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Deregulation of histone lysine methyltransferases contributes to oncogenic transformation of human bronchoepithelial cells
Hideo Watanabe, Kenzo Soejima, Hiroyuki Yasuda, Ichiro Kawada, Ichiro Nakachi, Satoshi Yoda, Katsuhiko Naoki, Akitoshi Ishizaka
Cancer Cell International , 2008, DOI: 10.1186/1475-2867-8-15
Abstract: We observed differential HKMT expression in a lung cancer model in which normal human bronchial epithelial (NHBE) cells expressing telomerase, SV40 large T antigen, and Ras were immortal, formed colonies in soft agar, and expressed specific HKMTs for H3 lysine 9 and 27 residues but not for H3 lysine 4 residue. Modifications in the H3 tails affect the binding of proteins to the histone tails and regulate protein function and the position of lysine methylation marks a gene to be either activated or repressed. In the present study, suppression by siRNA of HKMTs (EZH2, G9A, SETDB1 and SUV39H1) that are over-expressed in immortalized and transformed cells lead to reduced cell proliferation and much less anchorage-independent colony growth. We also found that the suppression of H3-K9, G9A and SUV39H1 induced apoptosis and the suppression of H3-K27, EZH2 caused G1 arrest.Our results indicate the potential of these HKMTs in addition to the other targets for epigenetics such as DNMTs and HDACs to be interesting therapeutic targets.Alterations in the processing of the genetic information in carcinogenesis result from stable genetic mutations involving tumor suppressor genes, oncogenes and DNA stability genes as well as from potentially reversible epigenetic changes leading to modifications in gene function [1,2]. It is well established that epigenetic modifications of nucleosomal histones are central to proper gene expression and aberrant DNA methylation of genes play an important role in tumor progression. However, still relatively little is known about histone modifications, especially methylation, with respect to tumorigenesis. The N-terminus of histone tails is modified by amino-acid phosphorylation, acetylation or methylation to form a code for specifying downstream events and consequently a certain chromatin structure. Tens of histone lysine methyltransferases (HKMTs) have been identified and histone lysine methylation is now considered to be a critical regulator of tra
Downregulation of Histone H3 Lysine 9 Methyltransferase G9a Induces Centrosome Disruption and Chromosome Instability in Cancer Cells  [PDF]
Yutaka Kondo, Lanlan Shen, Saira Ahmed, Yanis Boumber, Yoshitaka Sekido, Bassem R. Haddad, Jean-Pierre J. Issa
PLOS ONE , 2008, DOI: 10.1371/journal.pone.0002037
Abstract: Background Modifications of the histone amino-terminal tails affect access of regulatory factors and complexes to chromatin and thereby influence biological processes. Cancer cells are characterized by prominent epigenetic dysregulation, including histone modifications. However, the functional roles of the histone methyltransferases (HMT) in cancer remain unclear. Methodology/Principal Findings We studied RNAi-based inhibition (knockdown, KD) of 2 different H3K9 HMTs, SUV39H1 and G9a. Knockdown of the 2 HMTs in PC3 cancer cell line markedly inhibited cell growth and caused profound morphological changes with loss of telomerase activity and shortened telomeres. SUV39H1 KD cells showed substantial increase in G2/M fraction. G9a KD cells showed increased DNA content (1.7-fold in 2 independent clones) compared with FACS analyses to control. Karyotype analyses showed that this was due to an increased number of chromosomes (from 61 to 102) in G9a KD cells compared to parental PC3. Intriguingly, we found abnormal centrosome morphology and number in about 25% of the G9a KD cells, while centrosomes were morphologically normal in control cells. Microarray analyses after KD of SUV39H1 or G9a showed very few genes up-regulated among the 39,000 genes. The silenced tumor-suppressor genes p16 and RASSF1A were not activated in KD cells. Conclusions/Significance These data suggest that the 2 HMTs, SUV39H1 and G9a are required to perpetuate the malignant phenotype. Furthermore, G9a plays a critical role in regulating centrosome duplication presumably through chromatin structure rather than through affecting gene expression in cancer cells. Targeting these histone methyltransferases may be of therapeutic benefit in cancers.
Histone H1 variant-specific lysine methylation by G9a/KMT1C and Glp1/KMT1D
Thomas Weiss, Sonja Hergeth, Ulrike Zeissler, Annalisa Izzo, Philipp Tropberger, Barry M Zee, Miroslav Dundr, Benjamin A Garcia, Sylvain Daujat, Robert Schneider
Epigenetics & Chromatin , 2010, DOI: 10.1186/1756-8935-3-7
Abstract: In this study, we used a candidate screen to identify enzymes that methylate H1 and to map their corresponding methylation sites. We found that the histone lysine methyltransferases G9a/KMT1C and Glp1/KMT1D methylate H1.2 in vitro and in vivo, and we mapped this novel site to lysine 187 (H1.2K187) in the C-terminus of H1. This H1.2K187 methylation is variant-specific. The main target for methylation by G9a in H1.2, H1.3, H1.5 and H1.0 is in the C-terminus, whereas H1.4 is preferentially methylated at K26 (H1.4K26me) in the N-terminus. We found that the readout of these marks is different; H1.4K26me can recruit HP1, but H1.2K187me cannot. Likewise, JMJD2D/KDM4 only reverses H1.4K26 methylation, clearly distinguishing these two methylation sites. Further, in contrast to C-terminal H1 phosphorylation, H1.2K187 methylation level is steady throughout the cell cycle.We have characterised a novel methylation site in the C-terminus of H1 that is the target of G9a/Glp1 both in vitro and in vivo. To our knowledge, this is the first demonstration of variant-specific histone methylation by the same methyltransferases, but with differing downstream readers, thereby supporting the hypothesis of H1 variants having specific functions.In eukaryotic cells, DNA is packaged into chromatin. The building block of chromatin is the nucleosomal core particle containing a histone octamer (formed by the histones H2A, H2B, H3 and H4) around which 147 bp of DNA (147 bp) are wrapped [1]. The linker histone H1 binds to the DNA between the nucleosomal core particles, and is essential to stabilise higher order chromatin structures [2].Human cells possess up to 11 H1 variants, all consisting of a short N-terminal tail, a globular core domain and a C-terminal tail, making up approximately 50% of the whole protein [3,4]. H1.0 is mainly expressed in terminally differentiated cells. H1.1 expression has to date only been reported for a subset of tissues. H1.2 to H1.5 are expressed in almost all cells, wi
Nano-electrospray tandem mass spectrometric analysis of the acetylation state of histones H3 and H4 in stationary phase in Saccharomyces cerevisiae
Mzwanele Ngubo, Gabré Kemp, Hugh G Patterton
BMC Biochemistry , 2011, DOI: 10.1186/1471-2091-12-34
Abstract: We made use of nano-spray tandem mass spectrometry to perform a precursor ion scan to detect an m/z 126 immonium ion, diagnostic of an Nε-acetylated lysine residue that allowed unambiguous identification of acetylated as opposed to tri-methylated lysine. The fragmentation spectra of peptides thus identified were searched with Mascot against the Swiss-Prot database, and the y-ion and b-ion fragmentation series subsequently analyzed for mass shifts compatible with acetylated lysine residues. We found that K9, K14 and K36 of histone H3 and K12 and K16 of histone H4 were acetylated in exponential phase (bulk histones), but could not detect these modifications in histones isolated from stationary phase cells at the sensitivity level of the mass spectrometer. The corresponding un-acetylated peptides were, however, observed. A significantly higher level of acetylation of these residues in exponential phase was confirmed by immuno-blotting.H4K16 acetylation was previously shown to disrupt formation of condensed chromatin in vitro. We propose that de-acetylation of H4K16 allowed formation of condensed chromatin in stationary phase, and that acetylation of H3K9, H3K14, H3K36, and H4K12 reflected the active transcriptional state of the yeast genome in exponential phase.In 1963 Allfrey and colleagues showed that the acetylation of histone H3 and H4 alleviated the repressive effect of the histones on in vitro RNA synthesis in calf nuclei [1,2]. This initial report saw the birth of epigenetics and an appreciation that covalent modifications of histones provided a mechanism whereby DNA function could be regulated. The nucleosomal packaging of DNA in chromatin was subsequently shown to be an integral component in the regulatory mechanism of the transcription process [3], involving ATP-dependent remodeling complexes, reversible, chemical modification of core histone as well as histone isotype swapping. Many transcriptional activators and repressors were further shown to be enzymes t
The Human N-Alpha-Acetyltransferase 40 (hNaa40p/hNatD) Is Conserved from Yeast and N-Terminally Acetylates Histones H2A and H4  [PDF]
Kristine Hole, Petra Van Damme, Monica Dalva, Henriette Aksnes, Nina Glomnes, Jan Erik Varhaug, Johan R. Lillehaug, Kris Gevaert, Thomas Arnesen
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0024713
Abstract: Protein Nα-terminal acetylation (Nt-acetylation) is considered one of the most common protein modification in eukaryotes, and 80-90% of all soluble human proteins are modified in this way, with functional implications ranging from altered protein function and stability to translocation potency amongst others. Nt-acetylation is catalyzed by N-terminal acetyltransferases (NATs), and in yeast five NAT types are identified and denoted NatA-NatE. Higher eukaryotes additionally express NatF. Except for NatD, human orthologues for all yeast NATs are identified. yNatD is defined as the catalytic unit Naa40p (Nat4) which co-translationally Nt-acetylates histones H2A and H4. In this study we identified and characterized hNaa40p/hNatD, the human orthologue of the yeast Naa40p. An in vitro proteome-derived peptide library Nt-acetylation assay indicated that recombinant hNaa40p acetylates N-termini starting with the consensus sequence Ser-Gly-Gly-Gly-Lys-, strongly resembling the N-termini of the human histones H2A and H4. This was confirmed as recombinant hNaa40p Nt-acetylated the oligopeptides derived from the N-termini of both histones. In contrast, a synthetically Nt-acetylated H4 N-terminal peptide with all lysines being non-acetylated, was not significantly acetylated by hNaa40p, indicating that hNaa40p catalyzed H4 Nα-acetylation and not H4 lysine Nε-acetylation. Also, immunoprecipitated hNaa40p specifically Nt-acetylated H4 in vitro. Heterologous expression of hNaa40p in a yeast naa40-Δ strain restored Nt-acetylation of yeast histone H4, but not H2A in vivo, probably reflecting the fact that the N-terminal sequences of human H2A and H4 are highly similar to each other and to yeast H4 while the N-terminal sequence of yeast H2A differs. Thus, Naa40p seems to have co-evolved with the human H2A sequence. Finally, a partial co-sedimentation with ribosomes indicates that hNaa40p co-translationally acetylates H2A and H4. Combined, our results strongly suggest that human Naa40p/NatD is conserved from yeast. Thus, the NATs of all classes of N-terminally acetylated proteins in humans now appear to be accounted for.
The SET-domain protein superfamily: protein lysine methyltransferases
Shane C Dillon, Xing Zhang, Raymond C Trievel, Xiaodong Cheng
Genome Biology , 2005, DOI: 10.1186/gb-2005-6-8-227
Abstract: Nucleosomes, the main components of chromatin, consist of histones, and histone proteins have positively charged amino-terminal tails that are exposed on the outside of nucleosomes. These tails are subject to several post-translational covalent modifications, including acetylation, phosphorylation, ubiquitination, sumoylation and methylation (reviewed in [1]). Methylation been found on a range of lysine residues in various histones: K4 (using the single-letter amino-acid code for lysine), K9, K27, K36 and K79 in histone H3, K20 in histone H4, K59 in the globular domain of histone H4 [2] and K26 of histone H1B [3]. Several proteins responsible for the methylation of specific residues have been characterized, and all but one of these contains a SET domain; they make up the SET-domain protein methyltransferase family (Table 1). The exception to the rule is the DOT1 family, members of which methylate K79 in the globular region of histone H3 and which are structurally not related to SET-domain proteins [4-6]. Recent work suggests that SET-domain-containing proteins methylate a few proteins in addition to histones (see later); they should therefore be named protein lysine methyltransferases rather than histone lysine methyltransferases. The function of SET-domain proteins is to transfer a methyl group from S-adenosyl-L-methionine (AdoMet) to the amino group of a lysine residue on the histone or other protein, leaving a methylated lysine residue and the cofactor byproduct S-adenosyl-L-homocysteine (AdoHcy). Methylation of specific histone lysine residues serves as a post-translational epigenetic modification that controls the expression of genes by serving as 'markers' for the recruitment of particular complexes that direct the organization of chromatin.The SET domain (Figure 1) was first recognized as a conserved sequence in three Drosophila melanogaster proteins: a modifier of position-effect variegation, Suppressor of variegation 3-9 (Su(var)3-9) [7], the Polycomb-group
Histone Acetyl Transferase 1 Is Essential for Mammalian Development, Genome Stability, and the Processing of Newly Synthesized Histones H3 and H4  [PDF]
Prabakaran Nagarajan,Zhongqi Ge,Bianca Sirbu,Cheryl Doughty,Paula A. Agudelo Garcia,Michaela Schlederer,Anthony T. Annunziato,David Cortez,Lukas Kenner,Mark R. Parthun
PLOS Genetics , 2013, DOI: 10.1371/journal.pgen.1003518
Abstract: Histone acetyltransferase 1 is an evolutionarily conserved type B histone acetyltransferase that is thought to be responsible for the diacetylation of newly synthesized histone H4 on lysines 5 and 12 during chromatin assembly. To understand the function of this enzyme in a complex organism, we have constructed a conditional mouse knockout model of Hat1. Murine Hat1 is essential for viability, as homozygous deletion of Hat1 results in neonatal lethality. The lungs of embryos and pups genetically deficient in Hat1 were much less mature upon histological evaluation. The neonatal lethality is due to severe defects in lung development that result in less aeration and respiratory distress. Many of the Hat1?/? neonates also display significant craniofacial defects with abnormalities in the bones of the skull and jaw. Hat1?/? mouse embryonic fibroblasts (MEFs) are defective in cell proliferation and are sensitive to DNA damaging agents. In addition, the Hat1?/? MEFs display a marked increase in genome instability. Analysis of histone dynamics at sites of replication-coupled chromatin assembly demonstrates that Hat1 is not only responsible for the acetylation of newly synthesized histone H4 but is also required to maintain the acetylation of histone H3 on lysines 9, 18, and 27 during replication-coupled chromatin assembly.
Detection of Histone Acetylation Levels in the Dorsal Hippocampus Reveals Early Tagging on Specific Residues of H2B and H4 Histones in Response to Learning  [PDF]
Olivier Bousiges, Romain Neidl, Monique Majchrzak, Marc-Antoine Muller, Alexandra Barbelivien, Anne Pereira de Vasconcelos, Anne Schneider, Jean-Philippe Loeffler, Jean-Christophe Cassel, Anne-Laurence Boutillier
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0057816
Abstract: The recent literature provides evidence that epigenetic mechanisms such as DNA methylation and histone modification are crucial to gene transcription linked to synaptic plasticity in the mammalian brain - notably in the hippocampus - and memory formation. We measured global histone acetylation levels in the rat hippocampus at an early stage of spatial or fear memory formation. We found that H3, H4 and H2B underwent differential acetylation at specific sites depending on whether rats had been exposed to the context of a task without having to learn or had to learn about a place or fear therein: H3K9K14 acetylation was mostly responsive to any experimental conditions compared to naive animals, whereas H2B N-terminus and H4K12 acetylations were mostly associated with memory for either spatial or fear learning. Altogether, these data suggest that behavior/experience-dependent changes differently regulate specific acetylation modifications of histones in the hippocampus, depending on whether a memory trace is established or not: tagging of H3K9K14 could be associated with perception/processing of testing-related manipulations and context, thereby enhancing chromatin accessibility, while tagging of H2B N-terminus tail and H4K12 could be more closely associated with the formation of memories requiring an engagement of the hippocampus.
Trichostatin A and 5-azacytidine both cause an increase in global histone H4 acetylation and a decrease in global DNA and H3K9 methylation during mitosis in maize
Fei Yang, Lu Zhang, Jun Li, Jing Huang, Ruoyu Wen, Lu Ma, Dongfeng Zhou, Lijia Li
BMC Plant Biology , 2010, DOI: 10.1186/1471-2229-10-178
Abstract: Treatment with trichostatin A, which inhibits histone deacetylases, resulted in increased histone H4 acetylation accompanied by the decondensation of interphase chromatin and a decrease in both global H3K9 dimethylation and DNA methylation during mitosis in maize root tip cells. These observations suggest that histone acetylation may affect DNA and histone methylation during mitosis. Treatment with 5-azacytidine, a cytosine analog that reduces DNA methylation, caused chromatin decondensation and mediated an increase in H4 acetylation, in addition to reduced DNA methylation and H3K9 dimethylation during interphase and mitosis. These results suggest that decreased DNA methylation causes a reduction in H3K9 dimethylation and an increase in H4 acetylation.The interchangeable effects of 5-azacytidine and trichostatin A on H4 acetylation, DNA methylation and H3K9 dimethylation indicate a mutually reinforcing action between histone acetylation, DNA methylation and histone methylation with respect to chromatin modification. Treatment with trichostatin A and 5-azacytidine treatment caused a decrease in the mitotic index, suggesting that H4 deacetylation and DNA and H3K9 methylation may contain the necessary information for triggering mitosis in maize root tips.The basic unit of chromatin in eukaryotes is the nucleosome, which is composed of ~146 base pairs of DNA wrapped around an octameric core of the histone molecules H2A, H2B, H3 and H4 [1,2]. The amino-terminal tails of these histones are subject to various post-translational modifications such as methylation, acetylation, phosphorylation, ubiquitination and ADP-ribosylation [3]. Various histone-modifying enzymes able to add or remove chromatin modifications, including histone acetyltransferases (HATs), histone deacetylases (HDACs) and lysine methyltransferases, have been identified [3]. In yeast, HATs and HDACs have been found to alter global histone acetylation levels over large regions of chromatin [4]. DNA itself may
The Histone Methyltransferase SUV39H1 Suppresses Embryonal Rhabdomyosarcoma Formation in Zebrafish  [PDF]
Colleen E. Albacker, Narie Y. Storer, Erin M. Langdon, Anthony DiBiase, Yi Zhou, David M. Langenau, Leonard I. Zon
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0064969
Abstract: Epigenetics, or the reversible and heritable marks of gene regulation not including DNA sequence, encompasses chromatin modifications on both the DNA and histones and is as important as the DNA sequence itself. Chromatin-modifying factors are playing an increasingly important role in tumorigenesis, particularly among pediatric rhabdomyosarcomas (RMS), revealing potential novel therapeutic targets. We performed an overexpression screen of chromatin-modifying factors in a KRASG12D-driven zebrafish model for RMS. Here, we describe the identification of a histone H3 lysine 9 histone methyltransferase, SUV39H1, as a suppressor of embryonal RMS formation in zebrafish. This suppression is specific to the histone methyltransferase activity of SUV39H1, as point mutations in the SET domain lacked the effect. SUV39H1-overexpressing and control tumors have a similar proliferation rate, muscle differentiation state, and tumor growth rate. Strikingly, SUV39H1-overexpressing fish initiate fewer tumors, which results in the observed suppressive phenotype. We demonstrate that the delayed tumor onset occurs between 5 and 7 days post fertilization. Gene expression profiling at these stages revealed that in the context of KRASG12D overexpression, SUV39H1 may suppress cell cycle progression. Our studies provide evidence for the role of SUV39H1 as a tumor suppressor.
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