H4 Arg-3 methyltransferase

a nuclear receptor coactivator, exists as in a 330 kDa complex and is a H4 Arg-3 methyltransferase [133,215]. The enzyme appears to be a chromatin bound, and evidence from immunodepletion and knockout studies suggest that it is the principle, if not sole, H4 Arg-3 methyltransferase [133,215]. Mutation of the S-adenosyl methionine binding site in PRMTl annihilated its nuclear receptor coactivator activity with the androgen receptor, providing evidence for the importance of the methylation event in gene expression [215]. Yeast Rmtl, which is homologous to human PRMTl, methylates Arg-3 only in free H4 [208]. 

a member of the trithorax group of epigenetic activators, methylates H3 at Lys-4 and Lys-9 and H4 at Lys-20. Ashl is a SET domain protein that contains both pre- and post-SET domains [216]. 

Acetylated isoforms of H3 and H4 are often the targets of ongoing methylation [126,150,151,217,218]. In chicken immature erythrocytes, rapidly acetylated and deacetylated H3 and H4 are selectively methylated, while in Hela cells dynamically acetylated H3, but not H4, is methylated [150,219,220]. H4 that is slowly acetylated and deacetylated is methylated in HeLa [150]. Acetylated yeast H3 was preferentially methylated at Lys-4 [138]. These studies suggested that the processes of histone methylation and dynamic acetylation are not directly coupled, with neither modification predisposing H3 or H4 to the other [138,220]. 

In vitro studies with unmodified and modified N-terminal peptides of H3 demonstrated that Lys-14 acetylation did not interfere with methylation at Lys-9 by Suv39hl, while phosphorylation at Ser-10 and acetylation at Lys-9 did (Fig. 7). Further dimethylation of Lys-9 reduced enzymatic activity [186], A Suv39h double null primary mouse embryonic fibroblasts had higher levels of Ser-10 phos-phorylated H3 than wild type cells. These mutant cells had increased numbers of micro- and polynuclei. Oversized nuclei were characteristic of subpopulation of cells. The level of Lys-9 methylated FI3 in wild type cells and Suv39h double null cells was similar, demonstrating that other FI3 methyltransferases were involved [195]. Phosphorylation of Ser-10 by Ipll/aurora was also studied. Acetylation at Lys-14 promoted the activity of the mitotic kinase, while dimethylation, but not acetylation at Lys-9, reduced activity of the kinase [186]. 

The unmodified and Lys-9 methylated FI3 tail binds specifically to the HDAC complex NuRD. Methylation at Lys-4 prevents this interaction. A H3 tail methylated at Lys-9 does not affect activity of mammalian Set9. Methylation at Lys-4 does not alter activity of G9a, but does prevent the tail being a substrate for Suv39hl [198]. 

---