TRIM24 links a non-canonical histone signature to breast cancer


Recognition of modified histone species by distinct structural domains within ‘reader’ proteins plays a critical role in the regulation of gene expression. Readers that simultaneously recognize histones with multiple marks allow transduction of complex chromatin modification patterns into specific biological outcomes. Here we report that chromatin regulator tripartite motif-containing 24 (TRIM24) functions in humans as a reader of dual histone marks by means of tandem plant homeodomain (PHD) and bromodomain (Bromo) regions. The three-dimensional structure of the PHD-Bromo region of TRIM24 revealed a single functional unit for combinatorial recognition of unmodified H3K4 (that is, histone H3 unmodified at lysine 4, H3K4me0) and acetylated H3K23 (histone H3 acetylated at lysine 23, H3K23ac) within the same histone tail. TRIM24 binds chromatin and oestrogen receptor to activate oestrogen-dependent genes associated with cellular proliferation and tumour development. Aberrant expression of TRIM24 negatively correlates with survival of breast cancer patients. The PHD-Bromo of TRIM24 provides a structural rationale for chromatin activation through a non-canonical histone signature, establishing a new route by which chromatin readers may influence cancer pathogenesis.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: TRIM24 PHD finger interacts with unmethylated H3K4.
Figure 2: TRIM24 PHD-Bromo simultaneously binds H3K4me0 and acetylated histone lysines.
Figure 3: TRIM24 is recruited with ERα to ERE sites depleted of H3K4me2.
Figure 4: TRIM24 functions as a co-activator and stabilizes ERα–chromatin interactions.
Figure 5: Aberrant expression of TRIM24 correlates with poor survival of breast cancer patients.

Accession codes

Primary accessions

Gene Expression Omnibus

Protein Data Bank

Data deposits

The X-ray coordinates of TRIM24 PHD-Bromo in the free state and when bound to H3(1–10)K4, H3(13–32)K23ac, H3(23–31)K27ac and H4(14–19)K16ac peptides have been deposited in the Protein Data Bank (PDB) under accession numbers 3O33, 3O37, 3O34, 3O35 and 3O36, respectively. ChIP-sequencing files and data are deposited at the NCBI Gene Expression Omnibus (GEO) site as accession number GSE24166.


  1. 1

    Taverna, S. D. et al. How chromatin-binding modules interpret histone modifications: lessons from professional pocket pickers. Nature Struct. Mol. Biol. 14, 1025–1040 (2007)

    CAS  Article  Google Scholar 

  2. 2

    Jenuwein, T. & Allis, C. D. Translating the histone code. Science 293, 1074–1080 (2001)

    CAS  Article  Google Scholar 

  3. 3

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

    CAS  Article  Google Scholar 

  4. 4

    Berger, S. L. The complex language of chromatin regulation during transcription. Nature 447, 407–412 (2007)

    ADS  CAS  Article  Google Scholar 

  5. 5

    Baker, L. A., Allis, C. D. & Wang, G. G. PHD fingers in human diseases: disorders arising from misinterpreting epigenetic marks. Mutat. Res. 647, 3–12 (2008)

    CAS  Article  Google Scholar 

  6. 6

    Jacobson, R. H., Ladurner, A. G., King, D. S. & Tjian, R. Structure and function of a human TAFII250 double bromodomain module. Science 288, 1422–1425 (2000)

    ADS  CAS  Article  Google Scholar 

  7. 7

    Morinière, J. et al. Cooperative binding of two acetylation marks on a histone tail by a single bromodomain. Nature 461, 664–668 (2009)

    ADS  Article  Google Scholar 

  8. 8

    Lan, F. et al. Recognition of unmethylated histone H3 lysine 4 links BHC80 to LSD1-mediated gene repression. Nature 448, 718–722 (2007)

    ADS  CAS  Article  Google Scholar 

  9. 9

    Org, T. et al. The autoimmune regulator PHD finger binds to non-methylated histone H3K4 to activate gene expression. EMBO Rep. 9, 370–376 (2008)

    CAS  Article  Google Scholar 

  10. 10

    Ragvin, A. et al. Nucleosome binding by the bromodomain and PHD finger of the transcriptional cofactor p300. J. Mol. Biol. 337, 773–788 (2004)

    CAS  Article  Google Scholar 

  11. 11

    Zhou, Y. & Grummt, I. The PHD finger/bromodomain of NoRC interacts with acetylated histone H4K16 and is sufficient for rDNA silencing. Curr. Biol. 15, 1434–1438 (2005)

    CAS  Article  Google Scholar 

  12. 12

    Peña, P. V. et al. Molecular mechanism of histone H3K4me3 recognition by plant homeodomain of ING2. Nature 442, 100–103 (2006)

    ADS  Article  Google Scholar 

  13. 13

    Li, H. et al. Molecular basis for site-specific read-out of histone H3K4me3 by the BPTF PHD finger of NURF. Nature 442, 91–95 (2006)

    ADS  CAS  Article  Google Scholar 

  14. 14

    Lange, M. et al. Regulation of muscle development by DPF3, a novel histone acetylation and methylation reader of the BAF chromatin remodeling complex. Genes Dev. 22, 2370–2384 (2008)

    CAS  Article  Google Scholar 

  15. 15

    Koh, A. S. et al. Aire employs a histone-binding module to mediate immunological tolerance, linking chromatin regulation with organ-specific autoimmunity. Proc. Natl Acad. Sci. USA 105, 15878–15883 (2008)

    ADS  CAS  Article  Google Scholar 

  16. 16

    Hung, T. et al. ING4 mediates crosstalk between histone H3 K4 trimethylation and H3 acetylation to attenuate cellular transformation. Mol. Cell 33, 248–256 (2009)

    CAS  Article  Google Scholar 

  17. 17

    Wang, Z. et al. Pro isomerization in MLL1 PHD3-bromo cassette connects H3K4me readout to CyP33 and HDAC-mediated repression. Cell 141, 1183–1194 (2010)

    CAS  Article  Google Scholar 

  18. 18

    Wang, G. G. et al. Haematopoietic malignancies caused by dysregulation of a chromatin-binding PHD finger. Nature 459, 847–851 (2009)

    ADS  CAS  Article  Google Scholar 

  19. 19

    Allton, K. et al. Trim24 targets endogenous p53 for degradation. Proc. Natl Acad. Sci. USA 106, 11612–11616 (2009)

    ADS  CAS  Article  Google Scholar 

  20. 20

    Poleshko, A. et al. Identification of a functional network of human epigenetic silencing factors. J. Biol. Chem. 285, 422–433 (2009)

    Article  Google Scholar 

  21. 21

    Meroni, G. & Diez-Roux, G. TRIM/RBCC, a novel class of 'single protein RING finger' E3 ubiquitin ligases. Bioessays 27, 1147–1157 (2005)

    CAS  Article  Google Scholar 

  22. 22

    Reymond, A. et al. The tripartite motif family identifies cell compartments. EMBO J. 20, 2140–2151 (2001)

    CAS  Article  Google Scholar 

  23. 23

    Le Douarin, B. et al. A possible involvement of TIF1 alpha and TIF1 beta in the epigenetic control of transcription by nuclear receptors. EMBO J. 15, 6701–6715 (1996)

    CAS  Article  Google Scholar 

  24. 24

    Soliman, M. A. & Riabowol, K. After a decade of study-ING, a PHD for a versatile family of proteins. Trends Biochem. Sci. 32, 509–519 (2007)

    CAS  Article  Google Scholar 

  25. 25

    Peña, P. V. et al. Histone H3K4me3 binding is required for the DNA repair and apoptotic activities of ING1 tumor suppressor. J. Mol. Biol. 380, 303–312 (2008)

    Article  Google Scholar 

  26. 26

    Thénot, S., Henriquet, C., Rochefort, H. & Cavailles, V. Differential interaction of nuclear receptors with the putative human transcriptional coactivator hTIF1. J. Biol. Chem. 272, 12062–12068 (1997)

    Article  Google Scholar 

  27. 27

    Garcia-Bassets, I. et al. Histone methylation-dependent mechanisms impose ligand dependency for gene activation by nuclear receptors. Cell 128, 505–518 (2007)

    CAS  Article  Google Scholar 

  28. 28

    Fullwood, M. J. et al. An oestrogen-receptor-α-bound human chromatin interactome. Nature 462, 58–64 (2009)

    ADS  CAS  Article  Google Scholar 

  29. 29

    Lupien, M. et al. FoxA1 translates epigenetic signatures into enhancer-driven lineage-specific transcription. Cell 132, 958–970 (2008)

    CAS  Article  Google Scholar 

  30. 30

    Lin, C. Y. et al. Whole-genome cartography of estrogen receptor α binding sites. PLoS Genet. 3, e87 (2007)

    Article  Google Scholar 

  31. 31

    Huang, W. Sherman, B. T. & Lempicki, R. A. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nature Protocols 4, 44–57 (2009)

    Article  Google Scholar 

  32. 32

    Eckert, R. L. & Katzenellenbogen, B. S. Physical properties of estrogen receptor complexes in MCF-7 human breast cancer cells. Differences with anti-estrogen and estrogen. J. Biol. Chem. 257, 8840–8846 (1982)

    CAS  PubMed  Google Scholar 

  33. 33

    Yanagisawa, J. et al. Nuclear receptor function requires a TFTC-type histone acetyl transferase complex. Mol. Cell 9, 553–562 (2002)

    CAS  Article  Google Scholar 

  34. 34

    Stavropoulos, P., Blobel, G. & Hoelz, A. Crystal structure and mechanism of human lysine-specific demethylase-1. Nature Struct. Mol. Biol. 13, 626–632 (2006)

    CAS  Article  Google Scholar 

  35. 35

    Shi, Y. et al. Histone demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell 119, 941–953 (2004)

    CAS  Article  Google Scholar 

  36. 36

    Wissmann, M. et al. Cooperative demethylation by JMJD2C and LSD1 promotes androgen receptor-dependent gene expression. Nature Cell Biol. 9, 347–353 (2007)

    CAS  Article  Google Scholar 

  37. 37

    Perillo, B. et al. DNA oxidation as triggered by H3K9me2 demethylation drives estrogen-induced gene expression. Science 319, 202–206 (2008)

    ADS  CAS  Article  Google Scholar 

  38. 38

    Katzenellenbogen, B. S. Estrogen receptors: bioactivities and interactions with cell signaling pathways. Biol. Reprod. 54, 287–293 (1996)

    CAS  Article  Google Scholar 

  39. 39

    Cheskis, B. J., Greger, J. G., Nagpal, S. & Freedman, L. P. Signaling by estrogens. J. Cell. Physiol. 213, 610–617 (2007)

    CAS  Article  Google Scholar 

  40. 40

    Zhong, S. et al. A RA-dependent, tumour-growth suppressive transcription complex is the target of the PML-RARα and T18 oncoproteins. Nature Genet. 23, 287–295 (1999)

    CAS  Article  Google Scholar 

  41. 41

    Klugbauer, S. & Rabes, H. M. The transcription coactivator HTIF1 and a related protein are fused to the RET receptor tyrosine kinase in childhood papillary thyroid carcinomas. Oncogene 18, 4388–4393 (1999)

    CAS  Article  Google Scholar 

  42. 42

    Belloni, E. et al. 8p11 myeloproliferative syndrome with a novel t(7;8) translocation leading to fusion of the FGFR1 and TIF1 genes. Genes Chromosom. Cancer 42, 320–325 (2005)

    CAS  Article  Google Scholar 

  43. 43

    Xia, W. et al. Phosphorylation/cytoplasmic localization of p21Cip1/WAF1 is associated with HER2/neu overexpression and provides a novel combination predictor for poor prognosis in breast cancer patients. Clin. Cancer Res. 10, 3815–3824 (2004)

    CAS  Article  Google Scholar 

  44. 44

    Tsai, F. T. & Sigler, P. B. Structural basis of preinitiation complex assembly on human pol II promoters. EMBO J. 19, 25–36 (2000)

    CAS  Article  Google Scholar 

  45. 45

    Tsai, W. W., Nguyen, T. T., Shi, Y. & Barton, M. C. p53-targeted LSD1 functions in repression of chromatin structure and transcription in vivo. Mol. Cell. Biol. 28, 5139–5146 (2008)

    CAS  Article  Google Scholar 

  46. 46

    Bonéy-Montoya, J. et al. Long-range transcriptional control of progesterone receptor gene expression. Mol. Endocrinol. 24, 346–358 (2010)

    Article  Google Scholar 

  47. 47

    Kuhn, R. M. et al. The UCSC Genome Browser Database: update 2009. Nucleic Acids Res. 37 (Database issue). D755–D761 (2009)

    CAS  Article  Google Scholar 

  48. 48

    Bentley, D. R. et al. Accurate whole human genome sequencing using reversible terminator chemistry. Nature 456, 53–59 (2008)

    ADS  CAS  Article  Google Scholar 

  49. 49

    Zhang, Y. et al. Model-based analysis of ChIP-Seq (MACS). Genome Biol. 9, R137 (2008)

    Article  Google Scholar 

  50. 50

    Shi, X. et al. Proteome-wide analysis in Saccharomyces cerevisiae identifies several PHD fingers as novel direct and selective binding modules of histone H3 methylated at either lysine 4 or lysine 36. J. Biol. Chem. 282, 2450–2455 (2007)

    CAS  Article  Google Scholar 

  51. 51

    McCoy, A. J. Solving structures of protein complexes by molecular replacement with Phaser. Acta Crystallogr. D. 63, 32–41 (2007)

    CAS  Article  Google Scholar 

  52. 52

    Emsley, P. & Cowtan, K. Coot: model-building tools for molecular graphics. Acta Crystallogr. D 60, 2126–2132 (2004)

    Article  Google Scholar 

  53. 53

    Brunger, A. T. Version 1.2 of the Crystallography and NMR system. Nature Protocols 2, 2728–2733 (2007)

    CAS  Article  Google Scholar 

  54. 54

    Jacobs, S. A., Fischle, W. & Khorasanizadeh, S. Assays for the determination of structure and dynamics of the interaction of the chromodomain with histone peptides. Methods Enzymol. 376, 131–148 (2004)

    CAS  Article  Google Scholar 

Download references


This work was supported by funds from the National Institutes of Health (NIH GM081627) and the George and Cynthia Mitchell Foundation (to M.C.B.), from NIH (U54 RR025216 and P30DK078392-01) to B.A., from NIH (GM079641) to O.G., from the Sister Institution Fund of China Medical University and Hospital and MDACC to M.-C.H., from the Starr Foundation and the Leukemia and Lymphoma Society to D.J.P., from the Max Planck Society to W.F., and from the NCI Cancer Center (Support Grant) to the UT MD Anderson Cancer Center. W.-W.T. was supported in part by the Sowell-Huggins Foundation; S.W. by a long-term EMBO fellowship; T.T.Y. by T32 HD07325; and K.C.A. by the Center for Cancer Epigenetics. We thank J. Song, D.C. Jamison, A. Dose, Z. Coban and Y. Wei for technical support and assistance. We are grateful to S. Stratton, M. Lee, M. Bedford, G. Lozano, S. Dent, A. Nardulli and members of our laboratories for advice, reagents and discussions.

Author information




W.-W.T. identified ER interactions, and performed molecular biology and IHC studies; Z.W. solved the molecular structures of TRIM24 PHD-Bromo in the free and bound states, and performed ITC binding affinity studies; T.T.Y. performed mutagenesis, ChIP and clonogenic analyses; C.-Y.T. performed clonogenic assays; K.C.A. performed bioinformatic analyses; W.X. analysed patient samples; X.S. performed peptide array analyses; S.W., D.S. and W.F. performed and analysed FP experiments; O.G., B.A., W.P., W.F., M.-C. H., D.J.P. and M.C.B. discussed studies; and D.J.P. and M.C.B. designed structural and functional studies, analysed data and wrote the paper. W.-W.T. and Z.W. contributed equally to this work. All authors discussed and commented on the manuscript.

Corresponding authors

Correspondence to Dinshaw J. Patel or Michelle Craig Barton.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Tables 1-7 and Supplementary Figures 1-18 with legends. (PDF 2013 kb)

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Tsai, WW., Wang, Z., Yiu, T. et al. TRIM24 links a non-canonical histone signature to breast cancer. Nature 468, 927–932 (2010).

Download citation

Further reading


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing