SET7/9 mediated methylation of non-histone proteins in mammalian cells

New England Biolabs Inc, Ipswich, MA, USA.
Epigenetics: official journal of the DNA Methylation Society (Impact Factor: 4.78). 09/2009; 4(6):383-7. DOI: 10.4161/epi.4.6.9450
Source: PubMed


Lysine methylation has emerged as a major posttranslational modification for histones in eukaryotes. Crosstalk between lysine methylation and other posttranslational modifications is crucial for transcriptional gene regulation and epigenetic inheritance. In addition to histones, several other cellular proteins including transcription factors, tumor suppressor and membrane-associated receptors are subject to lysine methylation. SET7/9 plays a prominent role in lysine methylation of histone and non-histone proteins. Recent reports have suggested a new mechanism of epigenetic gene regulation via SET7/9 modulated DNMT1 methylation. In this mechanism, SET7/9 may methylate DNMT1 leading to proteasome mediated protein degradation, and antagonist lysine specific demethylase (LSD), may prevent this degradation by removing the methyl mark. Thus a fine-tuning and balance between cellular SET7/9 and LSD interaction with DNMT1 may be means for epigenetic gene regulation.

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    • "These post-translational modifications can occur in an exclusive or combined manner, and may reinforce or diminish the potential of PGC-1a to co-activate transcription under diverse metabolic conditions (Cantó and Auwerx, 2009), resulting in defective control of multiple transcriptional networks (Lerin et al., 2006; Li et al., 2007; Teyssier et al., 2005). On the other hand, lysine methylation by the histone mono-methyltransferase SET7/9, and lysine demethylation by the Lysine Specific Demethylase 1 (LSD1), have been shown to play an important role in non-histone proteins such as p53 and DNMT1 (Chuikov et al., 2004; Estè ve et al., 2009; Nicholson and Chen, 2009; Pradhan et al., 2009; Wang et al., 2009). Chemical modification also occurs on RNA, functioning as a sensor of the metabolic status to influence gene regulatory networks at the epigenetic level (Towns and Begley, 2012). "
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    ABSTRACT: The Peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1α) is a transcriptional co-activator that plays a central role in adapted metabolic responses. PGC-1α is dynamically methylated and unmethylated at the residue K779 by the methyltransferase SET7/9 and the Lysine Specific Demethylase 1A (LSD1), respectively. Interactions of methylated PGC-1α[K779me] with the Spt-Ada-Gcn5-acetyltransferase (SAGA) complex, the Mediator members MED1 and MED17, and the NOP2/Sun RNA methytransferase 7 (NSUN7) reinforce transcription, and are concomitant with the m5C mark on enhancer RNAs (eRNAs). Consistently, loss of Set7/9 and NSun7 in liver cell model systems resulted in depletion of the PGC-1α target genes Pfkl, Sirt5, Idh3b, and Hmox2, which was accompanied by a decrease in the eRNAs levels associated with these loci. Enrichment of m5C within eRNA species coincides with metabolic stress of fasting in vivo. Collectively, these findings illustrate the complex epigenetic circuitry imposed by PGC-1α at the eRNA level to fine-tune energy metabolism.
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    • "Set7 is a KMT that was initially identified as a monomethylase of histone H3 lysine 4 (H3K4) in vitro (Wang et al., 2001). However , because Set7 is unable to methylate nucleosomes at H3K4 (Chuikov et al., 2004) and Setd7 À/À mouse embryonic fibroblasts (MEFs) have normal levels of H3K4 methylation (Lehnertz et al., 2011), it is more likely that the primary role for Set7 is methylation of nonhistone substrates (Pradhan et al., 2009). Indeed, Set7 has been shown to methylate and alter function of a wide variety of proteins including Dnmt1, Taf10, p53, Stat3, and NF-kB in vitro (Chuikov et al., 2004; Ea and Baltimore, 2009; Estè ve et al., 2009; Kouskouti et al., 2004; Kurash et al., 2008; Yang et al., 2009, 2010a, 2010b). "
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    ABSTRACT: Methylation of nonhistone proteins is emerging as a regulatory mechanism to control protein function. Set7 (Setd7) is a SET-domain-containing lysine methyltransferase that methylates and alters function of a variety of proteins in vitro, but the in vivo relevance has not been established. We found that Set7 is a modifier of the Hippo pathway. Mice that lack Set7 have a larger progenitor compartment in the intestine, coinciding with increased expression of Yes-associated protein (Yap) target genes. Mechanistically, monomethylation of lysine 494 of Yap is critical for cytoplasmic retention. These results identify a methylation-dependent checkpoint in the Hippo pathway.
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    • "HKMT7 contains only one protein, Set7/9, which monomethylates histone at H3-K4 [68]. Set7/9 methylates also non-histone proteins, including p53, DNA methyltransferase 1 (DNMT1), nuclear factor kappa B (NFkB) and nuclear hormone estrogen receptor alpha (ER) [59]. HKMT8 includes only one member, RIZ1. "
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    ABSTRACT: Epigenetics is defined as heritable changes in gene activity and expression that occur without alteration in DNA sequence. The gene transcription is strictly correlated to chromatin structure, which could undergo to covalent modifications of histones involving acetylation, methylation, phosphorylation and ubiquitination. Alterations in histones are implicated in many diseases, included cancer, by leading to tumor suppressor silencing or pro-apoptotic proteins downregulation. Although post-translational addition of methyl groups to the histone lysine has been discovered three decades ago, the importance of this epigenetic modification is emerging only in the last few years. Thenceforward histone methyltransferase inhibitors have been developed as potential therapeutic cancer agents. It should not be long before some selective inhibitors make their way into clinical trials. This review is mainly focused on the evolution in the development of new epigenetic modifier molecules modulating histone marks.
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