The crystal structure of the ING5 PHD finger in complex with an H3K4me3 histone peptide

Abstract

Chromatin dynamics regulates diverse nuclear processes and influences cellular viability and tumorigenesis. The discrete chromatin states are linked to covalent histone modifications that control the extent of DNA accessibility to transacting factors. One of the most common epigenetic modifications is methylation of histone H3 at lysine 4 (H3K4). Lys4 can be mono-, di-, or tri-methylated, and the tri-methylated mark (H3K4me3) is normally associated with euchromatin and active gene transcription.1,2 The inhibitor of growth (ING) family of tumor suppressors contain a C-terminal plant homeodomain (PHD) finger. This conserved zinc-binding module is found in many nuclear proteins including transcription factors, histone modifying enzymes, and ATP dependent chromatin remodeling complexes.3-5 A subset of PHD fingers has recently been shown to bind methylated and unmodified histone tails,5-9 with the H3K4me3 mark being specifically recognized by ING proteins. Unlike ING1 and ING2, which have been identified as components of histone deacetylase (HDAC) complexes, ING5 associates with histone acetyltransferase (HAT) complexes containing MOZ (monocytic leukemia zinc finger protein)/MORF (MOZ-related factor) and HBO1.10 To establish the structural basis of chromatin targeting by the HAT associated ING proteins, we determined the crystal structure of the ING5 PHD finger in complex with its histone target (H3K4me3). We also measured binding affinities for unmodified, mono-, di-, and tri-methylated histone peptides, and showed that both full-length ING5 and methylated H3K4 are essential for the acetyltransferase activity of the MOZ/MORF and HBO1 complexes. This functional data are the first direct evidence supporting the critical role of ING5 in directing the MOZ/MORF and HBO1 complexes to chromatin, which consequently increases the local HAT activity and stimulates chromatin remodeling.