title: 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.
authors.affiliation: 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.
authors.forename: Wen-Wei
authors.initials: WW
authors.lastname: Tsai
authors.forename: Zhanxin
authors.initials: Z
authors.lastname: Wang
authors.forename: Teresa T
authors.initials: TT
authors.lastname: Yiu
authors.forename: Kadir C
authors.initials: KC
authors.lastname: Akdemir
authors.forename: Weiya
authors.initials: W
authors.lastname: Xia
authors.forename: Stefan
authors.initials: S
authors.lastname: Winter
authors.forename: Cheng-Yu
authors.initials: CY
authors.lastname: Tsai
authors.forename: Xiaobing
authors.initials: X
authors.lastname: Shi
authors.forename: Dirk
authors.initials: D
authors.lastname: Schwarzer
authors.forename: William
authors.initials: W
authors.lastname: Plunkett
authors.forename: Bruce
authors.initials: B
authors.lastname: Aronow
authors.forename: Or
authors.initials: O
authors.lastname: Gozani
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Fischle
authors.forename: Mien-Chie
authors.initials: MC
authors.lastname: Hung
authors.forename: Dinshaw J
authors.initials: DJ
authors.lastname: Patel
authors.forename: Michelle Craig
authors.initials: MC
authors.lastname: Barton
mesh_terms: D000107:Acetylation; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002843:Chromatin / Q000378:metabolism; D042002:Chromatin Assembly and Disassembly; D018360:Crystallography, X-Ray; D047628:Estrogen Receptor alpha / Q000378:metabolism; D004967:Estrogens / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D057809:HEK293 Cells; D006657:Histones / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008745:Methylation; D040081:Protein Array Analysis; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D013379:Substrate Specificity; D015996:Survival Rate
chemical_list: D002352:Carrier Proteins; D002843:Chromatin; D047628:Estrogen Receptor alpha; D004967:Estrogens; D006657:Histones; C555317:TRIM24 protein, human