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    • br H AZ lysine methylation The

    2018-11-06


    H2AZ lysine methylation The lysine methyltransferases SETD6 and SET7 efficiently methylate H2AZ in vitro (Binda et al., 2013). In particular, a detailed study clearly identified lysine 7 as the preferred site of methylation by SETD6 on H2AZ. This result was confirmed by mass spectrometric analysis and it also specified that H2AZ is monomethylated at lysine 7 (H2AZK7me1) (Binda et al., 2013). Interestingly, the amino terminal tail of H2AZ is monomethylated on both lysines 4 and 7 (H2AZK4me1K7me1) in vivo (Binda et al., 2013). Strikingly, upon induction of cellular differentiation using retinoic TAPI-1 (RA), global levels of H2AZK4me1K7me1 increased by several folds in E14 mouse ES (mES) cells (Binda et al., 2013). However, the levels of SETD6 appear to lessen following the RA treatment (Binda et al., 2013), suggesting that perhaps SETD6 enzymatic activity is increased despite the lower amounts of SETD6 transcripts. SETD6 is ubiquitinated at the carboxy terminus within the substrate binding domain at lysine 441 (Kim et al., 2011). Therefore, ubiquitination of SETD6 could hypothetically regulate its methyltransferase activity or substrate specificity. Alternatively, SET7, or other KMTs, could also be responsible for the increased H2AZ methylation in differentiating E14 mES cells. Interestingly, the silencing of SETD6 in mES cells resulted in cellular differentiation, compromised self-renewal, and showed poor clonogenicity capacity (Binda et al., 2013). Since the methylation of H2AZK4 and H2AZK7 blocks the acetylation at those sites and the H2AZK4me1K7me1 and H2AZac marks are mutually exclusive (Binda et al., 2013), we propose that H2AZK4me1K7me1 is a transcriptional silencing mark. Indeed, upon RA treatment in E14 mES cells, H2AZK7me1 is removed along the silencing mark H3K27me3 from the promoters of Fgf5, FoxA2, and Hand2 (Binda et al., 2013), further suggesting that H2AZK7me1 is marking chromatin for silencing. Finally, although H2AZ and H2AZK7me1 occupy some promoters where H3K27me3 is present (Binda et al., 2013), the H2AZac and H3K27me3 marks do not overlap (Valdés-Mora et al., 2012), again supporting that H2AZK7me1 is involved in negative regulation of gene expression.
    H2AZ ubiquitination As essential components of chromatin, histones present many covalent modifications. Besides acetylation and methylation, histones can also be ubiquitinated. Interestingly, H2A was actually the first ubiquitinated protein identified (Goldknopf and Busch, 1977). Reminiscent of the canonical histone H2A, which is ubiquitinated on lysine 119 (H2AK119ub) (Cao et al., 2005; Wang et al., 2004), its variant, H2AZ, is ubiquitinated at lysine 121 (H2AZK121ub) (Draker et al., 2011; Sarcinella et al., 2007), as well as K120 and K125 (Sarcinella et al., 2007), but always occurs as a mono-ubiquitinated H2AZub1 form (Sarcinella et al., 2007) (Fig. 1). Interestingly, methyl-specific antibodies directed against H2AZK7me1 detect a slow-migrating form of H2AZ that, based on its molecular weight, may potentially be ubiquitinated (Binda et al., 2013), suggesting the coexistence of H2AZK7me1 and H2AZub1. H2A is ubiquitinated by the polycomb repressive complex 1 (PRC1) subunit RING1B (Cao et al., 2005), an E3 ubiquitin ligase that is also reported to modify H2AZ at lysines 120, 121, and 125 (Sarcinella et al., 2007). The H2AZub1 mark is removed by the ubiquitin-specific peptidase USP10 (Draker et al., 2011). Cellular localisation experiments highlight that H2AZub1 is found at transcriptionally silent facultative heterochromatin on the inactive X chromosome (Sarcinella et al., 2007), suggesting that H2AZub1 is a silencing mark. Furthermore, the silencing of USP10 results in elevated levels of H2AZub1, while loss of H2AZub1 at KLK3 and PSA promoters correlates with transcriptional activation (Draker et al., 2011).
    H2AZ SUMOylation In Saccharomyces cerevisiae, the SUMOylation of Htz1 on lysines 126 and 133 plays an important role in DNA double-stranded-break by relocating the unrepaired chromosomal break to the nuclear periphery (Kalocsay et al., 2009). The very carboxy terminus of H2AZ is not well conserved with Htz1 and does not harbor the ψKxE SUMOylation motif found at Htz1K126. Interestingly, the SUMOylation of Htz1 does not happen to be conserved in mammals, whereas the ubiquitination of H2AZ appears to occur solely in mammals, suggesting that some post-translational modifications of H2AZ were lost while others were gained during evolution.