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Recognition of enhancer element–specific histone methylation by TIP60 in transcriptional activation

Nature Structural & Molecular Biology volume 18, pages 1358–1365 (2011)Cite this article

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Abstract

Many co-regulator proteins are recruited by DNA-bound transcription factors to remodel chromatin and activate transcription. However, mechanisms for coordinating actions of multiple co-regulator proteins are poorly understood. We demonstrate that multiple protein-protein interactions by the protein acetyltransferase TIP60 are required for estrogen-induced transcription of a subset of estrogen receptor alpha (ERα) target genes in human cells. Estrogen-induced recruitment of TIP60 requires direct binding of TIP60 to ERα and the action of chromatin-remodeling ATPase BRG1, leading to increased recruitment of histone methyltransferase MLL1 and increased monomethylation of histone H3 at Lys4. TIP60 recruitment also requires preferential binding of the TIP60 chromodomain to histone H3 containing monomethylated Lys4, which marks active and poised enhancer elements. After recruitment, TIP60 increases acetylation of histone H2A at Lys5. Thus, complex cooperation of TIP60 with ERα and other chromatin-remodeling enzymes is required for estrogen-induced transcription.

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Figure 1: Requirement of endogenous TIP60 for expression of endogenous ERα target genes.
Figure 2: Interaction with ERα is critical for occupancy of ERα target genes by TIP60.
Figure 3: BRG1-dependent coactivator activity and occupancy of ERα target genes by TIP60.
Figure 4: Binding of TIP60 to H3K4me1 is required for TIP60 recruitment to ERα target genes.
Figure 5: Requirement of H3K4 methyltransferases for E2-induced expression of ERα target genes.
Figure 6: H3K4 methylation status of the TFF1 locus in MCF-7 cells depleted of MLL1, SET1A or BRG1.
Figure 7: Role of TIP60 histone acetyltransferase activity in TIP60 coactivator function.
Figure 8: Proposed model for recruitment of TIP60 to target genes of ERα.

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References

  1. Berk, A.J. Activation of RNA polymerase II transcription. Curr. Opin. Cell Biol. 11, 330–335 (1999).

    Article  CAS  PubMed  Google Scholar 

  2. McKenna, N.J. & O'Malley, B.W. Combinatorial control of gene expression by nuclear receptors and coregulators. Cell 108, 465–474 (2002).

    Article  CAS  PubMed  Google Scholar 

  3. Metivier, R. et al. Dynamics of estrogen receptor-mediated transcriptional activation of responsive genes in vivo: apprehending transcription in four dimensions. Adv. Exp. Med. Biol. 617, 129–138 (2008).

    Article  CAS  PubMed  Google Scholar 

  4. Metivier, R. et al. Estrogen receptor-alpha directs ordered, cyclical, and combinatorial recruitment of cofactors on a natural target promoter. Cell 115, 751–763 (2003).

    Article  CAS  PubMed  Google Scholar 

  5. Shang, Y., Hu, X., DiRenzo, J., Lazar, M.A. & Brown, M. Cofactor dynamics and sufficiency in estrogen receptor-regulated transcription. Cell 103, 843–852 (2000).

    Article  CAS  PubMed  Google Scholar 

  6. Burakov, D., Crofts, L.A., Chang, C.P. & Freedman, L.P. Reciprocal recruitment of DRIP/mediator and p160 coactivator complexes in vivo by estrogen receptor. J. Biol. Chem. 277, 14359–14362 (2002).

    Article  CAS  PubMed  Google Scholar 

  7. Utley, R.T. & Cote, J. The MYST family of histone acetyltransferases. Curr. Top. Microbiol. Immunol. 274, 203–236 (2003).

    CAS  PubMed  Google Scholar 

  8. Kusch, T. et al. Acetylation by Tip60 is required for selective histone variant exchange at DNA lesions. Science 306, 2084–2087 (2004).

    Article  CAS  PubMed  Google Scholar 

  9. Ikura, T. et al. Involvement of the TIP60 histone acetylase complex in DNA repair and apoptosis. Cell 102, 463–473 (2000).

    Article  CAS  PubMed  Google Scholar 

  10. Sapountzi, V., Logan, I.R. & Robson, C.N. Cellular functions of TIP60. Int. J. Biochem. Cell Biol. 38, 1496–1509 (2006).

    Article  CAS  PubMed  Google Scholar 

  11. Kimura, A. & Horikoshi, M. Tip60 acetylates six lysines of a specific class in core histones in vitro. Genes Cells 3, 789–800 (1998).

    Article  CAS  PubMed  Google Scholar 

  12. Yamamoto, T. & Horikoshi, M. Novel substrate specificity of the histone acetyltransferase activity of HIV-1-Tat interactive protein Tip60. J. Biol. Chem. 272, 30595–30598 (1997).

    Article  CAS  PubMed  Google Scholar 

  13. Tang, Y., Luo, J., Zhang, W. & Gu, W. Tip60-dependent acetylation of p53 modulates the decision between cell-cycle arrest and apoptosis. Mol. Cell 24, 827–839 (2006).

    Article  CAS  PubMed  Google Scholar 

  14. Sykes, S.M. et al. Acetylation of the p53 DNA-binding domain regulates apoptosis induction. Mol. Cell 24, 841–851 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Sun, Y., Jiang, X., Chen, S., Fernandes, N. & Price, B.D. A role for the Tip60 histone acetyltransferase in the acetylation and activation of ATM. Proc. Natl. Acad. Sci. USA 102, 13182–13187 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Patel, J.H. et al. The c-MYC oncoprotein is a substrate of the acetyltransferases hGCN5/PCAF and TIP60. Mol. Cell Biol. 24, 10826–10834 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Brady, M.E. et al. Tip60 is a nuclear hormone receptor coactivator. J. Biol. Chem. 274, 17599–17604 (1999).

    Article  CAS  PubMed  Google Scholar 

  18. Gaughan, L., Logan, I.R., Cook, S., Neal, D.E. & Robson, C.N. Tip60 and histone deacetylase 1 regulate androgen receptor activity through changes to the acetylation status of the receptor. J. Biol. Chem. 277, 25904–25913 (2002).

    Article  CAS  PubMed  Google Scholar 

  19. Jeong, K.W., Lee, Y.H. & Stallcup, M.R. Recruitment of the SWI/SNF chromatin remodeling complex to steroid hormone-regulated promoters by nuclear receptor coactivator flightless-I. J. Biol. Chem. 284, 29298–29309 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Pan, Y.F. et al. Regulation of estrogen receptor-mediated long range transcription via evolutionarily conserved distal response elements. J. Biol. Chem. 283, 32977–32988 (2008).

    Article  CAS  PubMed  Google Scholar 

  21. Sun, J., Nawaz, Z. & Slingerland, J.M. Long-range activation of GREB1 by estrogen receptor via three distal consensus estrogen-responsive elements in breast cancer cells. Mol. Endocrinol. 21, 2651–2662 (2007).

    Article  CAS  PubMed  Google Scholar 

  22. Carroll, J.S. et al. Genome-wide analysis of estrogen receptor binding sites. Nat. Genet. 38, 1289–1297 (2006).

    Article  CAS  PubMed  Google Scholar 

  23. Bretschneider, N. et al. E2-mediated cathepsin D (CTSD) activation involves looping of distal enhancer elements. Mol. Oncol. 2, 182–190 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  24. Gaughan, L., Brady, M.E., Cook, S., Neal, D.E. & Robson, C.N. Tip60 is a co-activator specific for class I nuclear hormone receptors. J. Biol. Chem. 276, 46841–46848 (2001).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. 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 

  27. Robertson, A.G. et al. Genome-wide relationship between histone H3 lysine 4 mono- and tri-methylation and transcription factor binding. Genome Res. 18, 1906–1917 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. 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 

  29. Bernstein, B.E. et al. Methylation of histone H3 Lys 4 in coding regions of active genes. Proc. Natl. Acad. Sci. USA 99, 8695–8700 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Kim, T.H. et al. A high-resolution map of active promoters in the human genome. Nature 436, 876–880 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  32. Jacobs, S.A. & Khorasanizadeh, S. Structure of HP1 chromodomain bound to a lysine 9-methylated histone H3 tail. Science 295, 2080–2083 (2002).

    Article  CAS  PubMed  Google Scholar 

  33. Nielsen, P.R. et al. Structure of the HP1 chromodomain bound to histone H3 methylated at lysine 9. Nature 416, 103–107 (2002).

    Article  CAS  PubMed  Google Scholar 

  34. Min, J., Zhang, Y. & Xu, R.M. Structural basis for specific binding of Polycomb chromodomain to histone H3 methylated at Lys 27. Genes Dev. 17, 1823–1828 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Flanagan, J.F. et al. Double chromodomains cooperate to recognize the methylated histone H3 tail. Nature 438, 1181–1185 (2005).

    Article  CAS  PubMed  Google Scholar 

  36. Milne, T.A. et al. Multiple interactions recruit MLL1 and MLL1 fusion proteins to the HOXA9 locus in leukemogenesis. Mol. Cell 38, 853–863 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Sun, Y. et al. Histone H3 methylation links DNA damage detection to activation of the tumour suppressor Tip60. Nat. Cell Biol. 11, 1376–1382 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Dreijerink, K.M. et al. Menin links estrogen receptor activation to histone H3K4 trimethylation. Cancer Res. 66, 4929–4935 (2006).

    Article  CAS  PubMed  Google Scholar 

  39. Mo, R., Rao, S.M. & Zhu, Y.J. Identification of the MLL2 complex as a coactivator for estrogen receptor alpha. J. Biol. Chem. 281, 15714–15720 (2006).

    Article  CAS  PubMed  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. Dou, Y. et al. Physical association and coordinate function of the H3 K4 methyltransferase MLL1 and the H4 K16 acetyltransferase MOF. Cell 121, 873–885 (2005).

    Article  CAS  PubMed  Google Scholar 

  42. Santos-Rosa, H. et al. Active genes are tri-methylated at K4 of histone H3. Nature 419, 407–411 (2002).

    Article  CAS  PubMed  Google Scholar 

  43. Ng, H.H., Robert, F., Young, R.A. & Struhl, K. Targeted recruitment of Set1 histone methylase by elongating Pol II provides a localized mark and memory of recent transcriptional activity. Mol. Cell 11, 709–719 (2003).

    Article  CAS  PubMed  Google Scholar 

  44. Choi, J., Heo, K. & An, W. Cooperative action of TIP48 and TIP49 in H2A.Z exchange catalyzed by acetylation of nucleosomal H2A. Nucleic Acids Res. 37, 5993–6007 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Wolf, E. et al. Crystal structure of a GCN5-related N-acetyltransferase: Serratia marcescens aminoglycoside 3-N-acetyltransferase. Cell 94, 439–449 (1998).

    Article  CAS  PubMed  Google Scholar 

  46. Park, J.H., Sun, X.J. & Roeder, R.G. The SANT domain of p400 ATPase represses acetyltransferase activity and coactivator function of TIP60 in basal p21 gene expression. Mol. Cell Biol. 30, 2750–2761 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Murr, R. et al. Histone acetylation by Trrap-Tip60 modulates loading of repair proteins and repair of DNA double-strand breaks. Nat. Cell Biol. 8, 91–99 (2006).

    Article  CAS  PubMed  Google Scholar 

  48. Sun, Y., Xu, Y., Roy, K. & Price, B.D. DNA damage-induced acetylation of lysine 3016 of ATM activates ATM kinase activity. Mol. Cell Biol. 27, 8502–8509 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Halkidou, K. et al. Expression of Tip60, an androgen receptor coactivator, and its role in prostate cancer development. Oncogene 22, 2466–2477 (2003).

    Article  CAS  PubMed  Google Scholar 

  50. Gorrini, C. et al. Tip60 is a haplo-insufficient tumour suppressor required for an oncogene-induced DNA damage response. Nature 448, 1063–1067 (2007).

    Article  CAS  PubMed  Google Scholar 

  51. Paro, R. & Hogness, D.S. The Polycomb protein shares a homologous domain with a heterochromatin-associated protein of Drosophila. Proc. Natl. Acad. Sci. USA 88, 263–267 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Ghisletti, S. et al. Identification and characterization of enhancers controlling the inflammatory gene expression program in macrophages. Immunity 32, 317–328 (2010).

    Article  CAS  PubMed  Google Scholar 

  53. Nishioka, K. et al. Set9, a novel histone H3 methyltransferase that facilitates transcription by precluding histone tail modifications required for heterochromatin formation. Genes Dev. 16, 479–489 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Dillon, S.C., Zhang, X., Trievel, R.C. & Cheng, X. The SET-domain protein superfamily: protein lysine methyltransferases. Genome Biol. 6, 227 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  55. Rozenblatt-Rosen, O. et al. The C-terminal SET domains of ALL-1 and TRITHORAX interact with the INI1 and SNR1 proteins, components of the SWI/SNF complex. Proc. Natl. Acad. Sci. USA 95, 4152–4157 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Lee, S. et al. Crucial roles for interactions between MLL3/4 and INI1 in nuclear receptor transactivation. Mol. Endocrinol. 23, 610–619 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Dou, Y. et al. Regulation of MLL1 H3K4 methyltransferase activity by its core components. Nat. Struct. Mol. Biol. 13, 713–719 (2006).

    Article  CAS  PubMed  Google Scholar 

  58. Collins, R.E. et al. The ankyrin repeats of G9a and GLP histone methyltransferases are mono- and dimethyllysine binding modules. Nat. Struct. Mol. Biol. 15, 245–250 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank J. Lee, D. Gerke and K. Chang (University of Southern California) for expert technical assistance; G.L. Greene (University of Chicago) for plasmid pGEX-ERα-LBD; A. Kralli (Scripps Research Institute, La Jolla, California) for the plasmid encoding TIP60; S. Brandt (Vanderbilt University Medical Center) for the plasmid expressing BRG1 and the BRG1(K/R) mutant; P. Kushner (University California San Francisco) for GST-ER-AF1; J. Hess (University of Michigan) for the plasmid expressing MLL; T.K. Archer (National Institutes of Health) for SW13 cells; M.T. Bedford for the H4, H4R3me2 and H4K20me peptides; Y. Zhang and N. Lee (University of North Carolina) for recombinant unmethylated H3 and K4 monomethylated H3 histones; and E. Cheung (Genome Institute of Singapore, Singapore) for TFF1 primer sequences for ChIP experiments. This work was supported by grants DK43093 to M.R.S., GM84209 to W.A. and HL089726 to T.S.U. from the US National Institutes of Health.

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, USC/Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California, USA

    Kwang Won Jeong, Kyunghwan Kim, Woojin An & Michael R Stallcup

  2. Department of Biochemistry and Molecular Biology, Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, California, USA

    Alan Jialun Situ & Tobias S Ulmer

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  1. Kwang Won Jeong
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Contributions

K.W.J. conceived and carried out the studies with the guidance of M.R.S. K.K. and W.A. carried out the experiments shown in Supplementary Figure 5h. A.J.S. and T.S.U. provided the expertise and instrumentation required for the experiment shown in Supplementary Figure 5g.

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Correspondence to Michael R Stallcup.

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Jeong, K., Kim, K., Situ, A. et al. Recognition of enhancer element–specific histone methylation by TIP60 in transcriptional activation. Nat Struct Mol Biol 18, 1358–1365 (2011). https://doi.org/10.1038/nsmb.2153

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