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    • JmjC domain containing histone demethylase C JMJD C

    2018-10-24

    JmjC domain-containing histone demethylase 2C (JMJD2C) is a histone lysine demethylase (HDM) specific for histones H3K9me3, H3K9me2, and H3K36me3 (Cloos et al., 2006; Klose et al., 2006; Whetstine et al., 2006). HDMs are histone-modifying enzymes with biological functions opposite to those of HMTs. JMJD2C removes the repressive histone-methylation at the promoters of pluripotent genes in ESCs. The JMJD2C-mediated reduction of H3K9me3 levels and the resulting alteration of chromatin structure are essential for maintaining ESC pluripotency (Das et al., 2014; Loh et al., 2007; Pedersen et al., 2014). Recent studies demonstrated that JMJD2B and JMJD2C are necessary for ESC self-renewal and induce the generation of pluripotent stem prostaglandin endoperoxide synthase (Das et al., 2014; Pedersen et al., 2014). Therefore, JMJD2C acts to maintain ESC self-renewal and pluripotency by lowering H3K9me3 levels (Chen et al., 2013a; Loh et al., 2007; Ng and Surani, 2011). PR/SET domain 14 (PRDM14) plays a role in the maintenance of the core pluripotent circuitry in ESCs by reducing protein levels of the DNMT3 family (Grabole et al., 2013; Hackett et al., 2013a; Yamaji et al., 2013). PRDM14 is a key regulator in the specification of primordial germ cells (PGCs) during mouse development (Yamaji et al., 2008). PRDM14 is a PR domain-containing (PRDM) transcription factor that contains a PR domain, a modified SET domain, and six tandemly repeated zinc fingers (Nakaki and Saitou, 2014). Downregulation of the DNMT3 family by PRDM14 is important for establishing genome-wide DNA hypomethylation in 2i culture conditions (Grabole et al., 2013; Hackett et al., 2013a; Yamaji et al., 2013). The mechanism by which PRDM14 regulates DNMT3 expression remains undefined. The ten-eleven translocation (TET) family of dioxygenases promotes DNA demethylation in ESCs and PGCs (Ito et al., 2010; Koh et al., 2011; Vincent et al., 2013). The TET family converts 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine, and 5-carboxylcytosine through a series of active DNA demethylation reactions (Gu et al., 2011; Hackett et al., 2013b; Tahiliani et al., 2009). Therefore, the TET family reduces genome-wide DNA methylation through the production of unmethylated cytosine aided by thymine-DNA glycosylase (Kohli and Zhang, 2013; Shen et al., 2013). In ESCs, TET1 is highly expressed and is required for self-renewal (Ito et al., 2010). The mechanism by which 2i treatment enhances TET1 activity is not yet known.
    Results
    Discussion A recent series of findings indicated that DNA methylation in 2i ESCs correlates with H3K27me3 (Marks et al., 2012) and H3K9me3 levels (Habibi et al., 2013). JMJD2C is an HDM specific for H3K9me3, H3K9me2, and H3K36me3 (Cloos et al., 2006; Klose et al., 2006; Whetstine et al., 2006), and plays important roles in the maintenance of self-renewal and pluripotency in ESCs (Das et al., 2014; Loh et al., 2007; Pedersen et al., 2014; Wang et al., 2010). MEKi increased JMJD2C protein levels, which was accompanied with H3K9me3 reduction and downregulated Jmjd2c transcript levels, indicating the existence of a post-translational modification. Because MEK1/2 is a dual-specificity kinase (Roskoski, 2012), there must be a T-X-Y motif present in JMJD2C. We identified a T-P-Y motif in the JmjC domain. Our findings attribute the phosphorylation of full-length JMJD2C by MEK1 to the presence of the T-P-Y motif in the JmjC domain. The phosphorylation of some proteins is coupled to protein degradation through ubiquitination (Huang et al., 2012; Hunter, 2007; Swaney et al., 2013). Hence, the phosphorylation of the Y177 residue in the T-P-Y motif of JMJD2C may play a role in recruiting an unknown E3 ligase to degrade JMJD2C. MEK1 expression increased JMJD2C ubiquitination; however, MEKi suppressed JMJD2C ubiquitination. The Y177F mutant JMJD2C was less ubiquitinated than wild-type JMJD2C in the presence of MEK1. Therefore, we propose that Y177 is a phosphodegron for JMJD2C protein degradation in ESCs.