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  • Thus far it is reported that

    2021-10-18

    Thus far, it is reported that the histone methyltransferase activity of SUV39H1 is regulated through some posttranslational modifications. For example, deacetylation of SUV39H1 at Lys-266 by SIRT1 deacetylase increases SUV39H1 activity [31], and methylation of SUV39H1 at Lys-105 and Lys-123 by SET7 methyltransferase decreases SUV39H1 activity [32]. In addition, our present study implies that tyrosine phosphorylation of SUV39H1 positively affects its methyltransferase activity. Since SUV39H1 phosphorylation at Tyr-297, -303, and -308 may introduce the negative charge on the SET domain, it could strengthen the binding of SUV39H1 to its cofactor or substrate for positive regulation of SUV39H1 activity. At the moment, it remains unclear how tyrosine phosphorylation modulates SUV39H1 activity.
    Conflicts of interest
    Acknowledgements We thank Dr. H. Miyoshi and Dr. M. Tagawa for the invaluable plasmid and cells. This work was supported in part by grants-in-aid for scientific research from the MEXT, Japan (15K07922) and the scholarship donation from the Daiichi Sankyo Co., Ltd.
    Introduction In eukaryotes, the challenge of condensing 1.8 m of DNA into a cell is solved by packaging it into chromatin. Chromatin is composed of nucleosome subunits: a 147 base-pair segment of DNA wrapped around a histone octamer (two dimers of histones H2A and H2B and a tetramer of H3 and H4). The N- and C- terminal histone tails protruding from the nucleosome core are subject to extensive covalent post-translational modifications, including acetylation, phosphorylation, ubiquitination and methylation (reviewed in (Audia and Campbell, 2016)). The patterns of histone marks are established and maintained through a dynamic interplay between histone readers, writers, and erasers (Greer and Shi, 2012, Zhang et al., 2015). Distinct modifications, or combinations of modifications can directly impact on chromatin organization and also serve as SB-3CT for specific modulatory proteins. Different patterns of modifications are associated with distinct transcriptional states, resulting from tightly packaged heterochromatin versus more accessible euchromatin. Histone methylation primarily occurs on histone tails of H3 and H4. More than 60 human histone methyltransferases (HMTs) have been identified and catalyze the transfer of methyl groups from S-adenosylmethionine (SAM) to amine residues (lysines and arginines) (Table 1). The state of methylation on a given residue (mono-, di- or trimethylation) enables a precise level of biological regulation (Table 1 and Figure 1) (Audia and Campbell, 2016, Barski et al., 2007, Onder et al., 2012, Zhang et al., 2015). Lysines can be mono-methylated (me1), dimethylated (me2) or trimethylated (me3) on their ε-amine group, while arginines can be mono-methylated (me1), symmetrically dimethylated (me2s) or asymmetrically dimethylated (me2a) on their guanidinyl group (reviewed in (Greer and Shi, 2012)). Cross-talk with adjacent modifications on the same histone tail, together with the level of cytosine methylation of the underlying DNA, results in distinct transcriptional states (active, poised and silent domains) and leads to dramatically different functional consequences. Genome-wide mapping of histone marks, largely performed in human T cells, has identified distinct patterns of histone methylation in SB-3CT the enhancer and promoter regions as well as in the gene body and correlated these with gene transcription (Figure 2). However, these patterns remain incompletely defined and the literature contains conflicting reports due to gene-specific modifications, the particular cell type or organism studied, and whether or not enrichment was correlated with gene transcription at a specific locus or genome-wide. At the level of active genes, however, mono-methylation of H3K4, H3K9, H3K27, H3K36, H4K20 are generally linked to activation (Barski et al., 2007, Heintzman et al., 2007, Vakoc et al., 2006), as is di-methylation of H3K79 (Okada et al., 2005, Onder et al., 2012) and trimethylation of H3K36 (Barski et al., 2007, Vakoc et al., 2006). On the other hand, H3K27 trimethylation is linked to repression and generally co-localizes with H3K27me2 (Barski et al., 2007, Squazzo et al., 2006), and H3K79 trimethylation has been reported at the promoters of both active and repressed genes (Barski et al., 2007, Vakoc et al., 2006). While H3K9 trimethylation is generally associated with heterochromatin, supporting a role in transcriptional silencing, it has also been reported to mark actively transcribed promoters (Squazzo et al., 2006, Vakoc et al., 2006). The effect of arginine marks on chromatin is less clear, however H3R2me2s marks are generally present in euchromatic regions, while H4R3me2s is considered a mark of transcriptional repression and H3R8me2s has been associated with both transcriptional activation and repression (Koh et al., 2015). It is also of interest that H3K9 and H3K27 can be acetylated in a manner that is mutually exclusive from methylation and leads to transcriptional activation (Zhang et al., 2015). In addition, there is mutual exclusivity between the presence of H3K4me3 and H3R2me2a and the marks antagonize one another (Guccione et al., 2007, Kirmizis et al., 2007).