An epigenetic road map for histone lysine methylation

Abstract

Histone N-termini (tails) undergo diverse post-translational modifications,including acetylation, phosphorylation, methylation, ubiquitination and ADP-ribosylation (van Holde,1988; Wolffe,1998). The discoveries of enzymes that perform these modifications and of chromatin-associated proteins that selectively bind to position-specific histone modifications(Strahl and Allis, 2000; Jenuwein and Allis, 2001)reveals that modified histone N-termini can significantly extend the information potential of the genetic code. Moreover, they appear to index chromatin regions, facilitating epigenetic control, lineage commitment and the overall functional organisation of chromosomes.FIG1Acetylation (Roth et al.,2001) and arginine methylation(Stallcup, 2001) have been linked mainly with transcriptional stimulation. Phosphorylation(Cheung et al., 2000a) instead is a marker for activation of immediate early genes and a signal for mitotic chromatin condensation. Here, we focus on histone lysine methylation. The roles of acetylation, phosphorylation and methylation are summarized in Table 1, and discussion of the interplay between these distinct modifications can be found elsewhere(Zhang and Reinberg, 2001; Berger, 2002; Kouzarides, 2002).At least five methylatable lysine positions exist in the N-termini of histones H3 (K4, K9, K27, K36) and H4 (K20); another occurs in the histone-fold domain of histone H3 (K79)(Feng et al., 2002; Lacoste et al., 2002; Ng et al., 2002; van Leeuwen et al., 2002). For clarity, we focus on H3-K4, H3-K9 and H3-K27 methylation to illustrate the general principles and complexities involved.The mammalian Suv39h enzymes and their S. pombe homologue, Clr4,were the first histone lysine methyltransferases (HMTases) identified(Rea et al., 2000). The conserved SET-domain of the Su(var)3-9-related HMTases catalyzes the methylation of H3-K9, creating a high-affinity binding site for the chromodomain of heterochromatin protein 1 (HP1) proteins(Lachner and Jenuwein, 2002). Other methylatable lysine positions might also be marked by position-specific SET-domain HMTases for methyl-binding chromodomain proteins. The human and mouse genomes each encode ≥50 predicted SET-domain proteins(Kouzarides, 2002) and ≥30 chromodomain-containing sequences (A. Schleiffer and F. Eisenhaber, personal communication). By contrast, S. pombe has only ∼10 putative SET domain HMTases, and S. cerevisiae has not more than seven(Briggs et al., 2001). Lysine residues are mono-, di- and tri-methylated in vivo(Paik and Kim, 1971; van Holde, 1988; Waterborg, 1993). A progressive conversion towards tri-methylation could contribute to the apparent stability of histone lysine methylation and is ideally suited to imparting additional layers of combinatorial control, which might allow both short-term and long-term chromatin imprints.The poster shows the dynamic cycle of histone lysine methylation in transcriptional stimulation or repression. `Exit routes' from this cycle reveal more extended reprogramming of the chromatin structure – for example, during cellular senescence, Polycomb-mediated transcriptional memory,X chromosome inactivation and constitutive heterochromatin formation. In this`road map', the various destinations for a chromatin region are indicated by road signs that reflect distinct methylation positions and states.In euchromatic regions, binding of transcription factors to specific promoter/enhancer sequences is the initiating step in altering a naive chromatin template. If positively acting complexes prevail, promoter-proximal nucleosomes sequentially adopt an activation-specific modification profile(Urnov and Wolffe, 2001; Zhang and Reinberg, 2001; Berger, 2002; Daujat et al., 2002). Fully activated promoters appear to be enriched in tri-methylated H3-K4(Santos-Rosa et al., 2002);basal transcription correlates with H3-K4 dimethylation, although the methylation potential of the HMTases involved needs to be defined(Briggs et al., 2001; Nishioka et al., 2002a; Wang et al., 2001a; Santos-Rosa et al., 2002).H3-K9 methylation, by contrast, is present mainly in silenced chromatin domains (Noma et al., 2001; Litt et al., 2001), and the`activated genome' of S. cerevisiae exhibits abundant H3-K4 methylation but lacks apparent H3-K9 di-methylation(Briggs et al., 2001). Recruitment of several H3-K9-specific HMTases induces gene repression within euchromatin (Tachibana et al.,2001; Nielsen et al.,2001; Vandel et al.,2001; Ogawa et al.,2002; Schultz et al.,2002; Tachibana et al.,2002; Yang et al.,2002). G9a and a closely related enzyme appear to be euchromatic HMTases that form complexes with HP1γ and a subset of E2F transcription factors (Ogawa et al., 2002). These enzymes might, by default, repress target promoters that fail to recruit additional activating complexes.In proliferating cells and for G9a-mediated in vivo methylation, the repressive signal appears to be primarily H3-K9 di-methylation(Tachibana et al., 2002) (A. H. Peters, S. Kub