TRIM24 links a noncanonical histone signature to breast cancer

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 TRIM24 functions as a reader of dual histone marks via tandem Plant Homeodomain (PHD) and Bromodomain (Bromo). The three-dimensional structure of TRIM24 PHD-Bromo revealed a single functional unit for combinatorial recognition of unmodified H3K4 (H3K4me0) and acetylated H3K23 (H3K23ac) within the same histone tail. TRIM24 binds chromatin and estrogen receptor to activate estrogen-dependent genes associated with cellular proliferation and tumor 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 via a noncanonical histone signature, establishing a new paradigm by which chromatin readers may influence cancer pathogenesis.