google Scholar 

  3. Kondo, M., Scherer, D. C., King, A. G., Manz, M. G. & Weissman, I. L. Lymphocyte development from hematopoietic stem cells. Curr. Opin. Genet. Dev. 11, 520–526 (2001).

    Article  CAS  PubMed  Google Scholar 

  4. Ren, B. et al. Genome-wide location and function of DNA binding proteins. Science 290, 2306–2309 (2000).

    Article  CAS  PubMed  Google Scholar 

  5. Iyer, V. R. et al. Genomic binding sites of the yeast cell-cycle transcription factor SBF and MBF. Nature 409, 533–538 (2001).

    Article  CAS  PubMed  Google Scholar 

  6. Ren, B. et al. E2F integrates cell cycle progression with DNA repair, replication, and G2/M checkpoints. Genes Dev. 16, 245–256 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Weinmann, A. S., Yan, P. S., Oberley, M. J., Huang, T. H. -M. & Farnham, P. J. Isolating human transcription factor targets by coupling chromatin immunoprecipitation and CpG island microarray analysis. Genes Dev. 16, 235–244 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Weinmann, A. S., Bartley, S. M., Zhang, M. Q., Zhang, T. & Farnham, P. J. The use of chromatin immunoprecipitation to clone novel E2F target promoters. Mol. Cell. Biol. 21, 6820–6832 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Martone, R. et al. Distribution of NF-κB binding sites across human chromsome 22. Proc. Natl Acad. Sci. USA 100, 12247–12252 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Horak, C. E. et al. GATA-1 binding sites mapped in the β-globin locus by using mammalian chIp-chip analysis. Proc. Natl Acad. Sci. USA 99, 2924–2929 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Smale, S. T. & Fisher, A. G. Chromatin structure and gene regulation in the immune system. Annu. Rev. Immunol. 20, 427–462 (2002).

    Article  CAS  PubMed  Google Scholar 

  12. Szabo, S. J. et al. A novel transcription factor, T-bet, directs TH1 lineage commitment. Cell 100, 655–669 (2000).

    Article  CAS  PubMed  Google Scholar 

  13. Szabo, S. J. et al. Distinct effects of T-bet in TH1 lineage commitment and IFNγ production in CD4 and CD8 T cells. Science 295, 338–342 (2002).

    Article  CAS  PubMed  Google Scholar 

  14. Lighvani, A. A. et al. T-bet is rapidly induced by interferon-γ in lymphoid and myeloid cells. Proc. Natl Acad. Sci. USA 98, 15137–15142 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Lugo-Villarino, G., Maldonado-Lopez, R., Possemato, R., Penaranda, C. & Glimcher, L. H. T-bet is required for optimal production of IFN-γ and antigen-specific T cell activation by dendritic cells. Proc. Natl Acad. Sci. USA 100, 7749–7754 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Liu, N., Ohnishi, N., Ni, L., Akira, S. & Bacon, K. B. CpG directly induces T-bet expression and inhibits IgG1 and IgE switching in B cells. Nature Immunol. 4, 687–693 (2003).

    Article  CAS  Google Scholar 

  17. Pearce, E. L. et al. Control of effector CD8+ T cell function by the transcription factor Eomesodermin. Science 302, 1041–1043 (2003).

    Article  CAS  PubMed  Google Scholar 

  18. Mullen, A. C. et al. Hlx is induced by and genetically interacts with T-bet to promote heritable TH1 gene induction. Nature Immunol. 3, 652–658 (2002).

    Article  CAS  Google Scholar 

  19. Afkarin, M. et al. T-bet is a STAT1-induced regulator of IL-12R expression in naive CD4+ T cells. Nature Immunol. 3, 549–557 (2002).

    Article  Google Scholar 

  20. Usui, T., Nishikomori, R., Kitani, A. & Strober, W. GATA-3 suppresses TH1 development by downregulation of Stat4 and not through effects on IL-12Rβ2 chain or T-bet. Immunity 18, 415–428 (2003).

    Article  CAS  PubMed  Google Scholar 

  21. Peng, S. L., Szabo, S. J. & Glimcher, L. H. T-bet regulates IgG class switching and pathogenic autoantibody production. Proc. Natl Acad. Sci. USA 99, 5545–5550 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Sullivan, B. M., Juedes, A., Szabo, S. J., von Herrath, M. & Glimcher, L. H. Antigen-driven effector CD8+ T cell function regulated by T-bet. Proc. Natl Acad. Sci. USA 100, 15818–15823 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Avni, O. et al. TH cell differentiation is accompanied by dynamic changes in histone acetylation of cytokine genes. Nature Immunol. 3, 643–651 (2002).

    Article  CAS  Google Scholar 

  24. Hoffmann, A., Leung, T. H. & Baltimore, D. Genetic analysis of NF-κB/Rel transcription factors defines functional specificities. EMBO J. 22, 5530–5539 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Hug, B. A., Ahmed, N., Robbins, J. A. & Lazar, M. A. A chromatin immunoprecipitation screen reveals protein kinase Cβ as a direct RUNX1 target gene. J. Biol. Chem. 279, 825–830 (2004).

    Article  CAS  PubMed  Google Scholar 

  26. Townsend, M. J. et al. T-bet regulates the terminal maturation and homeostasis of NK and Vα14i NKT cells. Immunity (in the press).

  27. Antequera, F. & Bird, A. CpG islands as genomic footprints of promoters that are associated with replication origins. Current Biol. 9, R661–R667 (1999).

    Article  CAS  Google Scholar 

  28. Hannenhalli, S. & Levy, S. Promoter prediction in the human genome. Bioinformatics 17, S90–S96 (2001).

    Article  PubMed  Google Scholar 

  29. Ioshikhes, I. P. & Zhang, M. Q. Large-scale human promoter mapping using CpG islands. Nature Genet. 26, 61–63 (2000).

    Article  CAS  PubMed  Google Scholar 

  30. Wells, J., Graveel, C. R., Bartley, S. M., Madore, S. J. & Farnham, P. J. The identification of E2F1-specific genes. Proc. Natl Acad. Sci. USA 99, 3890–3895 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Oberley, M. J., Inman, D. R. & Farnham, P. J. E2F6 negatively regulates BRCA1 in human cancer cells without methylation of histone H3 on lysine 9. J. Biol. Chem. 278, 42466–42476 (2003).

    Article  CAS  PubMed  Google Scholar 

  32. Odom, D. T. et al. Control of pancreas and liver gene expression by HNF transcription factors. Science 303, 1378–1381 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Ballestar, E. et al. Methyl-CpG binding proteins identify novel sites of epigenetic inactivation in human cancer. EMBO J. 22, 6335–6345 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Mao, D. Y. L. et al. Analysis of Myc bound loci identified by CpG island arrays shows that Max is essential for Myc-dependent repression. Current Biol. 13, 882–886 (2003).

    Article  CAS  Google Scholar 

  35. Li, Z. et al. A global transcriptional regulatory role for c-Myc in Burkitt's lymphoma cells. Proc. Natl Acad. Sci. USA 100, 8164–8169 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Cawley, S. et al. Unbiased mapping of transcription factor binding sites along human chromosome 21 and 22 points to widespread regulation of noncoding RNAs. Cell 116, 499–509 (2004).

    Article  CAS  PubMed  Google Scholar 

  37. Stevens, T. A., Iacovoni, J. S., Edelman, D. B. & Meech, R. Identification of novel binding elements and gene targets for the homeodomain protein BARX2. J. Biol. Chem. 279 , 14520 –14530 (2004).

    Article  CAS  PubMed  Google Scholar 

  38. Jishage, M., Fujino, T., Yamazaki, Y., Kuroda, H. & Nakamura, T. Identification of target genes for EWS/ATF-1 chimeric transcription factor. Oncogene 22, 41–49 (2003).

    Article  CAS  PubMed  Google Scholar 

  39. de Belle, I., Wu, J. X., Sperandio, S., Mercola, D. & Adamson, E. D. In vivo cloning and characterization of a new growth suppressor protein TOE1 as a direct target gene of Egr1. J. Biol. Chem. 278, 14306–14312 (2003).

    Article  CAS  PubMed  Google Scholar 

  40. Greenbaum, S. & Zhuang, Y. Identification of E2A target genes in B lymphocyte development by using a gene tagging-based chromatin immunoprecipitation system. Proc. Natl Acad. Sci. USA 99, 15030–15035 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Ladenburger, E. M., Keller, C. & Knippers, R. Identification of a binding region for human origin recognition complex proteins 1 and 2 that coincides with an origin of DNA replication. Mol. Cell. Biol. 22, 1036–1048 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

I thank S. Smale and P. Farnham for being very supportive mentors, and the members of their laboratories I worked so closely with in the past. I also thank K. Beima for helpful discussions and the Leukemia and Lymphoma Society for their generous support.

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Authors and Affiliations

  1. the Department of Immunology, University of Washington, Seattle, 98195, Washington, USA

    Amy S. Weinmann

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  1. Amy S. Weinmann
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DATABASES

LocusLink

c-MAF

GATA2

GATA3

IFN-γ

IL-4

RUNX1

STAT4

T-bet

FURTHER INFORMATION

Amy Weinmann's lab home page

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Weinmann, A. Novel ChIP-based strategies to uncover transcription factor target genes in the immune system. Nat Rev Immunol 4, 381–386 (2004). https://doi.org/10.1038/nri1353

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