TRIM24 links a non-canonical histone signature to breast cancer

Abstract

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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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.

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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.

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Acknowledgements

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.

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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.

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Correspondence to Dinshaw J. Patel or Michelle Craig Barton.

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Tsai, WW., Wang, Z., Yiu, T. et al. TRIM24 links a non-canonical histone signature to breast cancer. Nature 468, 927–932 (2010). https://doi.org/10.1038/nature09542

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