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Histone methylation is now considered a more dynamic modification with the discovery of Histone demethylases. Removal of methyl groups is mediated by LSD1, PAD14 and JmjC domain containing proteins.
Histone methylation at lysine and arginine residues has been linked to a number of cellular processes including DNA repair, replication, transcriptional activation and repression (Kouzarides, 2007). Arginine residues can accept one or two methyl groups, the latter in a symmetric or asymmetric conformation (Rme1, Rme2s, Rme2a). Lysine residues can be labelled with one, two or three methyl groups (Kme1, Kme2, Kme3). Histone methylation was regarded as a more permanent mark compared to other histone modifications such as acetylation or phosphorylation (Bannister et al., 2002). But with the discovery of novel histone demethylases it is now considered a more dynamic modification.
Figure 1: JHDM1a / FBXL11 antibody (ab27867).
It was proposed that reversal of arginine methylation might be catalyzed by deiminases (Bannister et al., 2002). Members of the peptidyl arginine deiminase family deiminate arginine residues by converting them into citrulline (Nakashima et al., 2002). PADI4 is a member of this family and localizes to the nucleus. Therefore it was hypothesized that it may deiminate histones (Cuthbert et al., 2004; Wang et al., 2004). Incubation of PADI4 with bulk histones results in an increase in citrullination on H3 and H4. Furthermore PADI4 can target arginines found within these histones in either the me1 or unmodified state (Figure 1).
Histone citrullination has been linked to estrogen regulated transcription of the pS2 promoter where gene activity is regulated in a cyclic fashion. After the initial increase in transcription, a decrease in arginine methylation is observed as RNA polymerase II drops away from the promoter (Bauer et al., 2002; Metivier et al., 2003). This correlates with an increase in both PADI4 recruitment and citrullination. Therefore, citrullination may antagonize arginine methylation. The removal of methyl groups from arginine may directly repress transcription, or the conversion may indicate that citrullination is a repressive modification. Arguably, PADI4 does not complete full demethylation as it converts methyl-arginine to citrulline rather than an unmodified arginine. Therefore further processing by histone replacement or aminotransferases will be needed for complete demethylation (Bannister et al., 2002).
Levels of lysine methylation are known to change during processes such as transcriptional regulation. Therefore it was proposed that specific enzymatic activity might remove the methyl groups (Bannister et al., 2002). Indeed recent work has confirmed the existence of enzymatic demethylation and two separate mechanisms of lysine demethylation have been demonstrated (Figure 2). Amine oxidation by LSD1 and hydroxylation by JmjC-domain containing proteins are novel histone modifying enzymes that can remove methyl groups on lysines (Shi et al., 2004; Tsukada et al., 2006).
Figure 2: PADI4-schematic. Deimination of mono-methyl (me1) arginine and (b) non-methylated arginine into citrulline.
Figure 2: Mechanisms of lysine demethylation by LSD1 and JHDM. (a) LSD1 demethylates H3K4me2/me1 via an amine oxidation reaction using FAD as a cofactor. The imine intermediate is hydrolyzed to an unstable carbinolamine that spontaneously degrades to release formaldehyde. (b) The JHDM proteins use alpha ketoglutarate and iron (Fe) as cofactors to hydroxylate the methylated substrate. Fe(II) in the active site, activates a molecule of dioxygen to form a highly reactive oxoferryl (Fe(IV)=O) species to react with the methyl group. The resulting carbinolamine spontaneously degrades to release formaldehye.
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