DOCSLIB.ORG

Histone Deacetylases in Viral Infections

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Histone Deacetylases in Viral Infections View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Springer - Publisher Connector Clin Epigenet (2010) 1:13–24 DOI 10.1007/s13148-010-0003-5 REVIEW Histone deacetylases in viral infections Georges Herbein & Daniel Wendling Received: 30 December 2009 /Accepted: 10 May 2010 /Published online: 30 May 2010 # Springer-Verlag 2010 Abstract Chromatin remodeling and gene expression are teins have prominent roles, too. The functions of chromatin regulated by histone deacetylases (HDACs) that condense are to package DNA into a smaller volume to fit in the cell, the chromatin structure by deacetylating histones. HDACs to strengthen the DNA to allow mitosis and meiosis, and to comprise a group of enzymes that are responsible for the serve as a mechanism to control expression and DNA regulation of both cellular and viral genes at the transcrip- replication. Changes in chromatin structure are affected by tional level. In mammals, a total of 18 HDACs have been chemical modifications of histone proteins and by non- identified and grouped into four classes, i.e., class I histone DNA-binding proteins. The non-histone proteins (HDACs 1, 2, 3, 8), class II (HDACs 4, 5, 6, 7, 9, 10), that are found associated with isolated chromatin fall into class III (Sirt1–Sirt7), and class IV (HDAC11). We review several functional categories such as chromatin-bound here the role of HDACs on viral replication and how enzymes, high mobility group proteins (HMG), transcrip- HDAC inhibitors could potentially be used as new tion factors, and scaffold proteins. Thus, acetylation of therapeutic tools in several viral infections. histone and non-histone chromosomal proteins by histone acetyl transferases (HATs) leads to decondensation of the Keywords HDAC . Viruses . HIV. HCMV. chromatin. Chromatin remodeling and gene expression is HDAC inhibitors simultaneously regulated by histone deacetylases (HDACs) that condense the chromatin structure by deacetylating histones. HDACs comprise a group of enzymes that are Introduction responsible for the removal of acetyl groups from a e-N- acetyl lysine amino acids. As the organization and Chromatin is the complex combination of DNA and packaging of eukaryotic DNA is achieved through the proteins that makes up chromosomes. It is divided between addition of core histones H2A, H2B, H3, and H4, which heterochromatin (condensed) and euchromatin (extended) form the chromatin, the modification of core histones is of forms. The major components of chromatin are DNA and fundamental importance to conformational changes in histone proteins, although many other chromosomal pro- chromatin. The level of acetylation influences transcription activity. The acetylation of histones results in the formation of G. Herbein (*) shapes of DNA that will serve as specific recruitment Department of Virology, UPRES EA 4266, IFR 133 INSERM, platforms for other protein and enzyme complexes. These Franche-Comte University, multiprotein complexes will result in enhanced transcrip- CHU Besançon, 2 place Saint-Jacques, tional activity (euchromatin). By contrast, HDACs present 25030 Besancon, France e-mail: [email protected] in a repressor complex deacetylate histone proteins, leading to the recruitment of histone methyltransferase and result- D. Wendling ing in subsequent methylation of histones. Ultimately, Department of Rheumatology, UPRES EA4266, proteins such as heterochromatin protein 1 (HP1) are IFR 133 INSERM, Franche-Comte University, CHU Besançon, recruited to the repressor complex, leading to the formation 25030 Besancon, France of condensed heterochromatin. Thus, HDAC activities are a 14 Clin Epigenet (2010) 1:13–24 prerequisite step allowing further modification of histone transcription factors to promoter regions. There are several proteins that promote the final heterochromatin formation. co-repressor complexes for distinct promoters, which recruit specific HDAC isoforms for silencing of target genes (Miska et al. 1999; Rayman et al. 2002). For example, HDACs 1, 2, HDAC family members and 3 are majorly responsible for catalytic core for different co-repressor complexes to achieve efficient transcriptional In mammals, a total of 18 HDACs have been identified and repression. HDAC1 and HDAC2 are present in the grouped into four classes, i.e., class I (HDACs 1, 2, 3, 8), CoREST, Mi2/NuRD, and Sin3 complexes, whereas class II (HDACs 4, 5, 6, 7, 9, 10), class III (Sirt1–Sirt7), and HDAC3 is responsible for the catalytic activity of the N- class IV (HDAC11) (Table 1). The members of class I CoR and SMRT co-repressor complexes (Cress and Seto HDACs contain a deacetylase domain and are the homo- 2000; Mahlknecht et al. 2004; Ng and Bird 2000). HDACs logs of yeast RPD3. They exhibit 45% to 93% amino acid cooperate with various other transcriptional regulators such sequence identity and localize in the nucleus, except for as HDAC1 and HDAC2 associate with DNA methyltrans- HDAC3. Class II HDACs are homologs of yeast Hda1 and ferases (Burgers et al. 2002; Fuks et al. 2001) and histone are present in both the nucleus and the cytoplasm (Martin et methyltransferases (HMTs) (Czermin et al. 2001). Further- al. 2009; Martin et al. 2007). HDAC6 is an exception which more, HDAC1 interacts with topoisomerase II enzyme that contains two deacetylase domains, at both the N- and C- is responsible for chromosome condensation (Tsai et al. terminus. The molecular weights of class II are twofold 2000). However, little is known about the specificity of a higher than class I HDACs. The members of class III, particular histone deacetylase enzyme for a specific lysine sirtuins, are homologs of yeast Sir2 and form a structurally residue. The preferential acetylation of H3K18 and H3K9 distinct class of NAD-dependent enzymes found in both the following knockdown of HDAC1 and HDAC3, respectively, nucleus and cytoplasm. HDAC11 has properties of both has been reported (Zhang et al. 2004). Non-histone class I and class II HDACs and represent class IV. deacetylation-based gene expression involves the deacety- HDACs work in multi-subunit transcriptional co- lation of various transcription factors by HDACs. Deacety- repressor complexes that are recruited by sequence-specific lation of sequence-specific transcription factors can Table 1 HDAC classification depending on sequence identity Histone Members Localization Target proteins (partial list) and domain organization classes Class I HDAC1 Nucleus AR, p53, E2F-1, SHP, STAT3, MyoD HDAC2 Nucleus STAT3, Bcl6, glucocorticoid receptor GATA-1, STAT-3, HDAC3 Nucleus/ SHP, RelA, YY-1 cytoplasm HDAC8 Nucleus – Class II HDAC4 Nucleus/ GCMa, GATA-1, HP-1 cytoplasm HDAC5 Nucleus/ GCMa, Smad7, HP-1 cytoplasm HDAC6 Mostly HSP70, Smad7, SHP, α-tubulin cytoplasm HDAC7 Nucleus/ PLAG1, PLAG2 cytoplasm HDAC9 Nucleus/ – cytoplasm HDAC10 Mostly – cytoplasm Class III SIRT1 Nucleus NF-κB, p53, FOXO SIRT2 Cytoplasm α-tubulin, H4 SIRT3 Nucleus/ Acetyl–CoA synthetases mitochondria SIRT4 Mitochondria Glutamate dehydrogenate SIRT5 Mitochondria – SIRT6 Nucleus DNA polymerase B SIRT7 Nucleus RNA polymerase 1 Class IV HDAC11 Nucleus/ – cytoplasm Clin Epigenet (2010) 1:13–24 15 decrease their DNA binding activity and subsequently may of HDACs in viral diseases including hepatitis B and C, repress transcription. The covalent modifications of several HIV and HPV infections, and infections with Herpesviridae transcriptional factors, including E2F, sp3, p53, GATA1, (HSV, HCMV, EBV) and Paramyxoviridae (RSV). and TFIIF, have been reported (Ammanamanchi et al. 2003; The hepatitis B virus x (HBx) protein plays a critical role Boyes et al. 1998; Braun et al. 2001; Gu and Roeder 1997; in liver carcinogenesis. HBx has been reported to activate Imhof et al. 1997; Marzio et al. 2000). The specificity of cyclin D1. HBx induces the expression of metastasis- HDAC1 for p53 deacetylation, resulting in the degradation associated protein 1 (MTA1), a protein closely related to of deacetylated p53 has been reported (Ito et al. 2002). tumor growth and metastasis in various cancers, especially in HDAC2 deacetylates the glucocorticoid receptor and hepatocellular carcinoma (HCC). In addition, HBx has been HDAC3 is needed for the deacetylation of myocyte reported to modulate hypoxia-inducible factor-1 alpha (HIF- enhancer factor-2 (MEF-2) (Gregoire et al. 2007; Ito et al. 1 alpha) expression and activity, and HIF-1 alpha increased 2006). HDACs are also involved in the deacetylation of expression has been correlated with tumor growth and poor non-nuclear proteins like tubulin45 and HSP90 (Hubbert et patient prognosis (Semenza 2004). Under conditions of al. 2002; Kovacs et al. 2005). normoxia, post-translational modifications including the hydroxylation of proline residues and acetylation of a lysine residue within the oxygen-dependent degradation HDAC in viral diseases domain promote HIF-1α interaction with von Hipple– Lindau (pVHL) ubiquitin E3 ligase complex. This occurs HDACs are involved in the regulation of the replication of concurrently with the hydroxylation of an asparagine numerous viruses (Table 2). We will described here the role residue by the aparaginyl hydroxylase FIH-1 and inhibits Table 2 Role of HDACs in viral infections Virus HDAC Molecular mechanism Clinical effect References DNA viruses HBV HDAC1, HBx forms a multiprotein complex Angiogenesis and metastasis of Semenza 2004; Yoo et al. 2008 2 HDAC1/2, MTA1, HIF-1 HBV-associated HCC HCMV HDAC3 HDAC3 represses the HCMV MIEP Repression of viral replication Meier 2001; Murphy et
Load more

Recommended publications
  • Insights Into Hp1a-Chromatin Interactions
    cells Review Insights into HP1a-Chromatin Interactions Silvia Meyer-Nava , Victor E. Nieto-Caballero, Mario Zurita and Viviana Valadez-Graham * Instituto de Biotecnología, Departamento de Genética del Desarrollo y Fisiología Molecular, Universidad Nacional Autónoma de México, Cuernavaca Morelos 62210, Mexico; [email protected] (S.M.-N.); [email protected] (V.E.N.-C.); [email protected] (M.Z.) * Correspondence: [email protected]; Tel.: +527773291631 Received: 26 June 2020; Accepted: 21 July 2020; Published: 9 August 2020 Abstract: Understanding the packaging of DNA into chromatin has become a crucial aspect in the study of gene regulatory mechanisms. Heterochromatin establishment and maintenance dynamics have emerged as some of the main features involved in genome stability, cellular development, and diseases. The most extensively studied heterochromatin protein is HP1a. This protein has two main domains, namely the chromoshadow and the chromodomain, separated by a hinge region. Over the years, several works have taken on the task of identifying HP1a partners using different strategies. In this review, we focus on describing these interactions and the possible complexes and subcomplexes associated with this critical protein. Characterization of these complexes will help us to clearly understand the implications of the interactions of HP1a in heterochromatin maintenance, heterochromatin dynamics, and heterochromatin’s direct relationship to gene regulation and chromatin organization. Keywords: heterochromatin; HP1a; genome stability 1. Introduction Chromatin is a complex of DNA and associated proteins in which the genetic material is packed in the interior of the nucleus of eukaryotic cells [1]. To organize this highly compact structure, two categories of proteins are needed: histones [2] and accessory proteins, such as chromatin regulators and histone-modifying proteins.
    [Show full text]
  • H19 Lncrna Controls Gene Expression of the Imprinted Gene Network by Recruiting MBD1
    H19 lncRNA controls gene expression of the Imprinted Gene Network by recruiting MBD1 Paul Monniera,b, Clémence Martineta, Julien Pontisc, Irina Stanchevad, Slimane Ait-Si-Alic, and Luisa Dandoloa,1 aGenetics and Development Department, Institut National de la Santé et de la Recherche Médicale U1016, Centre National de la Recherche Scientifique (CNRS) Unité Mixte de Recherche (UMR) 8104, University Paris Descartes, Institut Cochin, Paris 75014, France; bUniversity Paris Pierre and Marie Curie, Paris 75005, France; cUniversity Paris Diderot, Sorbonne Paris Cité, Laboratoire Epigénétique et Destin Cellulaire, CNRS UMR 7216, Paris 75013, France; and dWellcome Trust Centre for Cell Biology, University of Edinburgh, Edinburgh EH9 3JR, United Kingdom Edited by Marisa Bartolomei, University of Pennsylvania, Philadelphia, PA, and accepted by the Editorial Board November 11, 2013 (received for review May 30, 2013) The H19 gene controls the expression of several genes within the this control is transcriptional or posttranscriptional and whether Imprinted Gene Network (IGN), involved in growth control of the these nine targets are direct or indirect targets remain elusive. embryo. However, the underlying mechanisms of this control re- Several lncRNAs interact with chromatin-modifying com- main elusive. Here, we identified the methyl-CpG–binding domain plexes and appear to exert a transcriptional control by targeting fi protein 1 MBD1 as a physical and functional partner of the H19 local chromatin modi cations at discrete genomic regions (8, 9). long noncoding RNA (lncRNA). The H19 lncRNA–MBD1 complex is In the case of imprinted clusters, the DMRs controlling the ex- fi pression of imprinted genes exhibit parent-of-origin epigenetic required for the control of ve genes of the IGN.
    [Show full text]
  • Gene-Specific Targeting of H3K9 Methylation Is Sufficient for Initiating Repression in Vivo
    Current Biology, Vol. 12, 2159–2166, December 23, 2002, 2002 Elsevier Science Ltd. All rights reserved. PII S0960-9822(02)01391-X Gene-Specific Targeting of H3K9 Methylation Is Sufficient for Initiating Repression In Vivo Andrew W. Snowden, Philip D. Gregory,1 us to use an endogenous chromosomal gene as a tran- Casey C. Case, and Carl O. Pabo scriptional reporter system. All three constructs, G9A Sangamo BioSciences and both SUV39H1 deletion 76 and deletion 149 (re- Point Richmond Tech Center ferred to throughout as Suv Del 76 or Suv Del 149) 501 Canal Boulevard constructs, employed in this study contain the minimal Suite A100 catalytically active portions of the proteins [6, 14] (shown Richmond, California 94804 schematically in Figure 1A). Chimeras of ZFP-A with either G9A or the two SUV39H1 deletions were all able to efficiently repress the amount of VEGF-A protein (Figure Summary 1B) and mRNA (not shown) produced by the endoge- -fold, respectively, de-3ف and -2ف nous VEGF-A locus Covalent modifications of chromatin have emerged spite background VEGF-A gene expression from non- as key determinants of the genome’s transcriptional transfected cells. Fusion of an alternative repression competence [1–3]. Histone H3 lysine 9 (H3K9) methyla- domain encoding the LBD of v-ErbA, a viral relative of tion is an epigenetic signal that is recognized by HP1 avian thyroid hormone receptor protein and a known [4, 5] and correlates with gene silencing in a variety of HDAC3/NCoR recruitment domain, to ZFP-A led to a organisms [3]. Discovery of the enzymes that catalyze similar decrease in transcription from this locus (Figure H3K9 methylation [6–8] has identified a second gene- 1B).
    [Show full text]
  • Interaction with Suv39h1 Is Critical for Snail-Mediated E-Cadherin Repression in Breast Cancer
    Oncogene (2013) 32, 1351–1362 & 2013 Macmillan Publishers Limited All rights reserved 0950-9232/13 www.nature.com/onc ORIGINAL ARTICLE Interaction with Suv39H1 is critical for Snail-mediated E-cadherin repression in breast cancer C Dong1,2,YWu2,3, Y Wang1,2, C Wang2,4, T Kang5, PG Rychahou2,6, Y-I Chi1, BM Evers1,2,6 and BP Zhou1,2 Expression of E-cadherin, a hallmark of epithelial–mesenchymal transition (EMT), is often lost due to promoter DNA methylation in basal-like breast cancer (BLBC), which contributes to the metastatic advantage of this disease; however, the underlying mechanism remains unclear. Here, we identified that Snail interacted with Suv39H1 (suppressor of variegation 3-9 homolog 1), a major methyltransferase responsible for H3K9me3 that intimately links to DNA methylation. We demonstrated that the SNAG domain of Snail and the SET domain of Suv39H1 were required for their mutual interactions. We found that H3K9me3 and DNA methylation on the E-cadherin promoter were higher in BLBC cell lines. We showed that Snail interacted with Suv39H1 and recruited it to the E-cadherin promoter for transcriptional repression. Knockdown of Suv39H1 restored E-cadherin expression by blocking H3K9me3 and DNA methylation and resulted in the inhibition of cell migration, invasion and metastasis of BLBC. Our study not only reveals a critical mechanism underlying the epigenetic regulation of EMT, but also paves a way for the development of new treatment strategies against this disease. Oncogene (2013) 32, 1351–1362; doi:10.1038/onc.2012.169; published
    [Show full text]
  • Macrophage Migration Inhibitory Factor Mediates Peripheral Nerve Injury-Induced Hypersensitivity by Curbing Dopaminergic Descending Inhibition
    OPEN Experimental & Molecular Medicine (2018) 50, e445; doi:10.1038/emm.2017.271 Official journal of the Korean Society for Biochemistry and Molecular Biology www.nature.com/emm ORIGINAL ARTICLE Macrophage migration inhibitory factor mediates peripheral nerve injury-induced hypersensitivity by curbing dopaminergic descending inhibition Xian Wang1,6, Shaolei Ma2,6, Haibo Wu1,6, Xiaofeng Shen1,6, Shiqin Xu1, Xirong Guo3, Maria L Bolick4, Shizheng Wu5 and Fuzhou Wang1,4 Our previous works disclosed the contributing role of macrophage migration inhibitory factor (MIF) and dopaminergic inhibition by lysine dimethyltransferase G9a/Glp complex in peripheral nerve injury-induced hypersensitivity. We herein propose that the proinflammatory cytokine MIF participates in the regulation of neuropathic hypersensitivity by interacting with and suppressing the descending dopaminergic system. The lumbar spinal cord (L-SC) and ventral tegmental area (VTA) are two major locations with significant upregulation of MIF after chronic constriction injury (CCI) of the sciatic nerve, and they display time-dependent changes, along with a behavioral trajectory. Correspondingly, dopamine (DA) content shows the reverse characteristic change to MIF with a time-dependent curve in post-surgical behavior. The levels of both MIF and DA are reversed by the MIF tautomerase inhibitor ISO-1, and a negative relationship exists between MIF and DA. The reversed role of ISO-1 also affects tyrosine hydroxylase expression. Furthermore, CCI induces Th promoter CpG site methylation in the L-SC and VTA areas, and this effect could be abated by ISO-1 administration. G9a/SUV39H1 and H3K9me2/H3K9me3 enrichment within the Th promoter region following CCI in the L-SC and VTA was also decreased by ISO-1.
    [Show full text]
  • Effect of SUV39H1 Histone Methyltransferase Knockout On
    cells Article Effect of SUV39H1 Histone Methyltransferase Knockout on Expression of Differentiation-Associated Genes in HaCaT Keratinocytes Barbara Sobiak and Wiesława Le´sniak* Nencki Institute of Experimental Biology, Polish Academy of Sciences, 3 Pasteur Street, 02-093 Warsaw, Poland; [email protected] * Correspondence: [email protected]; Tel.: +48-22-5892-327; Fax: +48-22-822-5342 Received: 7 September 2020; Accepted: 4 December 2020; Published: 7 December 2020 Abstract: Keratinocytes undergo a complex differentiation process, coupled with extensive changes in gene expression through which they acquire distinctive features indispensable for cells that form the external body barrier—epidermis. Disturbed epidermal differentiation gives rise to multiple skin diseases. The involvement of epigenetic factors, such as DNA methylation or histone modifications, in the regulation of epidermal gene expression and differentiation has not been fully recognized yet. In this work we performed a CRISPR/Cas9-mediated knockout of SUV39H1, a gene-encoding H3K9 histone methyltransferase, in HaCaT cells that originate from spontaneously immortalized human keratinocytes and examined changes in the expression of selected differentiation-specific genes located in the epidermal differentiation complex (EDC) and other genomic locations by RT-qPCR. The studied genes revealed a diverse differentiation state-dependent or -independent response to a lower level of H3K9 methylation. We also show, by means of chromatin immunoprecipitation, that the expression of genes in the LCE1 subcluster of EDC was regulated by the extent of trimethylation of lysine 9 in histone H3 bound to their promoters. Changes in gene expression were accompanied by changes in HaCaT cell morphology and adhesion. Keywords: CRISPR/Cas9; epidermal differentiation; histone modifications; H3K9me3; LCE1 genes; SUV39H1 histone methyltransferase 1.
    [Show full text]
  • Epigenetic DNA Methylation of EBI3 Modulates Human Interleukin-35 Formation Via Nfkb Signaling: a Promising Therapeutic Option in Ulcerative Colitis
    International Journal of Molecular Sciences Article Epigenetic DNA Methylation of EBI3 Modulates Human Interleukin-35 Formation via NFkB Signaling: A Promising Therapeutic Option in Ulcerative Colitis Alexandra Wetzel 1, Bettina Scholtka 1 , Fabian Schumacher 2 , Harshadrai Rawel 1 , Birte Geisendörfer 1 and Burkhard Kleuser 2,* 1 Institute of Nutritional Science, University of Potsdam, 14558 Nuthetal, Germany; [email protected] (A.W.); [email protected] (B.S.); [email protected] (H.R.); [email protected] (B.G.) 2 Institute of Pharmacy, Freie Universität Berlin, 14195 Berlin, Germany; [email protected] * Correspondence: [email protected] Abstract: Ulcerative colitis (UC), a severe chronic disease with unclear etiology that is associated with increased risk for colorectal cancer, is accompanied by dysregulation of cytokines. Epstein–Barr virus- induced gene 3 (EBI3) encodes a subunit in the unique heterodimeric IL-12 cytokine family of either pro- or anti-inflammatory function. After having recently demonstrated that upregulation of EBI3 by histone acetylation alleviates disease symptoms in a dextran sulfate sodium (DSS)-treated mouse model of chronic colitis, we now aimed to examine a possible further epigenetic regulation of EBI3 Citation: Wetzel, A.; Scholtka, B.; by DNA methylation under inflammatory conditions. Treatment with the DNA methyltransferase Schumacher, F.; Rawel, H.; inhibitor (DNMTi) decitabine (DAC) and TNFα led to synergistic upregulation of EBI3 in human Geisendörfer, B.; Kleuser, B. colon epithelial cells (HCEC). Use of different signaling pathway inhibitors indicated NFκB signaling Epigenetic DNA Methylation of EBI3 was necessary and proportional to the synergistic EBI3 induction. MALDI-TOF/MS and HPLC-ESI- Modulates Human Interleukin-35 MS/MS analysis of DAC/TNFα-treated HCEC identified IL-12p35 as the most probable binding Formation via NFkB Signaling: A partner to form a functional protein.
    [Show full text]
  • Methylation of RUNX1 by PRMT1 Abrogates SIN3A Binding and Potentiates Its Transcriptional Activity
    Downloaded from genesdev.cshlp.org on September 30, 2021 - Published by Cold Spring Harbor Laboratory Press Methylation of RUNX1 by PRMT1 abrogates SIN3A binding and potentiates its transcriptional activity Xinyang Zhao,1 Vladimir Jankovic,1 Alexander Gural,1 Gang Huang,1 Animesh Pardanani,1 Silvia Menendez,1 Jin Zhang,1 Richard Dunne,1 Andrew Xiao,2 Hediye Erdjument-Bromage,1 C. David Allis,2 Paul Tempst,1 and Stephen D. Nimer1,3 1Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA; 2Rockefeller University, New York, New York 10021, USA RUNX1/AML1 is required for the development of definitive hematopoiesis, and its activity is altered by mutations, deletions, and chromosome translocations in human acute leukemia. RUNX1 function can be regulated by post-translational modifications and protein–protein interactions. We show that RUNX1 is arginine-methylated in vivo by the arginine methyltransferase PRMT1, and that PRMT1 serves as a transcriptional coactivator for RUNX1 function. Using mass spectrometry, and a methyl-arginine-specific antibody, we identified two arginine residues (R206 and R210) within the region of RUNX1 that interact with the corepressor SIN3A and are methylated by PRMT1. PRMT1- dependent methylation of RUNX1 at these arginine residues abrogates its association with SIN3A, whereas shRNA against PRMT1 (or use of a methyltransferase inhibitor) enhances this association. We find arginine-methylated RUNX1 on the promoters of two bona fide RUNX1 target genes, CD41 and PU.1 and show that shRNA against PRMT1 or RUNX1 down-regulates their expression. These arginine methylation sites and the dynamic regulation of corepressor binding are lost in the leukemia-associated RUNX1–ETO fusion protein, which likely contributes to its dominant inhibitory activity.
    [Show full text]
  • CBX5/G9a/H3k9me-Mediated Gene Repression Is Essential to Fibroblast Activation During Lung Fibrosis
    RESEARCH ARTICLE CBX5/G9a/H3K9me-mediated gene repression is essential to fibroblast activation during lung fibrosis Giovanni Ligresti,1 Nunzia Caporarello,1 Jeffrey A. Meridew,1 Dakota L. Jones,1 Qi Tan,1 Kyoung Moo Choi,1 Andrew J. Haak,1 Aja Aravamudhan,1 Anja C. Roden,2 Y.S. Prakash,1,3 Gwen Lomberk,4 Raul A. Urrutia,4 and Daniel J. Tschumperlin1 1Department of Physiology and Biomedical Engineering, 2Laboratory of Medicine and Pathology, and 3Department of Anesthesiology, Mayo Clinic, Rochester, Minnesota, USA. 4Division of Research,Department of Surgery and Genomic Sciences and Precision Medicine Center, Medical College of Wisconsin, Wauwatosa, Wisconsin, USA. Pulmonary fibrosis is a devastating disease characterized by accumulation of activated fibroblasts and scarring in the lung. While fibroblast activation in physiological wound repair reverses spontaneously, fibroblast activation in fibrosis is aberrantly sustained. Here we identified histone 3 lysine 9 methylation (H3K9me) as a critical epigenetic modification that sustains fibroblast activation by repressing the transcription of genes essential to returning lung fibroblasts to an inactive state. We show that the histone methyltransferase G9a (EHMT2) and chromobox homolog 5 (CBX5, also known as HP1α), which deposit H3K9me marks and assemble an associated repressor complex, respectively, are essential to initiation and maintenance of fibroblast activation specifically through epigenetic repression of peroxisome proliferator– activated receptor γ coactivator 1 α gene (PPARGC1A, encoding PGC1α). Both TGF-β and increased matrix stiffness potently inhibit PGC1α expression in lung fibroblasts through engagement of the CBX5/G9a pathway. Inhibition of the CBX5/G9a pathway in fibroblasts elevates PGC1α, attenuates TGF-β– and matrix stiffness–promoted H3K9 methylation, and reduces collagen accumulation in the lungs following bleomycin injury.
    [Show full text]
  • SUV39H1 Regulates the Progression of MLL-AF9-Induced Acute Myeloid Leukemia
    Oncogene (2020) 39:7239–7252 https://doi.org/10.1038/s41388-020-01495-6 ARTICLE SUV39H1 regulates the progression of MLL-AF9-induced acute myeloid leukemia 1 1 1,3 1 1 1 Yajing Chu ● Yangpeng Chen ● Huidong Guo ● Mengke Li ● Bichen Wang ● Deyang Shi ● 1 2 1 2 1 1 1 Xuelian Cheng ● Jinxia Guan ● Xiaomin Wang ● Chenghai Xue ● Tao Cheng ● Jun Shi ● Weiping Yuan Received: 17 February 2020 / Revised: 11 September 2020 / Accepted: 28 September 2020 / Published online: 9 October 2020 © The Author(s) 2020. This article is published with open access Abstract Epigenetic regulations play crucial roles in leukemogenesis and leukemia progression. SUV39H1 is the dominant H3K9 methyltransferase in the hematopoietic system, and its expression declines with aging. However, the role of SUV39H1 via its-mediated repressive modification H3K9me3 in leukemogenesis/leukemia progression remains to be explored. We found that SUV39H1 was down-regulated in a variety of leukemias, including MLL-r AML, as compared with normal individuals. Decreased levels of Suv39h1 expression and genomic H3K9me3 occupancy were observed in LSCs from MLL-r-induced AML mouse models in comparison with that of hematopoietic stem/progenitor cells. Suv39h1 overexpression increased MLL r Suv39h1 1234567890();,: 1234567890();,: leukemia latency and decreased the frequency of LSCs in - AML mouse models, while knockdown accelerated disease progression with increased number of LSCs. Increased Suv39h1 expression led to the inactivation of Hoxb13 and Six1, as well as reversion of Hoxa9/Meis1 downstream target genes, which in turn decelerated leukemia progression. Interestingly, Hoxb13 expression is up-regulated in MLL-AF9-induced AML cells, while knockdown of Hoxb13 in MLL-AF9 leukemic cells significantly prolonged the survival of leukemic mice with reduced LSC frequencies.
    [Show full text]
  • The N-Terminus of Histone H3 Is Required for De Novo DNA Methylation in Chromatin
    The N-terminus of histone H3 is required for de novo DNA methylation in chromatin Jia-Lei Hua,b, Bo O. Zhoua,b, Run-Rui Zhanga,b, Kang-Ling Zhangc, Jin-Qiu Zhoua,1, and Guo-Liang Xua,1 aThe State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China; bThe Graduate School, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China; and cDepartment of Biochemistry, School of Medicine, Loma Linda University, Loma Linda, CA 92350 Edited by Arthur D. Riggs, Beckman Research Institute of the City of Hope, Duarte, CA, and approved November 3, 2009 (received for review May 28, 2009) DNA methylation and histone modification are two major epige- maintenance methylation. For example, recent studies showed netic pathways that interplay to regulate transcriptional activity that G9a exerts its effect on DNA methylation independently of and other genome functions. Dnmt3L is a regulatory factor for the its enzymatic activity (6–8), and depletion of this protein might de novo DNA methyltransferases Dnmt3a and Dnmt3b. Although have an impact on the maintenance function of Dnmt1 (9, 10). recent biochemical studies have revealed that Dnmt3L binds to the While a repressive mark such as H3K9 methylation can tail of histone H3 with unmethylated lysine 4 in vitro, the require- presumably trigger DNA methylation, the active chromatin mark ment of chromatin components for DNA methylation has not been H3K4 methylation has been implicated as a repulsive signal (11). examined, and functional evidence for the connection of histone Dnmt3L, the regulatory protein that forms a complex with tails to DNA methylation is still lacking.
    [Show full text]
  • Crystal Structure of the Human SUV39H1 Chromodomain and Its Recognition of Histone H3k9me2/3
    Crystal Structure of the Human SUV39H1 Chromodomain and Its Recognition of Histone H3K9me2/3 Tao Wang1., Chao Xu2., Yanli Liu2,3, Kai Fan1, Zhihong Li2, Xing Sun2, Hui Ouyang2, Xuecheng Zhang4, Jiahai Zhang1, Yanjun Li2, Farrell MacKenzie2, Jinrong Min2,3*, Xiaoming Tu1* 1 Hefei National Laboratory for Physical Sciences at Microscale, School of Life Science, University of Science and Technology of China, Hefei, Anhui, People’s Republic of China, 2 Structural Genomics Consortium and Department of Physiology, University of Toronto, Toronto, Ontario, Canada, 3 Hubei Key Laboratory of Genetic Regulation and Integrative Biology, College of Life Science, Huazhong Normal University, Wuhan, People’s Republic of China, 4 School of Life Sciences, Anhui University, Hefei, Anhui, People’s Republic of China Abstract SUV39H1, the first identified histone lysine methyltransferase in human, is involved in chromatin modification and gene regulation. SUV39H1 contains a chromodomain in its N-terminus, which potentially plays a role in methyl-lysine recognition and SUV39H1 targeting. In this study, the structure of the chromodomain of human SUV39H1 was determined by X-ray crystallography. The SUV39H1 chromodomain displays a generally conserved structure fold compared with other solved chromodomains. However, different from other chromodomains, the SUV39H1 chromodomain possesses a much longer helix at its C-terminus. Furthermore, the SUV39H1 chromodomain was shown to recognize histone H3K9me2/3 specifically. Citation: Wang T, Xu C, Liu Y, Fan K, Li Z, et al. (2012) Crystal Structure of the Human SUV39H1 Chromodomain and Its Recognition of Histone H3K9me2/3. PLoS ONE 7(12): e52977. doi:10.1371/journal.pone.0052977 Editor: Esteban Ballestar, Bellvitge Biomedical Research Institute (IDIBELL), Spain Received May 21, 2012; Accepted November 22, 2012; Published December 28, 2012 Copyright: ß 2012 Wang et al.
    [Show full text]