DOCSLIB.ORG

O-Glcnac and EZH2-Mediated Epigenetic Regulation of Gene Expression During Consolidation of Fear Memories

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
O-Glcnac and EZH2-Mediated Epigenetic Regulation of Gene Expression During Consolidation of Fear Memories Downloaded from learnmem.cshlp.org on October 4, 2021 - Published by Cold Spring Harbor Laboratory Press Research O-GlcNAc and EZH2-mediated epigenetic regulation of gene expression during consolidation of fear memories Anderson A. Butler, Richard G. Sanchez, Timothy J. Jarome, William M. Webb, and Farah D. Lubin Department of Neurobiology, the University of Alabama at Birmingham, Birmingham, Alabama 35294, USA O-GlcNAcylation of serine/threonine residues on target proteins occurs dynamically in postmitotic neurons of the hip- pocampus and may serve to control both the stability and activity of target proteins. Remarkably, the addition and removal of the O-GlcNAc posttranslational modifications are catalyzed by a pair of enzymes, the O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA). More than thousands of proteins are modified by O-GlcNAcylation including epigenetic modifying enzymes. A critical target of OGT is the polycomb repressive complex 2 (PRC2) containing the histone lysine methyltrans- ferase EZH2 that mediates trimethylation of lysine 27 on histone H3 (H3K27me3). However, whether OGT and PRC2 ac- tivity in the hippocampus couple to regulate gene transcription mechanisms during memory consolidation remains unknown. Here, we found increases in OGT expression and global O-GlcNAcylation levels in dorsal area CA1 of the hip- pocampus during memory consolidation. Additionally, we observed that OGT exerts control over epigenetic regulation via EZH2-H3K27me3 during memory consolidation. Blocking O-GlcNAc signaling via RNAi within dorsal area CA1 led to the global and site-specific loss of activity-dependent epigenetic plasticity at genes regulated by H3K27me3 and impairment of hippocampus-dependent memory. Together, these findings illustrate a unique epigenetic role of OGT via regulation of histone methylation mediated by EZH2 during memory consolidation of fear conditioned memories. The posttranslational attachment of β-N-glucosamine (GlcNAc) O-GlcNAcylation of histones has been reported in both yeast and to serine/threonine residues of proteins (O-GlcNAcylation) is human cells (Sakabe et al. 2010) and observed to facilitate changes the product of the hexosamine biosynthetic pathway (HBP), which in other epigenetic marks, such as histone monoubiquitination on integrates glucose, amino acid, fatty acid, and nucleotide metabo- H2B (Fujiki et al. 2011). Based on these findings, the significance of lism to generate the donor substrate uridine diphosphate N-acetyl- direct histone O-GlcNAcylation in many mammalian cell types re- glucosamine (UDP-GlcNAc) (Hart and Akimoto 2009; Yang and mains in question (Gagnon et al. 2015). Qian 2017). O-GlcNAc signaling is highly sensitive to various In addition to directly modifying histones and signaling forms of cellular stress, including heat/cold shock (Kazemi et al. proteins, OGT interacts with and regulates numerous chromatin 2010; Yao et al. 2018), hypoxia (Liu et al. 2014), and neuronal exci- modifying enzymes (CMEs) including the TET family of DNA totoxicity (Zhu et al. 2015). Although the O-GlcNAc axis is only hydroxylases (Chen et al. 2013; Dehennaut et al. 2014) and the beginning to be described in neuronal alterations, many upstream H3K27 methyltransferase EZH2 (Chu et al. 2014). Learning- kinases important for memory consolidation are known to inter- induced epigenetic changes mediated by both O-GlcNAc signaling sect with signaling to OGT and O-GlcNAcylation, including (Lagerlöf and Hart 2014; Wang et al. 2016; Yang et al. 2017; Lagerlöf CamKII (Erickson et al. 2013), PKA (Xie et al. 2016), PKC (includ- 2018), as well as OGT-regulated CMEs are critical for long-term ing PKC-zeta [Miura et al. 2018]), CREB (Rexach et al. 2012; Xie memory formation (Jarome and Lubin 2013, 2014); however, the et al. 2016), and many others (Hart et al. 2011). As a result, role of OGT in precipitating learning-induced epigenetic changes O-GlcNAcylation has been observed to function as a signal integra- remains unexplored. In the present study, we observed that OGT tor regulating virtually every aspect of cellular function including is necessary for learning-induced activation of H3K27me3 epige- transcription, translation, signal transduction, and metabolism. netic marks and that OGT activity is critical for memory formation. Consistent with these observations, disruption of OGT signaling and O-GlcNAcylation processes has been implicated in numerous Results neurodegenerative diseases, including epilepsy (Sánchez et al. 2019), Alzheimer’s disease (Xie et al. 2016), and Parkinson’s disease Fear learning triggers increases in O-GlcNAcylation (Wani et al. 2017). and OGT protein levels in the hippocampus In contrast to other forms of posttranslational glycosyla- We therefore sought to investigate the role of this critical signaling tion, which occur largely in the endoplasmic reticulum, pathway in hippocampus-dependent long-term memory. To ascer- O-GlcNAcylation of proteins occurs in the cytoplasm and nucleus tain whether the expression of OGT and protein O-GlcNAcylation (Comer and Hart 2000; Hart and Akimoto 2009). In the nucleus, O-GlcNAcylation occurs on numerous target proteins, consistent with a cellular role as an integrator of signals. In particular, direct # 2019 Butler et al. This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first 12 months after the full-issue publication date (see http://learnmem.cshlp.org/site/misc/terms.xhtml). After 12 months, it is Corresponding author: fl[email protected] available under a Creative Commons License (Attribution-NonCommercial 4.0 Article is online at http://www.learnmem.org/cgi/doi/10.1101/lm.049023.118. International), as described at http://creativecommons.org/licenses/by-nc/4.0/. 26:373–379; Published by Cold Spring Harbor Laboratory Press 373 Learning & Memory ISSN 1549-5485/19; www.learnmem.org Downloaded from learnmem.cshlp.org on October 4, 2021 - Published by Cold Spring Harbor Laboratory Press O-GlcNAc and histone methylation in memory consolidation are dynamically regulated during normal memory formation, relative to similarly treated naive controls (Fig. 2F), as observed we compared hippocampal nuclear lysates from Sprague Dawley above in untreated animals (Fig. 1B). Animals treated with OGT rats after training in contextual fear conditioning, a hippo- siRNAs had significantly reduced expression of hippocampal campus-dependent long-term memory paradigm (Fig. 1A). We ob- OGT and O-GlcNAc after training, resembling untrained animals served rapidly increased expression of both OGT and protein (Fig. 2F). Nup62 expression, an OGT substrate, was not sig- O-GlcNAcylation, as soon as 1 h, in trained animals relative to na- nificantly altered during memory consolidation; however, it was ive animals, while animals which received a latent inhibition significantly down-regulated after treatment with OGT siRNAs shock paradigm did not have elevated OGT or O-GlcNAc (Fig. (Fig. 2F). 1B). Similar increases in both OGT and O-GlcNAcylation were ob- served at 24 h posttraining, suggesting that memory-induced O-GlcNAc signaling persists through the memory consolidation Ogt knockdown selectively prevents memory-induced process (Fig. 1C). global and site-specific increases in H3K27me3 levels Several studies have recently reported interactions between Ogt knockdown prevents memory-induced global O-GlcNAc signaling and other histone posttranslational modifica- increases in O-GlcNAcylation tions. Many of these histone marks are known to be important We next sought to examine the necessity of OGT for long-term for hippocampal memory formation (Jarome and Lubin 2014). memory. To determine whether artificially lowering OGT expres- Therefore, we next sought to investigate the potential role of sion increases global levels of O-GlcNacylation, we directly infused O-GlcNAc signaling on memory-related epigenetic crosstalk. To Accell siRNAs (Dharmacon) into the dorsal CA1 and collected tis- determine changes in both memory-relevant changes in bulk fi sue around the target infusion site for downstream analysis (Fig. histone PTMs and site-speci c epigenetic alterations, we assayed 2A). We confirmed infusion into area CA1 with fluorescently la- nuclear histones via both western blots and ChIP-qPCR (Fig. 3A). beled control siRNAs (Fig. 2B). At 5 d postinfusion, we observed sig- We observed global changes in expression of numerous memory- nificant reductions in both OGT protein expression (Fig. 2C) and related histone PTMs after CFC training, including H2BubiK120, OGT mRNA expression in area CA1 but not in the untargeted H3K27me3, H3K4me3, and H3K14ac. H3K27me3 was the only retrosplenial cortex (Fig. 2D). To verify the sufficiency of siRNA in- mark assayed that was sensitive to pretreatment with OGT siRNA fusions to preclude learning-induced increases in OGT and (Fig. 3B). To investigate the necessity of OGT for memory-induced fi O-GlcNAc expression, we assayed hippocampal O-GlcNAc and H3K27me3 in vivo in a gene-speci c manner, we performed OGT in siRNA-treated animals after training in CFC (Fig. 2E). We ChIP-qPCR at numerous gene loci. We observed memory-induced observed that animals treated with a nontargeting siRNA had ele- decreases in promoter H3K27me3 in several memory-relevant fi vated levels of hippocampal O-GlcNAc and OGT after CFC training genes, including Bdnf, and Pkc-zeta. These ndings are consistent with previously observed increases in Bdnf and Pkc-zeta transcrip- tion during memory consolidation, as well as a memory-depen- dent increase at the promoter
Load more

Recommended publications
  • The Cross-Talk Between Methylation and Phosphorylation in Lymphoid-Specific Helicase Drives Cancer Stem-Like Properties
    Signal Transduction and Targeted Therapy www.nature.com/sigtrans ARTICLE OPEN The cross-talk between methylation and phosphorylation in lymphoid-specific helicase drives cancer stem-like properties Na Liu1,2,3, Rui Yang1,2, Ying Shi1,2, Ling Chen1,2, Yating Liu1,2, Zuli Wang1,2, Shouping Liu1,2, Lianlian Ouyang4, Haiyan Wang1,2, Weiwei Lai1,2, Chao Mao1,2, Min Wang1,2, Yan Cheng5, Shuang Liu4, Xiang Wang6, Hu Zhou7, Ya Cao1,2, Desheng Xiao1 and Yongguang Tao1,2,6 Posttranslational modifications (PTMs) of proteins, including chromatin modifiers, play crucial roles in the dynamic alteration of various protein properties and functions including stem-cell properties. However, the roles of Lymphoid-specific helicase (LSH), a DNA methylation modifier, in modulating stem-like properties in cancer are still not clearly clarified. Therefore, exploring PTMs modulation of LSH activity will be of great significance to further understand the function and activity of LSH. Here, we demonstrate that LSH is capable to undergo PTMs, including methylation and phosphorylation. The arginine methyltransferase PRMT5 can methylate LSH at R309 residue, meanwhile, LSH could as well be phosphorylated by MAPK1 kinase at S503 residue. We further show that the accumulation of phosphorylation of LSH at S503 site exhibits downregulation of LSH methylation at R309 residue, which eventually promoting stem-like properties in lung cancer. Whereas, phosphorylation-deficient LSH S503A mutant promotes the accumulation of LSH methylation at R309 residue and attenuates stem-like properties, indicating the critical roles of LSH PTMs in modulating stem-like properties. Thus, our study highlights the importance of the crosstalk between LSH PTMs in determining its activity and function in lung cancer stem-cell maintenance.
    [Show full text]
  • O-Glcnacylation Regulates the Stability and Enzymatic Activity of the Histone Methyltransferase EZH2
    O-GlcNAcylation regulates the stability and enzymatic activity of the histone methyltransferase EZH2 Pei-Wen Loa, Jiun-Jie Shieb, Chein-Hung Chena, Chung-Yi Wua, Tsui-Ling Hsua, and Chi-Huey Wonga,1 aGenomics Research Center, Academia Sinica, Taipei 115, Taiwan; and bInstitute of Chemistry, Academia Sinica, Taipei 115, Taiwan Contributed by Chi-Huey Wong, May 16, 2018 (sent for review February 1, 2018; reviewed by Michael D. Burkart, Benjamin G. Davis, and Gerald W. Hart) Protein O-glycosylation by attachment of β-N-acetylglucosamine maintenance and differentiation in embryonic stem cells (14, 15). (GlcNAc) to the Ser or Thr residue is a major posttranslational It was suggested that O-GlcNAcylation might play an important glycosylation event and is often associated with protein folding, role in the regulation of PRC1-mediated gene expression, and stability, and activity. The methylation of histone H3 at Lys-27 along this line the O-GlcNAcylation of EZH2 at S76 in the PRC2 catalyzed by the methyltransferase EZH2 was known to suppress complex was reported to stablize EZH2 in our previous study (16). gene expression and cancer development, and we previously The PRC2 complex is composed of Enhancer of zeste 2 (EZH2), reported that the O-GlcNAcylation of EZH2 at S76 stabilized Suppressor of Zeste 12 (Suz12), Extraembryonic endoderm (EED), EZH2 and facilitated the formation of H3K27me3 to inhibit tumor AE binding protein 2 (AEBP2), and retinoblastoma binding protein suppression. In this study, we employed a fluorescence-based method 4/7 (RBBP4/7) (17, 18). Within the PRC2 complex, EZH2 catalyzes the di- and trimethylation of histone H3 at lysine 27 (K27) to form of sugar labeling combined with mass spectrometry to investigate H3K27me2/3 to regulate embryonic and cancer development EZH2 glycosylation and identified five O-GlcNAcylation sites.
    [Show full text]
  • The Mutational Landscape of Myeloid Leukaemia in Down Syndrome
    cancers Review The Mutational Landscape of Myeloid Leukaemia in Down Syndrome Carini Picardi Morais de Castro 1, Maria Cadefau 1,2 and Sergi Cuartero 1,2,* 1 Josep Carreras Leukaemia Research Institute (IJC), Campus Can Ruti, 08916 Badalona, Spain; [email protected] (C.P.M.d.C); [email protected] (M.C.) 2 Germans Trias i Pujol Research Institute (IGTP), Campus Can Ruti, 08916 Badalona, Spain * Correspondence: [email protected] Simple Summary: Leukaemia occurs when specific mutations promote aberrant transcriptional and proliferation programs, which drive uncontrolled cell division and inhibit the cell’s capacity to differentiate. In this review, we summarize the most frequent genetic lesions found in myeloid leukaemia of Down syndrome, a rare paediatric leukaemia specific to individuals with trisomy 21. The evolution of this disease follows a well-defined sequence of events and represents a unique model to understand how the ordered acquisition of mutations drives malignancy. Abstract: Children with Down syndrome (DS) are particularly prone to haematopoietic disorders. Paediatric myeloid malignancies in DS occur at an unusually high frequency and generally follow a well-defined stepwise clinical evolution. First, the acquisition of mutations in the GATA1 transcription factor gives rise to a transient myeloproliferative disorder (TMD) in DS newborns. While this condition spontaneously resolves in most cases, some clones can acquire additional mutations, which trigger myeloid leukaemia of Down syndrome (ML-DS). These secondary mutations are predominantly found in chromatin and epigenetic regulators—such as cohesin, CTCF or EZH2—and Citation: de Castro, C.P.M.; Cadefau, in signalling mediators of the JAK/STAT and RAS pathways.
    [Show full text]
  • Distinct Contributions of DNA Methylation and Histone Acetylation to the Genomic Occupancy of Transcription Factors
    Downloaded from genome.cshlp.org on October 8, 2021 - Published by Cold Spring Harbor Laboratory Press Research Distinct contributions of DNA methylation and histone acetylation to the genomic occupancy of transcription factors Martin Cusack,1 Hamish W. King,2 Paolo Spingardi,1 Benedikt M. Kessler,3 Robert J. Klose,2 and Skirmantas Kriaucionis1 1Ludwig Institute for Cancer Research, University of Oxford, Oxford, OX3 7DQ, United Kingdom; 2Department of Biochemistry, University of Oxford, Oxford, OX1 3QU, United Kingdom; 3Target Discovery Institute, University of Oxford, Oxford, OX3 7FZ, United Kingdom Epigenetic modifications on chromatin play important roles in regulating gene expression. Although chromatin states are often governed by multilayered structure, how individual pathways contribute to gene expression remains poorly under- stood. For example, DNA methylation is known to regulate transcription factor binding but also to recruit methyl-CpG binding proteins that affect chromatin structure through the activity of histone deacetylase complexes (HDACs). Both of these mechanisms can potentially affect gene expression, but the importance of each, and whether these activities are inte- grated to achieve appropriate gene regulation, remains largely unknown. To address this important question, we measured gene expression, chromatin accessibility, and transcription factor occupancy in wild-type or DNA methylation-deficient mouse embryonic stem cells following HDAC inhibition. We observe widespread increases in chromatin accessibility at ret- rotransposons when HDACs are inhibited, and this is magnified when cells also lack DNA methylation. A subset of these elements has elevated binding of the YY1 and GABPA transcription factors and increased expression. The pronounced ad- ditive effect of HDAC inhibition in DNA methylation–deficient cells demonstrates that DNA methylation and histone deacetylation act largely independently to suppress transcription factor binding and gene expression.
    [Show full text]
  • Small Nucleolar Rnas Determine Resistance to Doxorubicin in Human Osteosarcoma
    International Journal of Molecular Sciences Article Small Nucleolar RNAs Determine Resistance to Doxorubicin in Human Osteosarcoma Martina Godel 1, Deborah Morena 1, Preeta Ananthanarayanan 1, Ilaria Buondonno 1, Giulio Ferrero 2,3 , Claudia M. Hattinger 4, Federica Di Nicolantonio 1,5 , Massimo Serra 4 , 1 2 1, , 1, , Riccardo Taulli , Francesca Cordero , Chiara Riganti * y and Joanna Kopecka * y 1 Department of Oncology, University of Torino, 1026 Torino, Italy; [email protected] (M.G.); [email protected] (D.M.); [email protected] (P.A.); [email protected] (I.B.); [email protected] (F.D.N.); [email protected] (R.T.) 2 Department of Computer Science, University of Torino, 10149 Torino, Italy; [email protected] (G.F.); [email protected] (F.C.) 3 Department of Clinical and Biological Sciences, University of Torino, 10043 Orbassano, Italy 4 Laboratory of Experimental Oncology, Pharmacogenomics and Pharmacogenetics Research Unit, IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy; [email protected] (C.M.H.); [email protected] (M.S.) 5 Candiolo Cancer Institute, FPO–IRCCS, 10060 Candiolo, Italy * Correspondence: [email protected] (C.R.); [email protected] (J.K.); Tel.: +39-0116705857 (C.R.); +39-0116705849 (J.K.) These authors equally contributed to this work. y Received: 31 May 2020; Accepted: 21 June 2020; Published: 24 June 2020 Abstract: Doxorubicin (Dox) is one of the most important first-line drugs used in osteosarcoma therapy. Multiple and not fully clarified mechanisms, however, determine resistance to Dox. With the aim of identifying new markers associated with Dox-resistance, we found a global up-regulation of small nucleolar RNAs (snoRNAs) in human Dox-resistant osteosarcoma cells.
    [Show full text]
  • Automethylation of PRC2 Promotes H3K27 Methylation and Is Impaired in H3K27M Pediatric Glioma
    Downloaded from genesdev.cshlp.org on October 5, 2021 - Published by Cold Spring Harbor Laboratory Press Automethylation of PRC2 promotes H3K27 methylation and is impaired in H3K27M pediatric glioma Chul-Hwan Lee,1,2,7 Jia-Ray Yu,1,2,7 Jeffrey Granat,1,2,7 Ricardo Saldaña-Meyer,1,2 Joshua Andrade,3 Gary LeRoy,1,2 Ying Jin,4 Peder Lund,5 James M. Stafford,1,2,6 Benjamin A. Garcia,5 Beatrix Ueberheide,3 and Danny Reinberg1,2 1Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York 10016, USA; 2Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA; 3Proteomics Laboratory, New York University School of Medicine, New York, New York 10016, USA; 4Shared Bioinformatics Core, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA; 5Department of Biochemistry and Molecular Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA The histone methyltransferase activity of PRC2 is central to the formation of H3K27me3-decorated facultative heterochromatin and gene silencing. In addition, PRC2 has been shown to automethylate its core subunits, EZH1/ EZH2 and SUZ12. Here, we identify the lysine residues at which EZH1/EZH2 are automethylated with EZH2-K510 and EZH2-K514 being the major such sites in vivo. Automethylated EZH2/PRC2 exhibits a higher level of histone methyltransferase activity and is required for attaining proper cellular levels of H3K27me3. While occurring inde- pendently of PRC2 recruitment to chromatin, automethylation promotes PRC2 accessibility to the histone H3 tail. Intriguingly, EZH2 automethylation is significantly reduced in diffuse intrinsic pontine glioma (DIPG) cells that carry a lysine-to-methionine substitution in histone H3 (H3K27M), but not in cells that carry either EZH2 or EED mutants that abrogate PRC2 allosteric activation, indicating that H3K27M impairs the intrinsic activity of PRC2.
    [Show full text]
  • Ubiquitination/Deubiquitination and Acetylation/Deacetylation
    Acta Pharmacologica Sinica (2011) 32: 139–140 npg © 2011 CPS and SIMM All rights reserved 1671-4083/11 $32.00 www.nature.com/aps Research Highlight Ubiquitination/deubiquitination and acetylation/ deacetylation: Making DNMT1 stability more coordinated Qi HONG, Zhi-ming SHAO* Acta Pharmacologica Sinica (2011) 32: 139–140; doi: 10.1038/aps.2011.3 n mammals, DNA methylation plays important role in human cancers[7, 8]. abundance of DNMT1 mutant lacking Ia crucial role in the regulation of Ubiquitin­proteasome pathway is sig­ the HAUSP interaction domain, but not gene expression, telomere length, cell nificant in the stability of DNMT1[8], but the full­length protein. These results differentiation, X chromosome inactiva­ ubiquitin­mediated protein degradation show the coordination between ubiquit­ tion, genomic imprinting and tumori­ can be enhanced or attenuated by some ination of DNMT1 by UHRF1 and deu­ genesis[1]. DNA methylation patterns modifications like acetylation/deacety­ biquitination by HAUSP. Furthermore, are established de novo by DNA meth­ lation, protein methylation/demethyla­ they found that knockdown of HDAC1 yltransferases (DNMTs) 3a and 3b, tion, phosphorylation and S­nitrosy­ increased DNMT1 acetylation, and whereas DNMT1 maintains the parent­ lation[9–11]. Estève et al demonstrated reduced DNMT1 abundance. Addition­ specific methylation from parental cells that SET7­mediated lysine methy lation ally, acetyltransferase Tip60 which was to their progeny[2]. After DNA replica­ of DNMT1 decreased DNMT1 level found to acetylate DNMT1 promoted its tion, the new DNA strand is unmethy­ by ubiquitin­mediated degradation[10]. ubiquitination, then destabilized it. At lated. Thus with the mother methylated Furthermore, an early study[12] showed last, Tip60 and HAUSP were found to strand, the DNA is hemimethylated.
    [Show full text]
  • 1519038862M28translationand
    Paper No. : 15 Molecular Cell Biology Module : 28 Translation and Post-translation Modifications in Eukaryotes Development Team Principal Investigator : Prof. Neeta Sehgal Department of Zoology, University of Delhi Co-Principal Investigator : Prof. D.K. Singh Department of Zoology, University of Delhi Paper Coordinator : Prof. Kuldeep K. Sharma Department of Zoology, University of Jammu Content Writer : Dr. Renu Solanki, Deen Dayal Upadhyaya College Dr. Sudhida Gautam, Hansraj College, University of Delhi Mr. Kiran K. Salam, Hindu College, University of Delhi Content Reviewer : Prof. Rup Lal Department of Zoology, University of Delhi 1 Molecular Genetics ZOOLOGY Translation and Post-translation Modifications in Eukaryotes Description of Module Subject Name ZOOLOGY Paper Name Molecular Cell Biology; Zool 015 Module Name/Title Cell regulatory mechanisms Module Id M28: Translation and Post-translation Modifications in Eukaryotes Keywords Genome, Proteome diversity, post-translational modifications, glycosylation, phosphorylation, methylation Contents 1. Learning Objectives 2. Introduction 3. Purpose of post translational modifications 4. Post translational modifications 4.1. Phosphorylation, the addition of a phosphate group 4.2. Methylation, the addition of a methyl group 4.3. Glycosylation, the addition of sugar groups 4.4. Disulfide bonds, the formation of covalent bonds between 2 cysteine amino acids 4.5. Proteolysis/ Proteolytic Cleavage 4.6. Subunit binding to form a multisubunit protein 4.7. S-nitrosylation 4.8. Lipidation 4.9. Acetylation 4.10. Ubiquitylation 4.11. SUMOlytion 4.12. Vitamin C-Dependent Modifications 4.13. Vitamin K-Dependent Modifications 4.14. Selenoproteins 4.15. Myristoylation 5. Chaperones: Role in PTM and mechanism 6. Role of PTMs in diseases 7. Detecting and Quantifying Post-Translational Modifications 8.
    [Show full text]
  • Transcriptional Regulation by Histone Ubiquitination and Deubiquitination
    Downloaded from genesdev.cshlp.org on September 30, 2021 - Published by Cold Spring Harbor Laboratory Press PERSPECTIVE Transcriptional regulation by histone ubiquitination and deubiquitination Yi Zhang1 Department of Biochemistry and Biophysics, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, North Carolina 27599, USA Ubiquitin (Ub) is a 76-amino acid protein that is ubiqui- The fact that histone ubiquitination occurs in the largely tously distributed and highly conserved throughout eu- monoubiquitinated form and is not linked to degrada- karyotic organisms. Whereas the extreme C-terminal tion, in combination with the lack of information regard- four amino acids are in a random coil, its N-terminal 72 ing the responsible enzymes, prevented us from under- amino acids have a tightly folded globular structure (Vi- standing the functional significance of this modification. jay-Kumar et al. 1987; Fig. 1A). Since its discovery ∼28 Recent identification of the E2 and E3 proteins involved years ago (Goldknopf et al. 1975), a variety of cellular in H2B ubiquitination (Robzyk et al. 2000; Hwang et al. processes including protein degradation, stress response, 2003; Wood et al. 2003a) and the discovery of cross-talk cell-cycle regulation, protein trafficking, endocytosis sig- between histone methylation and ubiquitination (Dover naling, and transcriptional regulation have been linked et al. 2002; Sun and Allis 2002) have set the stage for to this molecule (Pickart 2001). Ubiquitylation is pro- functional analysis of histone ubiquitination. In a timely posed to serve as a signaling module, and the informa- paper published in the previous issue of Genes & Devel- tion transmitted by this tag may depend on the nature of opment, Shelley Berger and colleagues (Henry et al.
    [Show full text]
  • Polycomb Repressor Complex 2 Function in Breast Cancer (Review)
    INTERNATIONAL JOURNAL OF ONCOLOGY 57: 1085-1094, 2020 Polycomb repressor complex 2 function in breast cancer (Review) COURTNEY J. MARTIN and ROGER A. MOOREHEAD Department of Biomedical Sciences, Ontario Veterinary College, University of Guelph, Guelph, ON N1G2W1, Canada Received July 10, 2020; Accepted September 7, 2020 DOI: 10.3892/ijo.2020.5122 Abstract. Epigenetic modifications are important contributors 1. Introduction to the regulation of genes within the chromatin. The poly- comb repressive complex 2 (PRC2) is a multi‑subunit protein Epigenetic modifications, including DNA methylation complex that is involved in silencing gene expression through and histone modifications, play an important role in gene the trimethylation of lysine 27 at histone 3 (H3K27me3). The regulation. The dysregulation of these modifications can dysregulation of this modification has been associated with result in pathogenicity, including tumorigenicity. Research tumorigenicity through the increased repression of tumour has indicated an important influence of the trimethylation suppressor genes via condensing DNA to reduce access to the modification at lysine 27 on histone H3 (H3K27me3) within transcription start site (TSS) within tumor suppressor gene chromatin. This methylation is involved in the repression promoters. In the present review, the core proteins of PRC2, as of multiple genes within the genome by condensing DNA well as key accessory proteins, will be described. In addition, to reduce access to the transcription start site (TSS) within mechanisms controlling the recruitment of the PRC2 complex gene promoter sequences (1). The recruitment of H1.2, an H1 to H3K27 will be outlined. Finally, literature identifying the histone subtype, by the H3K27me3 modification has been a role of PRC2 in breast cancer proliferation, apoptosis and suggested as a mechanism for mediating this compaction (1).
    [Show full text]
  • Engaging Chromatin: PRC2 Structure Meets Function
    www.nature.com/bjc REVIEW ARTICLE Engaging chromatin: PRC2 structure meets function Paul Chammas1, Ivano Mocavini1 and Luciano Di Croce1,2,3 Polycomb repressive complex 2 (PRC2) is a key epigenetic multiprotein complex involved in the regulation of gene expression in metazoans. PRC2 is formed by a tetrameric core that endows the complex with histone methyltransferase activity, allowing it to mono-, di- and tri-methylate histone H3 on lysine 27 (H3K27me1/2/3); H3K27me3 is a hallmark of facultative heterochromatin. The core complex of PRC2 is bound by several associated factors that are responsible for modulating its targeting specificity and enzymatic activity. Depletion and/or mutation of the subunits of this complex can result in severe developmental defects, or even lethality. Furthermore, mutations of these proteins in somatic cells can be drivers of tumorigenesis, by altering the transcriptional regulation of key tumour suppressors or oncogenes. In this review, we present the latest results from structural studies that have characterised PRC2 composition and function. We compare this information with data and literature for both gain-of function and loss-of-function missense mutations in cancers to provide an overview of the impact of these mutations on PRC2 activity. British Journal of Cancer (2020) 122:315–328; https://doi.org/10.1038/s41416-019-0615-2 BACKGROUND and embryonic ectoderm development (EED) (Table 1). These Transcriptional diversity is one of the hallmarks of cellular three proteins form the minimal core that confers histone identity. It is largely regulated at the level of chromatin, where methyltransferase (HMT) activity. A fourth factor, retinoblastoma- different protein complexes act as initiators, enhancers and/or binding protein (RBBP)4/7 (also known as RBAP48/46), has a repressors of transcription.
    [Show full text]
  • Targeting the MTF2-MDM2 Axis Sensitizes Refractory Acute Myeloid Leukemia to Chemotherapy
    Author Manuscript Published OnlineFirst on August 16, 2018; DOI: 10.1158/2159-8290.CD-17-0841 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Targeting the MTF2-MDM2 Axis Sensitizes Refractory Acute Myeloid Leukemia to Chemotherapy Harinad B. Maganti1,2,3†, Hani Jrade1,2,4†, Christopher Cafariello1,2,4, Janet L. Manias Rothberg1,2,4, Christopher J. Porter5, Julien Yockell-Lelièvre1,2, Hannah L. Battaion1,2,4, Safwat T. Khan1, Joel P. Howard1, Yuefeng Li1,2,4, Adrian T. Grzybowski6, Elham Sabri9, Alexander J. Ruthenburg6, F. Jeffrey Dilworth1,2,4, Theodore J. Perkins1,3,5, Mitchell Sabloff7,8, Caryn Y. Ito1,4* & William L. Stanford1,2,3,4* 1The Sprott Center for Stem Cell Research, Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada K1H 8L6; 2Ottawa Institute of Systems Biology, Ottawa, Ontario, Canada; 3Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada; 4Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada; 5Ottawa Bioinformatics Core Facility, The Sprott Center for Stem Cell Research, Ottawa Hospital Research Institute, Ottawa, ON, Canada K1H 8L6 6Department of Molecular Genetics and Cell Biology, The University of Chicago, Chicago, Illinois, USA 60637 7Division of Hematology, Department of Medicine, University of Ottawa, Ottawa, Canada 8Ottawa Hospital Research Institute, Ottawa, ON, Canada Canada K1H 8L6 9Clinical Epidemiology Methods Centre, Ottawa Hospital Research Institute, Ottawa, ON, Canada K1H 8L6 †These authors contributed equally to this work. *Correspondence to: Caryn Ito, [email protected]; William L. Stanford, [email protected] Ottawa Hospital, 501 Smyth Rd, Box 511 Ottawa, ON K1H 8L6 CANADA 613-737-8899 ext.
    [Show full text]