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.
Nature. 2010 Dec 16;468(7326):927-32. 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.
特定结构域内的“读取器”蛋白对修饰组蛋白的识别在基因表达调控中起着关键作用。同时识别具有多个标记的组蛋白的读取器可以将复杂的染色质修饰模式转化为特定的生物学结果。在这里，我们报告说，染色质调节剂三基序蛋白 24（TRIM24）在人类中作为双重组蛋白标记的读取器发挥作用，其通过串联植物同源结构域（PHD）和溴结构域（Bromo）区域实现。TRIM24 的 PHD-Bromo 区域的三维结构揭示了单个功能单元，用于组合识别同一组蛋白尾部中的未修饰的 H3K4（即赖氨酸 4 未修饰的组蛋白 H3，H3K4me0）和乙酰化的 H3K23（赖氨酸 23 乙酰化的组蛋白 H3，H3K23ac）。TRIM24 结合染色质和雌激素受体以激活与细胞增殖和肿瘤发展相关的雌激素依赖性基因。TRIM24 的异常表达与乳腺癌患者的生存呈负相关。TRIM24 的 PHD-Bromo 为通过非典型组蛋白特征进行染色质激活提供了结构基础，为染色质读取器可能影响癌症发病机制的新途径奠定了基础。
