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

Abstract

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.

Detection of novel mRNA splice variants of human ING4 tumor suppressor gene

“…The NLS1 domain is responsible for ING4 nuclear localization and interaction with p53 Zhang et al, 2005). The PHD domain, a zinc finger motif present in many nuclear proteins (Bienz, 2006), is involved in interaction with HPH-2 (Ozer et al, 2005) and H3K4me2/3 (Pena et al, 2006;Shi et al, 2006), thus linking ING4 to regulation of gene expression. A deletion mutant lacking the C-terminal 40 amino acids, including the PHD domain, is unable to interact with p65, thus abrogating the inhibitory effect of ING4 on NF-kB activity (Garkavtsev et al, 2004).…”

“…Our data are in keeping with previous study showing that the deletion of the last 40 amino acids abrogates the effect of ING4 on NF-kB activa tion. Interestingly, the region lacking in ING4-DEx6A contains the PHD domain, involved in the binding to HPH-2, and H3K4me2/3 (Ozer et al, 2005;Pena et al, 2006;Shi et al, 2006). Thus, alternative splicing producing ING4-DEx6 variants could impair some important functions of ING4 and modulate its contribution to specific pathways.…”

“…In a recent report the ING PHD domain has been shown capable to interact with histone H3 di-or tri-methylated at lysine 4 (H3K4me2/3). In particular, with respect to ING2, such interaction results in gene repression (Pena et al, 2006;Shi et al, 2006).…”

“…More recently, ING4 has been shown to interact with HIF-associated prolyl hydroxylase (HPH)-2, and to regulate the activity of the hypoxia-inducible factor (HIF)-1a transcription factor, thus suppressing the expression of HIF-1a responsive genes under hypoxic conditions (Ozer et al, 2005). The interaction with HPH-2 requires the ING4 PHD domain; interestingly, such domain has been recently shown involved in the association with histone H3K4me2/3 (Pena et al, 2006;Shi et al, 2006).…”

The vitamin D receptor in cancer

“…The apo and holo nuclear receptor complexes initiate specific and coordinated histone modifications (69,70) to govern transcriptional responsiveness of the promoter. There is good evidence that specific histone modifications also determine the assembly of transcription factors on the promoter and control individual promoter transcriptional responsiveness (71)(72)(73) . It is less clear to what extent nuclear receptors recognize basal histone modifications on target gene promoters; functional studies of the SANT motif contained in the co-repressor NCoR2/SMRT support this latter idea (74) .…”