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The chromatin-remodeling enzyme BRG1 coordinates CIITA induction through many interdependent distal enhancers

Abstract

The chromatin-remodeling enzyme BRG1 is critical for interferon-γ (IFN-γ)-mediated gene induction. Promoter-proximal elements are sufficient to mediate BRG1 dependency at some IFN-γ targets. In contrast, we show here that at CIITA, which encodes the 'master regulator' of induction of major histocompatibility complex class II, distal elements conferred BRG1 dependency. At the uninduced locus, many sites formed BRG1-independent loops. One loop juxtaposed a far downstream element adjacent to a far upstream site. Notably, BRG1 was recruited to the latter site, which triggered the appearance of a histone 'mark' linked to activation. This subtle change was crucial, as subsequent IFN-γ-induced recruitment of the transcription factors STAT1, IRF1 and p300, as well as histone modifications, accessibility and additional loops, showed BRG1 dependency. Like BRG1, each remote element was critical for the induction of CIITA expression. Thus, BRG1 regulates CIITA through many interdependent remote enhancers, not through the promoter alone.

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Figure 1: Distal IFN-γ-induced chromatin activity at CIITA.
Figure 2: Basal and IFN-γ-induced looping at CIITA.
Figure 3: BRG1-dependent distal events at CIITA.
Figure 4: IFN-γ-induced accessibility at distal sites is BRG1 dependent.
Figure 5: BRG1-dependent and BRG1-independent chromatin looping.
Figure 6: Remote regions confer BRG1 dependency on CIITA.
Figure 7: BRG1 and distal elements are required for CIITA induction.
Figure 8: There is a BRG1-independent H3-K79me3 mark at +59 kb.

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References

  1. Wright, K.L. & Ting, J.P. Epigenetic regulation of MHC-II and CIITA genes. Trends Immunol. 27, 405–412 (2006).

    Article  CAS  PubMed  Google Scholar 

  2. Swanberg, M. et al. MHC2TA is associated with differential MHC molecule expression and susceptibility to rheumatoid arthritis, multiple sclerosis and myocardial infarction. Nat. Genet. 37, 486–494 (2005).

    Article  CAS  PubMed  Google Scholar 

  3. Holling, T.M., van Eggermond, M.C., Jager, M.J. & van den Elsen, P.J. Epigenetic silencing of MHC2TA transcription in cancer. Biochem. Pharmacol. 72, 1570–1576 (2006).

    Article  CAS  PubMed  Google Scholar 

  4. Dunn, G.P., Koebel, C.M. & Schreiber, R.D. Interferons, immunity and cancer immunoediting. Nat. Rev. Immunol. 6, 836–848 (2006).

    Article  CAS  PubMed  Google Scholar 

  5. Maher, S.G., Romero-Weaver, A.L., Scarzello, A.J. & Gamero, A.M. Interferon: cellular executioner or white knight? Curr. Med. Chem. 14, 1279–1289 (2007).

    Article  CAS  PubMed  Google Scholar 

  6. Ullrich, E. et al. Therapy-induced tumor immunosurveillance involves IFN-producing killer dendritic cells. Cancer Res. 67, 851–853 (2007).

    Article  CAS  PubMed  Google Scholar 

  7. Muhlethaler-Mottet, A., Di Berardino, W., Otten, L.A. & Mach, B. Activation of the MHC class II transactivator CIITA by interferon-γ requires cooperative interaction between Stat1 and USF-1. Immunity 8, 157–166 (1998).

    Article  CAS  PubMed  Google Scholar 

  8. Morris, A.C., Beresford, G.W., Mooney, M.R. & Boss, J.M. Kinetics of a gamma interferon response: expression and assembly of CIITA promoter IV and inhibition by methylation. Mol. Cell. Biol. 22, 4781–4791 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Ni, Z. et al. Apical role for BRG1 in cytokine-induced promoter assembly. Proc. Natl. Acad. Sci. USA 102, 14611–14616 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Muhlethaler-Mottet, A., Otten, L.A., Steimle, V. & Mach, B. Expression of MHC class II molecules in different cellular and functional compartments is controlled by differential usage of multiple promoters of the transactivator CIITA. EMBO J. 16, 2851–2860 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. van der Stoep, N. et al. Constitutive and IFNγ-induced activation of MHC2TA promoter type III in human melanoma cell lines is governed by separate regulatory elements within the PIII upstream regulatory region. Mol. Immunol. 44, 2036–2046 (2007).

    Article  CAS  PubMed  Google Scholar 

  12. Piskurich, J.F., Linhoff, M.W., Wang, Y. & Ting, J.P. Two distinct gamma interferon-inducible promoters of the major histocompatibility complex class II transactivator gene are differentially regulated by STAT1, interferon regulatory factor 1, and transforming growth factor beta. Mol. Cell. Biol. 19, 431–440 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Chi, T. A BAF-centred view of the immune system. Nat. Rev. Immunol. 4, 965–977 (2004).

    Article  CAS  PubMed  Google Scholar 

  14. Kadam, S. & Emerson, B.M. Transcriptional specificity of human SWI/SNF BRG1 and BRM chromatin remodeling complexes. Mol. Cell 11, 377–389 (2003).

    Article  CAS  PubMed  Google Scholar 

  15. Muchardt, C. & Yaniv, M. When the SWI/SNF complex remodels...the cell cycle. Oncogene 20, 3067–3075 (2001).

    Article  CAS  PubMed  Google Scholar 

  16. Trotter, K.W. & Archer, T.K. Nuclear receptors and chromatin remodeling machinery. Mol. Cell. Endocrinol. 265–266, 162–167 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  17. Agalioti, T., Chen, G. & Thanos, D. Deciphering the transcriptional histone acetylation code for a human gene. Cell 111, 381–392 (2002).

    Article  CAS  PubMed  Google Scholar 

  18. Salma, N., Xiao, H., Mueller, E. & Imbalzano, A.N. Temporal recruitment of transcription factors and SWI/SNF chromatin-remodeling enzymes during adipogenic induction of the peroxisome proliferator-activated receptor γ nuclear hormone receptor. Mol. Cell. Biol. 24, 4651–4663 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Armstrong, J.A., Bieker, J.J. & Emerson, B.M.A. SWI/SNF-related chromatin remodeling complex, E-RC1, is required for tissue-specific transcriptional regulation by EKLF in vitro. Cell 95, 93–104 (1998).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  21. Liu, R. et al. Regulation of CSF1 promoter by the SWI/SNF-like BAF complex. Cell 106, 309–318 (2001).

    Article  CAS  PubMed  Google Scholar 

  22. Liu, H., Kang, H., Liu, R., Chen, X. & Zhao, K. Maximal induction of a subset of interferon target genes requires the chromatin-remodeling activity of the BAF complex. Mol. Cell. Biol. 22, 6471–6479 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Chi, T.H. et al. Reciprocal regulation of CD4/CD8 expression by SWI/SNF-like BAF complexes. Nature 418, 195–199 (2002).

    Article  CAS  PubMed  Google Scholar 

  24. Cai, S., Lee, C.C. & Kohwi-Shigematsu, T. SATB1 packages densely looped, transcriptionally active chromatin for coordinated expression of cytokine genes. Nat. Genet. 38, 1278–1288 (2006).

    Article  CAS  PubMed  Google Scholar 

  25. Im, H. et al. Chromatin domain activation via GATA-1 utilization of a small subset of dispersed GATA motifs within a broad chromosomal region. Proc. Natl. Acad. Sci. USA 102, 17065–17070 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. O'Neill, D. et al. Tissue-specific and developmental stage-specific DNA binding by a mammalian SWI/SNF complex associated with human fetal-to-adult globin gene switching. Proc. Natl. Acad. Sci. USA 96, 349–354 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Bultman, S.J., Gebuhr, T.C. & Magnuson, T.A. Brg1 mutation that uncouples ATPase activity from chromatin remodeling reveals an essential role for SWI/SNF-related complexes in β-globin expression and erythroid development. Genes Dev. 19, 2849–2861 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Kim, S.I., Bultman, S.J., Jing, H., Blobel, G.A. & Bresnick, E.H. Dissecting molecular steps in chromatin domain activation during hematopoietic differentiation. Mol. Cell. Biol. 27, 4551–4565 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Bazett-Jones, D.P., Cote, J., Landel, C.C., Peterson, C.L. & Workman, J.L. The SWI/SNF complex creates loop domains in DNA and polynucleosome arrays and can disrupt DNA-histone contacts within these domains. Mol. Cell. Biol. 19, 1470–1478 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Pattenden, S.G., Klose, R., Karaskov, E. & Bremner, R. Interferon-gamma-induced chromatin remodeling at the CIITA locus is BRG1 dependent. EMBO J. 21, 1978–1986 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Huang, M. et al. Chromatin-remodelling factor BRG1 selectively activates a subset of interferon-α-inducible genes. Nat. Cell Biol. 4, 774–781 (2002).

    Article  CAS  PubMed  Google Scholar 

  32. Cui, K. et al. The chromatin-remodeling BAF complex mediates cellular antiviral activities by promoter priming. Mol. Cell. Biol. 24, 4476–4486 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Yan, Z. et al. PBAF chromatin-remodeling complex requires a novel specificity subunit, BAF200, to regulate expression of selective interferon-responsive genes. Genes Dev. 19, 1662–1667 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Ni, Z. & Bremner, R. Brahma-related gene 1-dependent STAT3 recruitment at IL-6-inducible genes. J. Immunol. 178, 345–351 (2007).

    Article  CAS  PubMed  Google Scholar 

  35. Bernstein, B.E. et al. Genomic maps and comparative analysis of histone modifications in human and mouse. Cell 120, 169–181 (2005).

    Article  CAS  PubMed  Google Scholar 

  36. 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 

  37. Bernstein, B.E., Meissner, A. & Lander, E.S. The mammalian epigenome. Cell 128, 669–681 (2007).

    Article  CAS  PubMed  Google Scholar 

  38. Dekker, J., Rippe, K., Dekker, M. & Kleckner, N. Capturing chromosome conformation. Science 295, 1306–1311 (2002).

    Article  CAS  PubMed  Google Scholar 

  39. Bultman, S.J. et al. Maternal BRG1 regulates zygotic genome activation in the mouse. Genes Dev. 20, 1744–1754 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Nakamura, T. et al. ALL-1 is a histone methyltransferase that assembles a supercomplex of proteins involved in transcriptional regulation. Mol. Cell 10, 1119–1128 (2002).

    Article  CAS  PubMed  Google Scholar 

  41. Baiker, A. et al. Mitotic stability of an episomal vector containing a human scaffold/matrix-attached region is provided by association with nuclear matrix. Nat. Cell Biol. 2, 182–184 (2000).

    Article  CAS  PubMed  Google Scholar 

  42. Warming, S., Costantino, N., Court, D.L., Jenkins, N.A. & Copeland, N.G. Simple and highly efficient BAC recombineering using galK selection. Nucleic Acids Res. 33, e36 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  44. Azuara, V. et al. Chromatin signatures of pluripotent cell lines. Nat. Cell Biol. 8, 532–538 (2006).

    Article  CAS  PubMed  Google Scholar 

  45. Hartman, S.E. et al. Global changes in STAT target selection and transcription regulation upon interferon treatments. Genes Dev. 19, 2953–2968 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Bhinge, A.A., Kim, J., Euskirchen, G.M., Snyder, M. & Iyer, V.R. Mapping the chromosomal targets of STAT1 by sequence tag analysis of genomic enrichment (STAGE). Genome Res. 17, 910–916 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Robertson, G. et al. Genome-wide profiles of STAT1 DNA association using chromatin immunoprecipitation and massively parallel sequencing. Nat. Methods 4, 651–657 (2007).

    Article  CAS  PubMed  Google Scholar 

  48. Christova, R. et al. P-STAT1 mediates higher-order chromatin remodelling of the human MHC in response to IFNγ. J. Cell. Sci. 120, 3262–3270 (2007).

    Article  CAS  PubMed  Google Scholar 

  49. Zhang, W. et al. Aldosterone-sensitive repression of ENaCα transcription by a histone H3 lysine-79 methyltransferase. Am. J. Physiol. Cell Physiol. 290, C936–C946 (2006).

    Article  CAS  PubMed  Google Scholar 

  50. Steger, D.J. et al. DOT1L/KMT4 recruitment and H3K79 methylation are ubiquitously coupled with gene transcription in mammalian cells. Mol Cell Biol (2008).

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

    Article  CAS  PubMed  Google Scholar 

  52. Pattenden, S. Analysis of chromatin remodeling in an IFN-γ responsive system. Thesis, Univ. Toronto (2003).

    Google Scholar 

  53. Reid, G. et al. Cyclic, proteasome-mediated turnover of unliganded and liganded ERα on responsive promoters is an integral feature of estrogen signaling. Mol. Cell 11, 695–707 (2003).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank L. Zeng for technical assistance; D. Torti for help with statistics; P. Farnham for protocols and advice for ChIP on tiled genome arrays; R Métivier for protocols and advice for 're-ChIP'; N. Copeland (National Cancer Institute) for reagents and advice for recombination-mediated genetic engineering; and H. Lipps (University Witten/Herdecke), J.F. Piskurich (Mercer University School of Medicine) and K. Zhao (National Institutes of Health) for plasmids. Supported by the National Cancer Institute of Canada with funds from the Canadian Cancer Society and from the Krembil Foundation, Ontario Graduate Studentships (Z.N.), the Vision Science Research Program (Z.N.), the Frank Fletcher Memorial Fund (Z.N.), Dr. R. Dittakavi & Dr. P. Rao Graduate Award (Z.N.) and the Krembil Foundation (M.A.E.H.).

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Z.N. and M.A.E.H designed and did experiments, analyzed data and wrote the manuscript; Z.X. analyzed data; T.Y. did experiments; and R.B. designed and supervised the research, analyzed data and wrote the manuscript.

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Correspondence to Rod Bremner.

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Ni, Z., Hassan, M., Xu, Z. et al. The chromatin-remodeling enzyme BRG1 coordinates CIITA induction through many interdependent distal enhancers. Nat Immunol 9, 785–793 (2008). https://doi.org/10.1038/ni.1619

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