Methylation: lost in hydroxylation?

Abstract

Methylation of histone tails is a key determinant in forming active and silent states of chromatin. Histone methylation was regarded as irreversible until the recent identification of a lysinespecific histone demethylase (LSD1), which acts specifically on mono-and dimethylated histone H3 lysine 4. Here, we propose that the fission yeast protein Epe1 is a putative histone demethylase that could act by oxidative demethylation. Epe1 modulates the stability of silent chromatin and contains a JmjC domain. The Epe1 protein can be modelled onto the structure of the 2-oxoglutarate-Fe(II)-dependent dioxygenase, factor inhibiting hypoxia inducible factor (FIH), which is a protein hydroxylase that also contains a JmjC domain. Thus, Epe1 and certain other chromatin-associated JmjC-domain proteins may be protein hydroxylases that catalyse a novel histone modification. Another intriguing possibility is that, by hydroxylating the methyl groups, Epe1 and certain other JmjC-domain proteins may be able to demethylate mono-, di-or trimethylated histones.

Roles of jumonji and jumonji family genes in chromatin regulation and development

“…Recent structure analysis of jmjC of HIF1AN/FIH, which has a 2-oxoglutarate (2-OG)-Fe(II)-dependent dioxygenase activity, revealed residues binding to the cofactors 2-OG and Fe(II), and showed that the domain contains a doublestranded ␤-helix motif (Elkins et al, 2003). A sequence alignment of the jmjC domains of various jumonji family proteins suggested that these features are conserved (Elkins et al, 2003;Trewick et al, 2005). Recently, one jumonji family protein, FBXL11/ JHDM1A was shown to be a 2-OGFe(II)-dependent histone demethylase .…”

“…Recently, one jumonji family protein, FBXL11/ JHDM1A was shown to be a 2-OGFe(II)-dependent histone demethylase . The alignment of sequences for the dendrogram was made by taking previously predicted conservative residues such as cofactor binding sites (Clissold et al, 2001;Trewick et al, 2005; SMART and Pfam databases; Fig. 2).…”

“…HIF1AN/FIH and FBXL11/ JHDM1A catalyze protein hydroxylation and histone demethylation, respectively, through the dioxygenase activity (Hewitson et al, 2002;Tsukada et al, 2006). In addition, the structure of jmjC involved in the enzymatic activity appears to be conserved in many members (Trewick et al, 2005; Fig. 2).…”

“…Many jumonji family proteins have domains involved in DNA binding, chromatin binding, or transcription, such as ARID (Kortschak et al, 2000;Wilsker et al, 2005), PHD finger (Bienz, 2006), or Zn-fingers, and jmjC domains showing metalloenzyme-like structures, suggesting that jumonji family proteins regulate transcription or chromatin function or both (Balciunas and Ronne, 2000;Clissold and Ponting, 2001;Trewick et al, 2005).…”

“…In this figure, only human proteins are shown as examples. Asterisks and # mark the Fe (II) and 2-OG binding residues, respectively (predicted; Trewick et al, 2005), of which identical residues with HIF1AN/FIH are highlighted with a red background. Residues that the frequency of the most common residue is Ն 0.5 or the frequency of the most common group of similar residues (Dayhoff et al, 1979) is Ն 0.7 are highlighted with a blue background.…”