ING2 PHD domain links histone H3 lysine 4 methylation to active gene repression

• Published in: Nature 2006-07, Vol.442 (7098), p.96-99
• Main Authors: Gozani, Or, 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
• Format: Article
• Language: English
• Subjects: Amino Acid Motifs; Biological and medical sciences; Biomedical research; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Chromatin; Chromatin - metabolism; Deoxyribonucleic acid; DNA; DNA damage; Environmental Sciences; Fundamental and applied biological sciences. Psychology; Gene expression; Gene Silencing; Genomics; Histone Deacetylases - metabolism; Histones - chemistry; Histones - metabolism; Homeodomain Proteins - chemistry; Homeodomain Proteins - genetics; Homeodomain Proteins - metabolism; Humanities and Social Sciences; letter; Life Sciences; Lysine - metabolism; Methylation; Molecular and cellular biology; Molecular biology; multidisciplinary; Protein Binding; Protein Structure, Tertiary; Science; Science (multidisciplinary); Substrate Specificity; Tumor Suppressor Proteins - chemistry; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism; Tumors
• ISSN: 0028-0836; 1476-4687; 1476-4679
• DOI: 10.1038/nature04835

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.