Cooperative binding of two acetylation marks on a histone tail by a single bromodomain. Structure and function of a human TAFII250 double bromodomain module. PHD fingers in human diseases: disorders arising from misinterpreting epigenetic marks. The complex language of chromatin regulation during transcription. Multivalent engagement of chromatin modifications by linked binding modules. How chromatin-binding modules interpret histone modifications: lessons from professional pocket pickers. 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. Aberrant expression of TRIM24 negatively correlates with survival of breast cancer patients. TRIM24 binds chromatin and oestrogen receptor to activate oestrogen-dependent genes associated with cellular proliferation and tumour development. 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. 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. Readers that simultaneously recognize histones with multiple marks allow transduction of complex chromatin modification patterns into specific biological outcomes. Recognition of modified histone species by distinct structural domains within ‘reader’ proteins plays a critical role in the regulation of gene expression.
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