ChemInform Abstract: Structure and Function of Histone H3 Lysine 9 Methyltransferases and Demethylases.
ABSTRACT Histone lysine methylation is a dynamic chromatin modification that plays key regulatory roles in gene expression and other genomic functions. Methylation of Lys9 in histone H3 (H3K9) is a prominent modification that has been implicated in diverse processes, including transcriptional silencing, heterochromatin formation, and DNA methylation. In this review, we summarize recent advances in understanding the structure and substrate specificity of the H3K9-specific methyltransferases G9A and GLP and explore current efforts to develop inhibitors of these enzymes. In addition, we discuss the structure and specificity of the recently discovered PHF8 family of histone demethylases that target H3K9 as well as other methylation sites in histones H3 and H4. Finally, we conclude by comparing the H3K9 binding modes displayed by these enzymes and examine the relevance of these studies to their biological functions and to structure-based inhibitor design.
- SourceAvailable from: Kayla A Chase
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- "Restrictive assemblies effectively seal the gene promoter from regulation by transcription factors, often by post-translational methylation of the ninth lysine of histone H3 (H3K9me2; Krauss, 2008; Lyons and Lomvardas, 2014). In particular, the formation of H3K9me2 is catalyzed by histone methyltransferases (HMTs), including G9a, GLP, and SETDB1 (Krishnan et al., 2011; Shinkai and Tachibana, 2011). The majority of studies report increases in restrictive chromatin (Chase et al., 2013; Gavin et al., 2008, 2009b; Sharma et al., 2008) and resulting down-regulation of gene transcription of several candidate genes in patients with schizophrenia (Akbarian et al., 1995; Guidotti et al., 2000; Impagnatiello et al., 1998; Jindal et al., 2010). "
ABSTRACT: When compared to women, men have a higher incidence of schizophrenia, with increases in negative and cognitive symptoms, and an overall poorer disease course. Schizophrenia is conceptualized as a disorder of aberrant gene transcription and regulation. Thus, epigenetics, the study of environmentally induced changes in gene regulation, could advance our understanding of the molecular underpinnings of schizophrenia. Peripheral histone methyltransferase (HMT) mRNA levels have been previously shown to be significantly increased in patients with schizophrenia and correlate with symptomology. In this independent study, peripheral lymphocytes were extracted and clinical symptoms were measured on 74 participants, (40 patients with schizophrenia (19 women, 21 men) and 34 healthy individuals (19 women, 15 men)). HMT (G9α, SETDB1 and GLP) mRNA levels and their resulting histone modification H3K9me2 were measured with RT-PCR and ELISA respectively. Plasma estradiol levels were also measured via ELISA and correlated with HMT mRNA. Clinical symptoms were measured utilizing the Positive and Negative Syndrome Scale (PANSS) and the Heinrichs Carpenter Quality of Life Scale (QLS). The results indicate that men with schizophrenia expressed the highest levels of G9α, SETDB1 mRNA and H3K9me2 protein levels. Additionally, higher levels of symptom presentation and an overall poorer quality of life were correlated with higher HMT mRNA and H3K9me2 protein levels in a sex-dependent pattern. These data support the hypothesis of a sex-dependent restrictive epigenome contributing towards the etiology of schizophrenia. The histone methyltransferases measured here could be potential future therapeutic targets for small molecule pharmacology. Published by Elsevier Ltd.Journal of Psychiatric Research 04/2015; 65. DOI:10.1016/j.jpsychires.2015.04.005 · 4.09 Impact Factor
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- "Phylogenetic analysis and domain organization of histone methyltransferases The methylation of lysine residues in histones, with the exception of H3K79 methylation, is carried out by enzymes that contain an evolutionary conserved SET domain, named after three Drosophila genes (Su(var)3-9, Enhancer of zeste, and Trithorax) (Casas-Mollano et al., 2007; Bannister and Kouzarides, 2011; Huang et al., 2011; Derkacheva and Hennig, 2014). The SET domain constitutes the catalytic site of these lysine methyltransferases (KMTs), but flanking sequences, more distant protein domains, and possibly some cofactors are also important for enzyme activity and specificity (Huang et al., 2011; Krishnan et al., 2011; Derkacheva and Hennig, 2014). To begin characterizing the occurrence and the role(s) of H3K9 and/or H3K27 methyltransferases in microalgae, we surveyed 14 complete or near-complete algal genomes in the Archaeplastida supergroup for the presence of SETdomain polypeptides (Table 1). "
ABSTRACT: Microalgae exhibit enormous diversity and can potentially contribute to the production of biofuels and high value compounds. However, for most species, our knowledge of their physiology, metabolism, and gene regulation is fairly limited. In eukaryotes, gene silencing mechanisms play important roles in both the reversible repression of genes that are required only in certain contexts and the suppression of genome invaders such at transposons. The recent sequencing of several algal genomes is providing insights into the complexity of these mechanisms in microalgae. Collectively, glaucophyte, red, and green microalgae contain the machineries involved in repressive histone H3 lysine methylation, DNA cytosine methylation, and RNA interference. However, individual species often only have subsets of these gene silencing mechanisms. Moreover, current evidence suggests that algal silencing systems function in transposon and transgene repression but their role(s) in gene regulation or other cellular processes remains virtually unexplored, hindering rational genetic engineering efforts. Copyright © 2014 Elsevier Ltd. All rights reserved.Bioresource Technology 10/2014; 184. DOI:10.1016/j.biortech.2014.10.119 · 5.04 Impact Factor
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- "Moreover, 26 menarche related genes are connected to two or more TRG central nodes. Many of the genes that are connected to multiple TRG genes are themselves potential regulators of gene expression, such as KDM3B (also known as JMJD1B), a histone demethylase involved in removal of the repressive H3K9me2 and H3K9me1 histone marks (Kim et al., 2012; Krishnan et al., 2011). Overall, these results indicate the existence of significant interrelationships in regulation and expression between TRG central nodes, bovine puberty genes, and menarche-related genes discovered through GWAS studies. "
ABSTRACT: Substantial progress has been made in recent years towards deciphering the molecular and genetic underpinnings of the pubertal process. The availability of powerful new methods to interrogate the human genome has led to the identification of genes that are essential for puberty to occur. Evidence has also emerged suggesting that the initiation of puberty requires the coordinated activity of gene sets organized into functional networks. At a cellular level, it is currently thought that loss of transsynaptic inhibition, accompanied by an increase in excitatory inputs, results in the pubertal activation of GnRH release. This concept notwithstanding, a mechanism of epigenetic repression targeting genes required for the pubertal activation of GnRH neurons was recently identified as a core component of the molecular machinery underlying the central restraint of puberty. In this chapter we will discuss the potential contribution of various mechanisms of epigenetic regulation to the hypothalamic control of female puberty.Frontiers in Neuroendocrinology 08/2014; 36. DOI:10.1016/j.yfrne.2014.08.003 · 7.58 Impact Factor