Shi Xiaobing, Hong Tao, Walter Kay L, Ewalt Mark, Michishita Eriko, Hung Tiffany, Carney Dylan, Peña Pedro, Lan Fei, Kaadige Mohan R, Lacoste Nicolas, Cayrou Christelle, Davrazou Foteini, Saha Anjanabha, Cairns Bradley R, Ayer Donald E, Kutateladze Tatiana G, Shi Yang, Côté Jacques, Chua Katrin F, Gozani Or
Department of Biological Sciences, Stanford University, Stanford, California 94305, USA.
Nature. 2006 Jul 6;442(7098):96-9. doi: 10.1038/nature04835. Epub 2006 May 21.
Dynamic regulation of diverse nuclear processes is intimately linked to covalent modifications of chromatin. Much attention has focused on methylation at lysine 4 of histone H3 (H3K4), owing to its association with euchromatic genomic regions. H3K4 can be mono-, di- or tri-methylated. Trimethylated H3K4 (H3K4me3) is preferentially detected at active genes, and is proposed to promote gene expression through recognition by transcription-activating effector molecules. Here we identify a novel class of methylated H3K4 effector domains--the PHD domains of the ING (for inhibitor of growth) family of tumour suppressor proteins. The ING PHD domains are specific and highly robust binding modules for H3K4me3 and H3K4me2. ING2, a native subunit of a repressive mSin3a-HDAC1 histone deacetylase complex, binds with high affinity to the trimethylated species. In response to DNA damage, recognition of H3K4me3 by the ING2 PHD domain stabilizes the mSin3a-HDAC1 complex at the promoters of proliferation genes. This pathway constitutes a new mechanism by which H3K4me3 functions in active gene repression. Furthermore, ING2 modulates cellular responses to genotoxic insults, and these functions are critically dependent on ING2 interaction with H3K4me3. Together, our findings establish a pivotal role for trimethylation of H3K4 in gene repression and, potentially, tumour suppressor mechanisms.
多种核过程的动态调控与染色质的共价修饰密切相关。由于其与常染色质基因组区域相关联，组蛋白H3赖氨酸4位点（H3K4）的甲基化受到了广泛关注。H3K4可发生单甲基化、二甲基化或三甲基化。三甲基化的H3K4（H3K4me3）优先在活跃基因处被检测到，并被认为通过转录激活效应分子的识别来促进基因表达。在此，我们鉴定出一类新型的甲基化H3K4效应结构域——肿瘤抑制蛋白ING（生长抑制因子）家族的PHD结构域。ING PHD结构域是H3K4me3和H3K4me2特异性且高度稳定的结合模块。ING2是抑制性mSin3a - HDAC1组蛋白去乙酰化酶复合物的天然亚基，它与三甲基化形式具有高亲和力结合。在DNA损伤应答中，ING2的PHD结构域对H3K4me3的识别可使mSin3a - HDAC1复合物在增殖基因的启动子处稳定。该途径构成了H3K4me3在活跃基因抑制中发挥作用的一种新机制。此外，ING2调节细胞对基因毒性损伤的应答，且这些功能严重依赖于ING2与H3K4me3的相互作用。总之，我们的研究结果确立了H3K4三甲基化在基因抑制以及潜在的肿瘤抑制机制中的关键作用。
