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Chromatin-remodelling factor BRG1 selectively activates a subset of interferon-α-inducible genes

Nature Cell Biology volume 4, pages 774–781 (2002)Cite this article

Abstract

Brahma-related gene 1 (BRG1 ) is a key component of the ATP-dependent chromatin-remodelling SWI2–SNF2 complex and has been implicated in regulating gene expression, cell-cycle control and tumorigenesis. Here we report that BRG1 interacts with signal transducer and activator of transcription 2 (STAT2) — a transcription factor that regulates gene expression mediated by interferon-α (IFN-α). BRG1 enhances the IFN-α-induced expression of 9-27 and IFI27 but not that of four other target genes tested, showing that the activation of different target genes by STAT2 may involve alternative chromatin modifiers. Our results also suggest that the recruitment and activation of BRG1 may require other cis-acting and trans-acting elements in addition to STAT2. Our study links the SWI2–SNF2 complex to the regulation of cytokine-induced gene expression and may identify a molecular mechanism of BRG1-mediated gene activation and tumorigenesis.

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Figure 1: Interaction of BRG1 and STAT2.
Figure 2: Involvement of BRG1 in IFN-α-induced expression of 9–27 and IFI27.
Figure 3: Selective modulation of a subset of IFN-α-inducible genes by BRG1.
Figure 4: Recruitment of SWI2–SNF2 to the 9–27 but not the 6–16 promoter.
Figure 5: Chromatin-remodelling dependence of the IFN-α-induced expression of 9–27 and IFI27 mediated by BRG1.
Figure 6: STAT2 and ISRE dependence of the IFN-α induced expression of 9–27 and IFI27 mediated by BRG1.
Figure 7: Mapping of BRG1–STAT2 interaction region.
Figure 8: BRG1–STAT2 interaction is required for IFN-α-induced expression of 9–27 and IFI27.

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References

  1. Stark, G. R., Kerr, I. M., Williams, B. R. G., Silverman, R. H. & Schreiber, R. D. How cells respond to interferons. Annu. Rev. Biochem. 67, 227–264 (1998).

    Article  CAS  PubMed  Google Scholar 

  2. Darnell J. E. Jr STATs & gene regulation. Science 277, 1630–1635 (1997).

    Article  CAS  PubMed  Google Scholar 

  3. Leonard, W. J. & O'Shea J. J. JAKs & STATs: biological implications. Annu. Rev. Immunol. 16, 293–322 (1998).

    Article  CAS  PubMed  Google Scholar 

  4. Ihle, J. N. The Stat family in cytokine signaling. Curr. Opin. Cell Biol. 13, 211–217 (2001).

    Article  CAS  PubMed  Google Scholar 

  5. Becker, S., Groner, B. & Muller, C. W. Three-dimensional structure of the Stat3β homodimer bound to DNA. Nature 394, 145–151 (1998).

    Article  CAS  PubMed  Google Scholar 

  6. Chen, X. et al. Crystal structure of a tyrosine phosphorylated STAT-1 dimer bound to DNA. Cell 93, 827–839 (1998).

    Article  CAS  PubMed  Google Scholar 

  7. Wen, Z., Zhong, Z. & Darnell, J. E. Jr Maximal activation of transcription by Stat1 and Stat3 requires both tyrosine and serine phosphorylation. Cell 82, 241–250 (1995).

    Article  CAS  PubMed  Google Scholar 

  8. Wen, Z. & Darnell, J. E. Jr Mapping of Stat3 serine phosphorylation to a single residue (727) and evidence that serine phosphorylation has no influence on DNA binding of Stat1 and Stat3. Nucleic Acids Res. 25, 2062–2067 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Park, C., Li, S., Cha, E & Schindler, C. Immune response in Stat2 knockout mice. Immunity 13, 795–804 (2000).

    Article  CAS  PubMed  Google Scholar 

  10. Khavari, P. A., Peterson, C. L., Tamkun, J. W., Mendel, D. B. & Crabtree, G. R. BRG1 contains a conserved domain of the SWI2/SNF2 family necessary for normal mitotic growth and transcription. Nature 366, 170–174 (1993).

    Article  CAS  PubMed  Google Scholar 

  11. Muchardt, C. & Yaniv, M. A human homologue of Saccharomyces cerevisiae SNF2/SWI2 and Drosophila brm genes potentiates transcriptionl activation by the glucocorticoid receptor. EMBO J. 12, 4279–4290 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Wang, W. et al. Purification and biochemical heterogeneity of the mammalian SWI–SNF complex. EMBO J. 15, 5370–5382 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Wang, W. et al. Diversity and specialization of mammalian SWI/SNF complexes. Genes Dev. 10, 2117–2130 (1996).

    Article  CAS  PubMed  Google Scholar 

  14. Kingston, R. E. & Narlikar, G. J. ATP-dependent remodeling and acetylation as regulators of chromatin fluidity. Genes Dev. 13, 2339–2352 (1999).

    Article  CAS  PubMed  Google Scholar 

  15. Vignali, M., Hassan, A. H., Neely, K. E. & Workman, J. L. ATP-dependent chromatin-remodeling complexes. Mol. Cell. Biol. 20, 1899–1910 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Reid, L. E. et al. A single DNA response element can confer inducibility by both α- and γ-interferons. Proc. Natl Acad. Sci. USA 86, 840–844 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Rasmussen, U. B. et al. Identification of a new interferon-α-inducible gene (p27) on human chromosome 14q32 and its expression in breast carcinoma. Cancer Res. 53, 4096–4104 (1993).

    CAS  PubMed  Google Scholar 

  18. Tamkun, J. W. et al. Brahma: a regulator of Drosophila homeotic genes structurally related to the yeast transcription activator SNF2/SWI2. Cell 68, 561–572 (1992).

    Article  CAS  PubMed  Google Scholar 

  19. Kwon, H., Imbalzano, A. N., Khavari, P. A., Kingston, R. E. & Green, M. R. Nucleosome disruption and enhancement of activator binding by a human SWI/SNF complex. Nature 370, 477–481 (1994).

    Article  CAS  PubMed  Google Scholar 

  20. Fryer, C. J. & Archer, T. K. Chromatin remodeling by the glucocorticoid receptor requires the BRG1 complex. Nature 393, 88–91 (1998).

    Article  CAS  PubMed  Google Scholar 

  21. PHeLan, M. L., Sif, S., Narlikar, G. J. & Kingston, R. E. Reconstitution of a core chromatin remodeling complex from SWI/SNF subunits. Mol. Cell 3, 247–253 (1999).

    Article  CAS  PubMed  Google Scholar 

  22. Zhao, K. et al. Rapid and phosphoinositol-dependent binding of the SWI/SNF-like BAF complex to chromatin after T lymphocyte receptor signaling. Cell 95, 625–636 (1998).

    Article  CAS  PubMed  Google Scholar 

  23. Cote, J., Quinn, J., Workman, J. L. & Peterson, C. L. Stimulation of GAL4 derivative binding to nucleosomal DNA by the yeast SWI/SNF complex. Science 265, 53–60 (1994).

    Article  CAS  PubMed  Google Scholar 

  24. Hirschhorn, J. N., Brown, S. A., Clark, C. D. & Winston, F. Evidence that SNF2/SWI2 and SNF5 activate transcription in yeast by altering chromatin structure. Genes Dev. 6, 2288–2298 (1992).

    Article  CAS  PubMed  Google Scholar 

  25. Leung, S., Qureshi, S. A., Kerr, I. M., Darnell, J. E. Jr & Stark, G. R. Role of STAT2 in the α interferon signaling pathway. Mol. Cell. Biol. 15, 1312–1317 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Der, S. D., Zhou, A., Williams, B. G. & Silverman, R. H. Identification of genes differentially regulated by interferon α, β or γ using oligonucleotide arrays. Proc. Natl Acad. Sci. USA 95, 15623–15628 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Dunaief, J. L. et al. The retinoblastoma protein and BRG1 form a complex and cooperate to induce cell cycle arrest. Cell 79, 119–130 (1994).

    Article  CAS  PubMed  Google Scholar 

  28. Liu, R., Liu, H., Chen, X., Kirby, M., Brown, P. O. & Zhao, K. Regulation of CSF1 promoter by the SWI/SNF-like BAF complex. Cell 106, 309–318 (2001).

    Article  CAS  PubMed  Google Scholar 

  29. Ramana, C. V. et al. Regulation of c-Myc expression by IFNγ through Stat1-dependent and -independent pathways. EMBO J. 19, 263–272 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Ramana, C. V. et al. Stat1-independent regulation of gene expression in response to IFN-γ. Proc. Natl Acad. Sci. USA 98, 6674–6679 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Gil, M. P. et al. Biological consequence of Stat1-independent IFN signaling. Proc. Natl Acad. Sci. USA 98, 6680–6685 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Barker, N., Hurlstone, A., Musisi, H., Miles, A., Bienz, M. & Clevers, H. The chromatin remodelling factor Brg-1 interacts with β-catenin to promote target gene activation. EMBO J. 20, 4935–4943 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Bhattacharya, S. et al. Cooperation of Stat2 and p300/CBP in signaling induced by interferon-α. Nature 383, 344–347 (1996).

    Article  CAS  PubMed  Google Scholar 

  34. Chen, H., Tini, M. & Evans, R. M. HATs on and beyond chromatin. Curr. Opin. Cell Biol. 13, 218–224 (2001).

    Article  CAS  PubMed  Google Scholar 

  35. Farrants, A.O, Blomquist, P., Kwon, H. & Wrange, O. Glucocorticoid receptor-glucocorticoid response element binding stimulates nucleosome disruption by the SWI/SNF complex. Mol. Cell. Biol. 17, 895–905 (1997).

    Article  Google Scholar 

  36. Direnzo, J. et al. BRG-1 is recruited to estrogen-responsive promoters and cooperates with factors involved in histone acetylation. Mol. Cell. Biol. 20, 7541–7549 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Bochar, D. A. et al. BRCA1 is associated with a human SWI/SNF-related complex: linking chromatin remodeling to breast cancer. Cell 102, 257–265 (2000).

    Article  CAS  PubMed  Google Scholar 

  38. Bultman, S. et al. A Brg1 null mutation in the mouse reveals functional differences among mammalian SWI/SNF complexes. Mol. Cell 6, 1287–1295 (2000).

    Article  CAS  PubMed  Google Scholar 

  39. Wong, A. K. C. et al. BRG1, a component of the SWI–SNF complex, is mutated in multiple human tumor cell lines. Cancer Res. 60, 6171–6177 (2000).

    CAS  PubMed  Google Scholar 

  40. Versteege, I. et al. Truncating mutations of hSNF5/INI1 in aggressive paediatric cancer. Nature 394, 203–206 (1998).

    Article  CAS  PubMed  Google Scholar 

  41. Deblandre, G. A. et al. Expression cloning of an interferon-inducible 17-kDa membrane protein implicated in the control of cell growth. J. Biol. Chem. 270, 23860–23866 (1995).

    Article  CAS  PubMed  Google Scholar 

  42. Paulson, M., Press, C., Smith, E., Tanese, N. & Levy, D. E. IFN-stimulated transcription through a TBP-free acetyltransferase complex escapes viral shutoff. Nature Cell Biol. 4, 140–147 (2002).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank J. Darnell, G. Stark and I. Kerr for the STAT2 cDNA, 2fTGH, U6 and 293T cells; K. Zhao for SW-13 and C33A cells, BRG1 cDNA, antibodies against BRG1 and BAFs; B. Jiao and Y. Law for technical support; and S. Lin and D. Liu for critically reading the manuscript. This work was supported by the Agency for Science, Technology and Research (Z.W.).

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  1. Laboratory of Molecular and Developmental Immunology, Institute of Molecular and Cell Biology, 30 Medical Drive, 117609, Singapore

    Mei Huang, Feng Qian, Yuanyu Hu, Chengeng Ang, Zhong Li & Zilong Wen

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Supplementary information

Supplementary figures

Figure S1 Quantification of the Northern blot analysis of 9-27 and IFI27 gene. SW (PDF 27 kb)

Figure S2 -184 to -128bp region of 9-27 promoter is responsible for IFNα induction and BRG1-mediated activation.

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Huang, M., Qian, F., Hu, Y. et al. Chromatin-remodelling factor BRG1 selectively activates a subset of interferon-α-inducible genes. Nat Cell Biol 4, 774–781 (2002). https://doi.org/10.1038/ncb855

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