TRIM24 links a non-canonical histone signature to breast cancer

• Published in: Nature (London) 2010-12, Vol.468 (7326), p.927-932
• Main Authors: Patel, Dinshaw J, Barton, Michelle Craig, Tsai, Wen-Wei, Wang, Zhanxin, Yiu, Teresa T, Akdemir, Kadir C, Xia, Weiya, Winter, Stefan, Tsai, Cheng-Yu, Shi, Xiaobing, Schwarzer, Dirk, Plunkett, William, Aronow, Bruce, Gozani, Or, Fischle, Wolfgang, Hung, Mien-Chie
• Format: Article
• Language: English
• Subjects: 631/45; 692/699/67/1347; Acetylation; Biological and medical sciences; Breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Carrier Proteins - chemistry; Carrier Proteins - genetics; Carrier Proteins - metabolism; Cell Line, Tumor; Chromatin; Chromatin - metabolism; Chromatin Assembly and Disassembly; Crystallography, X-Ray; Development and progression; Estrogen Receptor alpha - metabolism; Estrogens - metabolism; Gene expression; Gene Expression Regulation, Neoplastic - genetics; Genetic aspects; Gynecology. Andrology. Obstetrics; Health aspects; HEK293 Cells; Histones; Histones - chemistry; Histones - metabolism; Humanities and Social Sciences; Humans; Mammary gland diseases; Medical sciences; Methylation; multidisciplinary; Physiological aspects; Protein Array Analysis; Protein Binding; Protein Structure, Tertiary; Proteins; Science; Science (multidisciplinary); Structure; Substrate Specificity; Survival Rate; Tumors
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature09542

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. TRIM24 links histone code to breast cancer The post-translational modification of histones is a crucial mechanism in the regulation of gene expression. The modifications occur in combinations that must be faithfully translated by histone reader proteins. A study of the crystal structure of the transcription and chromatin regulator TRIM24 shows it to be a unique histone reader capable of combinatorial recognition of dual marks on the histone H3 tail. TRIM24 is involved in activation of oestrogen-dependent genes and is aberrantly expressed in breast cancer, and this work establishes a new route by which chromosome readers may influence carcinogenesis. A crystal structure of the tandem PHD and bromodomain regions of the transcription and chromatin regulator TRIM24 reveals combinatorial recognition of dual marks on the histone H3 tail. TRIM24 is involved in activation of oestrogen-dependent genes and is aberrantly expressed in breast cancer.