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.

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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.


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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

Author notes

    • Wen-Wei Tsai
    •  & Zhanxin Wang

    These authors contributed equally to this work.


  1. Department of Biochemistry and Molecular Biology, Program in Genes and Development, Graduate School of Biomedical Sciences, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA

    • Wen-Wei Tsai
    • , Teresa T. Yiu
    • , Xiaobing Shi
    •  & Michelle Craig Barton
  2. Centers for Cancer Epigenetics and Stem Cell and Developmental Biology, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA

    • Teresa T. Yiu
    • , Kadir C. Akdemir
    • , Xiaobing Shi
    •  & Michelle Craig Barton
  3. Structural Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA

    • Zhanxin Wang
    •  & Dinshaw J. Patel
  4. Department of Molecular and Cellular Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA

    • Weiya Xia
    •  & Mien-Chie Hung
  5. Department of Biostatistics and Bioinformatics, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA

    • Kadir C. Akdemir
  6. Laboratory of Chromatin Biochemistry, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Goettingen, Germany

    • Stefan Winter
    •  & Wolfgang Fischle
  7. Department of Experimental Therapeutics, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA

    • Cheng-Yu Tsai
    •  & William Plunkett
  8. Department of Chemical Biology/Protein Chemistry, Leibniz-Institut für Molekulare Pharmakologie (FMP), Robert-Roessle-Strasse 10, 13125 Berlin, Germany

    • Dirk Schwarzer
  9. Computational Medicine Center, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA

    • Bruce Aronow
  10. Department of Biological Sciences, Stanford University, Stanford, California 94305, USA

    • Or Gozani
  11. Center for Molecular Medicine and Graduate Institute of Cancer Biology, China Medical University and Hospital, Taichung 404, Taiwan

    • Mien-Chie Hung


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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.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Dinshaw J. Patel or Michelle Craig Barton.

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