1. Department of Biological Sciences, Stanford University, and
2. Department of Medicine, Stanford University School of Medicine, Stanford, California 94305, USA
3. Department of Pharmacology, University of Colorado Health Sciences Center, Aurora, Colorado 80045, USA
4. Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA
5. Huntsman Cancer Institute and Department of Oncological Sciences, University of Utah, Salt Lake City, Utah 84112, USA
6. Laval University Cancer Research Center, Quebec City, Quebec G1R 2J6, Canada
7. Geriatric Research, Education and Clinical Center, VA Palo Alto Health Care System, Palo Alto, California 94304, USA

Correspondence to: Or Gozani¹ Correspondence and requests for materials should be addressed to O.G. (Email: ogozani@stanford.edu).

Abstract

Dynamic regulation of diverse nuclear processes is intimately linked to covalent modifications of chromatin^{1, 2}. Much attention has focused on methylation at lysine 4 of histone H3 (H3K4), owing to its association with euchromatic genomic regions^{3, 4}. 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 molecules⁵. 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 complex⁶, 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.

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