Dynamics of Histone Lysine Methylation: Structures of Methyl Writers and Erasers

Department of Biochemistry, Emory University School of Medicine, 1510 Clifton Road, Atlanta, Georgia 30322, USA.
Fortschritte der Arzneimittelforschung. Progress in drug research. Progrès des recherches pharmaceutiques 01/2011; 67:107-24. DOI: 10.1007/978-3-7643-8989-5_6
Source: PubMed


In Eukarya, the packaging of DNA into chromatin provides a barrier that allows for regulation of access to the genome. Chromatin is refractory to processes acting on DNA. ATP-dependent chromatin remodeling machines and histone-modifying complexes can overcome this barrier (or strengthen it in silencing processes). Both components of chromatin (DNA and histones) are subject to postsynthetic covalent modifications, including methylation of lysines (the focus of this chapter). These lysine marks are generated by a host of histone lysine methyltransferases (writers) and can be removed by histone lysine demethylases (erasers). Importantly, epigenetic modifications impact chromatin structure directly or can be read by effector regulatory modules. Here, we summarize current knowledge on structural and functional properties of various histone lysine methyltransfereases and demethylases, with emphasis on their importance as druggable targets.

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    • "The PTHMs change the interaction of histones with DNA [28] [29]. The actions of PTHMs include: acetylation of lysine (K), methylation of K and arginine (R), phosphorylation of serine (S) and threonine (T), and ubiquitination of K [30] [31] [32]. The actions of PTHMs enzymes are responsible for the reversible remodeling of heterochromatin to euchromatin, which are respectively fundamental mechanisms of silencing or inducing gene transcription (Table 1) [33] [34]. "
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    ABSTRACT: There is growing evidence that epigenetic regulation of gene expression including post-translational histone modifications (PTHMs), DNA methylation and microRNA (miRNA)-regulation of mRNA translation could play a crucial role in the development of chronic complications. Hyperglycemia can induce an abnormal action of PTHMs and DNA methyltransferases as well as alter the levels of numerous miRNAs in endothelial cells, vascular smooth muscle cells, cardiomyocytes, retina, and renal cells. These epigenetic abnormalities result in changes in the expression of numerous genes contributing to effects such as development of chronic inflammation, impaired clearance of reactive oxygen species (ROS), endothelial cell dysfunction and/or the accumulation of extracellular matrix in the kidney, which causing the development of retinopathy, nephropathy or cardiomyopathy. Some epigenetic modifications, for example PTHMs and DNA methylation, become irreversible over time. Therefore these processes have gained much attention in explaining the long-lasting detrimental consequences of hyperglycaemia causing the development of chronic complications even after improved glycaemic control is achieved. Our review suggests that the treatment of chronic complications should focus on erasing metabolic memory by targeting chromatin modification enzymes and by restoring miRNAs levels.
    Diabetes research and clinical practice 08/2014; 105(2). DOI:10.1016/j.diabres.2014.03.019 · 2.54 Impact Factor
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    • "One crucial histone modification is histone lysine methylation (HKM) at histone H3 lysine 9 (H3K9). H3K9 can be mono-(H3K9me1), di-(H3K9me2), or tri-methylated (H3K9me3), and each modification is associated with different biological responses, i.e., gene repression and gene activation (Fuks, 2005; Greer and Shi, 2012; Upadhyay and Cheng, 2011). H3K9me3 has a silencing effect on genes and repeat sequences , including endogenous proviruses (Matsui et al., 2010). "
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    ABSTRACT: Histone lysine methylation (HKM) is an epigenetic change that establishes cell-specific gene expression and determines cell fates. In this study, we investigated the expression patterns of histone H3 lysine 9 methyltransferases (H3K9MTases) G9a (euchromatic histone lysine N-methyltransferase 2, Ehmt2), GLP (euchromatic histone lysine N-methyltransferase 1, Ehmt1), SETDB1 (SET domain, bifurcated 1), PRDM2 (PR domain containing 2), SUV39H1 (suppressor of variegation 3-9 homolog 1), and SUV39H2, as well as the distribution of 3 types of HKM at histone H3 lysine 9:mono- (H3K9me1), di- (H3K9me2), or tri-methylation (H3K9me3), during mouse growth plate development. In the forelimb cartilage primordial at embryonic day 12.5 (E12.5), none of the H3K9MTases were detected and H3K9me1, H3K9me2, and H3K9me3 were scarcely detected. At E14.5, the H3K9MTases were expressed at low levels in proliferating chondrocytes and at high levels in prehypertrophic and hypertrophic chondrocytes. Among the H3K9 methylations, H3K9me1 and H3K9me3 were markedly noted in these chondrocytes. At E16.5, G9, GLP, SETDB1, PRDM2, SUV39H1, and SUV39H2, as well as H3K9me1, H3K9me2, and H3K9me3, were detected in prehypertrophic and hypertrophic chondrocytes in the growth plate. Western blotting and real-time quantitative polymerase chain reaction analysis revealed the distributions of G9 and GLP proteins and the expression of all the H3K9MTase mRNAs in prehypertrophic and hypertrophic chondrocytes. These data suggest that H3K9 methyltransferases are predominantly expressed in prehypertrophic and hypertrophic chondrocytes, and that they could be involved in the regulation of gene expression and progression of chondrocyte differentiation by affecting the methylation state of histone H3 lysine 9 in the mouse growth plate.
    Gene Expression Patterns 01/2013; 13(3-4). DOI:10.1016/j.gep.2013.01.002 · 1.38 Impact Factor
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    • "We first confirmed that doses as low as 1 μM DZNeP were able to almost abolish EZH2 expression (Figure 2A) and reduced histone H3K27 trimethylation by 33% (quantification performed by LI-COR Odyssey IR Imaging System; Additional File 1). This is in line with the evidence that histone lysine methylation can be mediated by enzymes other than EZH2[28]. In LNCaP cells, EZH2 silencing was already evident after 3 days, while in DU145 cells we could find an effect after 5 days. "
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    ABSTRACT: Polycomb repressive complex 2 (PRC2) mediates gene silencing through histone H3K27 methylation. PRC2 components are over-expressed in metastatic prostate cancer (PC), and are required for cancer stem cell (CSC) self-renewal. 3-Dezaneplanocin-A (DZNeP) is an inhibitor of PRC2 with broad anticancer activity. we investigated the effects of DZNeP on cell proliferation, tumorigenicity and invasive potential of PC cell lines (LNCaP and DU145). Exploring GEO and Oncomine databases, we found that specific PRC2 genes (EED, EZH2, SUZ12) predict poor prognosis in PC. Non-toxic DZNeP concentrations completely eradicated LNCaP and DU145 prostatosphere formation, and significantly reduced the expression of CSC markers. At comparable doses, other epigenetic drugs were not able to eradicate CSCs. DZNeP was also able to reduce PC cell invasion. Cells pre-treated with DZNeP were significantly less tumorigenic (LNCaP) and formed smaller tumors (DU145) in immunocompromised mice. DZNeP is effective both in vitro and in vivo against PC cells. DZNeP antitumor activity is in part mediated by inhibition of CSC tumorigenic potential.
    Molecular Cancer 04/2011; 10(1):40. DOI:10.1186/1476-4598-10-40 · 4.26 Impact Factor
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