Global DNA Methylation Patterns in Human Gliomas and Their Interplay with Other Epigenetic Modifications
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Suppression of DNA Double-Strand Break Formation by DNA Polymerase B in Active DNA Demethylation Is Required for Development of Hippocampal Pyramidal Neurons
9012 • The Journal of Neuroscience, November 18, 2020 • 40(47):9012–9027 Development/Plasticity/Repair Suppression of DNA Double-Strand Break Formation by DNA Polymerase b in Active DNA Demethylation Is Required for Development of Hippocampal Pyramidal Neurons Akiko Uyeda,1 Kohei Onishi,1 Teruyoshi Hirayama,1,2,3 Satoko Hattori,4 Tsuyoshi Miyakawa,4 Takeshi Yagi,1,2 Nobuhiko Yamamoto,1 and Noriyuki Sugo1 1Graduate School of Frontier Biosciences, Osaka University, Suita, Osaka 565-0871, Japan, 2AMED-CREST, Japan Agency for Medical Research and Development, Suita, Osaka 565-0871, Japan, 3Department of Anatomy and Developmental Neurobiology, Tokushima University Graduate School of Medical Sciences, Kuramoto, Tokushima 770-8503, Japan, and 4Institute for Comprehensive Medical Science, Fujita Health University, Toyoake, Aichi 470-1192, Japan Genome stability is essential for brain development and function, as de novo mutations during neuronal development cause psychiatric disorders. However, the contribution of DNA repair to genome stability in neurons remains elusive. Here, we demonstrate that the base excision repair protein DNA polymerase b (Polb) is involved in hippocampal pyramidal neuron fl/fl differentiation via a TET-mediated active DNA demethylation during early postnatal stages using Nex-Cre/Polb mice of ei- ther sex, in which forebrain postmitotic excitatory neurons lack Polb expression. Polb deficiency induced extensive DNA dou- ble-strand breaks (DSBs) in hippocampal pyramidal neurons, but not dentate gyrus granule cells, and to a lesser extent in neocortical neurons, during a period in which decreased levels of 5-methylcytosine and 5-hydroxymethylcytosine were observed in genomic DNA. Inhibition of the hydroxylation of 5-methylcytosine by expression of microRNAs miR-29a/b-1 diminished DSB formation. -
Oxidative Stress in Sperm Affects the Epigenetic Reprogramming in Early
Wyck et al. Epigenetics & Chromatin (2018) 11:60 https://doi.org/10.1186/s13072-018-0224-y Epigenetics & Chromatin RESEARCH Open Access Oxidative stress in sperm afects the epigenetic reprogramming in early embryonic development Sarah Wyck1,2,3, Carolina Herrera1, Cristina E. Requena4,5, Lilli Bittner1, Petra Hajkova4,5, Heinrich Bollwein1* and Rafaella Santoro2* Abstract Background: Reactive oxygen species (ROS)-induced oxidative stress is well known to play a major role in male infer- tility. Sperm are sensitive to ROS damaging efects because as male germ cells form mature sperm they progressively lose the ability to repair DNA damage. However, how oxidative DNA lesions in sperm afect early embryonic develop- ment remains elusive. Results: Using cattle as model, we show that fertilization using sperm exposed to oxidative stress caused a major developmental arrest at the time of embryonic genome activation. The levels of DNA damage response did not directly correlate with the degree of developmental defects. The early cellular response for DNA damage, γH2AX, is already present at high levels in zygotes that progress normally in development and did not signifcantly increase at the paternal genome containing oxidative DNA lesions. Moreover, XRCC1, a factor implicated in the last step of base excision repair (BER) pathway, was recruited to the damaged paternal genome, indicating that the maternal BER machinery can repair these DNA lesions induced in sperm. Remarkably, the paternal genome with oxidative DNA lesions showed an impairment of zygotic active DNA demethylation, a process that previous studies linked to BER. Quantitative immunofuorescence analysis and ultrasensitive LC–MS-based measurements revealed that oxidative DNA lesions in sperm impair active DNA demethylation at paternal pronuclei, without afecting 5-hydroxymethyl- cytosine (5hmC), a 5-methylcytosine modifcation that has been implicated in paternal active DNA demethylation in mouse zygotes. -
Tet2-Mediated Epigenetic Drive for Astrocyte Differentiation from Embryonic Neural Stem Cells Fei He1,Haowu2,3, Liqiang Zhou1,Quanlin4,Yincheng4 and Yi E
He et al. Cell Death Discovery (2020) 6:30 https://doi.org/10.1038/s41420-020-0264-5 Cell Death Discovery ARTICLE Open Access Tet2-mediated epigenetic drive for astrocyte differentiation from embryonic neural stem cells Fei He1,HaoWu2,3, Liqiang Zhou1,QuanLin4,YinCheng4 and Yi E. Sun1,4,5 Abstract DNA methylation and demethylation at CpG di-nucleotide sites plays important roles in cell fate specification of neural stem cells (NSCs). We have previously reported that DNA methyltransferases, Dnmt1and Dnmt3a, serve to suppress precocious astrocyte differentiation from NSCs via methylation of astroglial lineage genes. However, whether active DNA demethylase also participates in astrogliogenesis remains undetermined. In this study, we discovered that a Ten- eleven translocation (Tet) protein, Tet2, which was critically involved in active DNA demethylation through oxidation of 5-Methylcytosine (5mC), drove astrocyte differentiation from NSCs by demethylation of astroglial lineage genes including Gfap. Moreover, we found that an NSC-specific bHLH transcription factor Olig2 was an upstream inhibitor for Tet2 expression through direct association with the Tet2 promoter, and indirectly inhibited astrocyte differentiation. Our research not only revealed a brand-new function of Tet2 to promote NSC differentiation into astrocytes, but also a novel mechanism for Olig2 to inhibit astrocyte formation. Introduction stages (E11-12) mainly give rise to neurons, even in the 1234567890():,; 1234567890():,; 1234567890():,; 1234567890():,; Neural stem cells (NSCs) are self-renewing, multipotent presence of glial induction factors (e.g., bone morphoge- stem cells that possess both the ability to proliferate and netic protein (Bmp) or leukemia inhibitory factor (LIF)). self-renew and to differentiate into three major cell During in vitro culturing, NSCs gradually acquire com- lineages in the central nervous system (CNS), namely petence for astrogliogenesis and dampen their neurogenic neurons, astrocytes, and oligodendrocytes1. -
Aneuploidy: Using Genetic Instability to Preserve a Haploid Genome?
Health Science Campus FINAL APPROVAL OF DISSERTATION Doctor of Philosophy in Biomedical Science (Cancer Biology) Aneuploidy: Using genetic instability to preserve a haploid genome? Submitted by: Ramona Ramdath In partial fulfillment of the requirements for the degree of Doctor of Philosophy in Biomedical Science Examination Committee Signature/Date Major Advisor: David Allison, M.D., Ph.D. Academic James Trempe, Ph.D. Advisory Committee: David Giovanucci, Ph.D. Randall Ruch, Ph.D. Ronald Mellgren, Ph.D. Senior Associate Dean College of Graduate Studies Michael S. Bisesi, Ph.D. Date of Defense: April 10, 2009 Aneuploidy: Using genetic instability to preserve a haploid genome? Ramona Ramdath University of Toledo, Health Science Campus 2009 Dedication I dedicate this dissertation to my grandfather who died of lung cancer two years ago, but who always instilled in us the value and importance of education. And to my mom and sister, both of whom have been pillars of support and stimulating conversations. To my sister, Rehanna, especially- I hope this inspires you to achieve all that you want to in life, academically and otherwise. ii Acknowledgements As we go through these academic journeys, there are so many along the way that make an impact not only on our work, but on our lives as well, and I would like to say a heartfelt thank you to all of those people: My Committee members- Dr. James Trempe, Dr. David Giovanucchi, Dr. Ronald Mellgren and Dr. Randall Ruch for their guidance, suggestions, support and confidence in me. My major advisor- Dr. David Allison, for his constructive criticism and positive reinforcement. -
CPTC-CDK1-1 (CAB079974) Immunohistochemistry
CPTC-CDK1-1 (CAB079974) Uniprot ID: P06493 Protein name: CDK1_HUMAN Full name: Cyclin-dependent kinase 1 Tissue specificity: Isoform 2 is found in breast cancer tissues. Function: Plays a key role in the control of the eukaryotic cell cycle by modulating the centrosome cycle as well as mitotic onset; promotes G2-M transition, and regulates G1 progress and G1-S transition via association with multiple interphase cyclins. Required in higher cells for entry into S-phase and mitosis. Phosphorylates PARVA/actopaxin, APC, AMPH, APC, BARD1, Bcl-xL/BCL2L1, BRCA2, CALD1, CASP8, CDC7, CDC20, CDC25A, CDC25C, CC2D1A, CENPA, CSNK2 proteins/CKII, FZR1/CDH1, CDK7, CEBPB, CHAMP1, DMD/dystrophin, EEF1 proteins/EF-1, EZH2, KIF11/EG5, EGFR, FANCG, FOS, GFAP, GOLGA2/GM130, GRASP1, UBE2A/hHR6A, HIST1H1 proteins/histone H1, HMGA1, HIVEP3/KRC, LMNA, LMNB, LMNC, LBR, LATS1, MAP1B, MAP4, MARCKS, MCM2, MCM4, MKLP1, MYB, NEFH, NFIC, NPC/nuclear pore complex, PITPNM1/NIR2, NPM1, NCL, NUCKS1, NPM1/numatrin, ORC1, PRKAR2A, EEF1E1/p18, EIF3F/p47, p53/TP53, NONO/p54NRB, PAPOLA, PLEC/plectin, RB1, TPPP, UL40/R2, RAB4A, RAP1GAP, RCC1, RPS6KB1/S6K1, KHDRBS1/SAM68, ESPL1, SKI, BIRC5/survivin, STIP1, TEX14, beta-tubulins, MAPT/TAU, NEDD1, VIM/vimentin, TK1, FOXO1, RUNX1/AML1, SAMHD1, SIRT2 and RUNX2. CDK1/CDC2-cyclin-B controls pronuclear union in interphase fertilized eggs. Essential for early stages of embryonic development. During G2 and early mitosis, CDC25A/B/C-mediated dephosphorylation activates CDK1/cyclin complexes which phosphorylate several substrates that trigger at least centrosome separation, Golgi dynamics, nuclear envelope breakdown and chromosome condensation. Once chromosomes are condensed and aligned at the metaphase plate, CDK1 activity is switched off by WEE1- and PKMYT1-mediated phosphorylation to allow sister chromatid separation, chromosome decondensation, reformation of the nuclear envelope and cytokinesis. -
Sex-Specific Effects of Cytotoxic Chemotherapy Agents
www.impactaging.com AGING, April 2016, Vol 8 No 4 Research Paper Sex‐specific effects of cytotoxic chemotherapy agents cyclophospha‐ mide and mitomycin C on gene expression, oxidative DNA damage, and epigenetic alterations in the prefrontal cortex and hippocampus – an aging connection 1 2 2 2 Anna Kovalchuk , Rocio Rodriguez‐Juarez , Yaroslav Ilnytskyy , Boseon Byeon , Svitlana 3,4 4 3 1,5,6 2,5 Shpyleva , Stepan Melnyk , Igor Pogribny , Bryan Kolb, , and Olga Kovalchuk 1 Department of Neuroscience, University of Lethbridge, Lethbridge, AB, T1K3M4, Canada 2 Department of Biological Sciences, University of Lethbridge, Lethbridge, AB, T1K3M4, Canada 3 Division of Biochemical Toxicology, Food and Drug Administration National Center for Toxicological Research, Jefferson, AR 72079, USA 4Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72202, USA 5 Alberta Epigenetics Network, Calgary, AB, T2L 2A6, Canada 6 Canadian Institute for Advanced Research, Toronto, ON, M5G 1Z8, Canada Key words: chemotherapy, chemo brain, epigenetics, DNA methylation, DNA hydroxymethylation, oxidative stress, transcriptome, aging Received: 01/08/16; Accepted: 01/30/1 6; Published: 03/30/16 Corresponden ce to: Bryan Kolb, PhD; Olga Kovalchuk, PhD; E‐mail: [email protected]; [email protected] Copyright: Kovalchuk et al. This is an open‐access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited Abstract: Recent research shows that chemotherapy agents can be more toxic to healthy brain cells than to the target cancer cells. They cause a range of side effects, including memory loss and cognitive dysfunction that can persist long after the completion of treatment. -
DNA Excision Repair Proteins and Gadd45 As Molecular Players for Active DNA Demethylation
Cell Cycle ISSN: 1538-4101 (Print) 1551-4005 (Online) Journal homepage: http://www.tandfonline.com/loi/kccy20 DNA excision repair proteins and Gadd45 as molecular players for active DNA demethylation Dengke K. Ma, Junjie U. Guo, Guo-li Ming & Hongjun Song To cite this article: Dengke K. Ma, Junjie U. Guo, Guo-li Ming & Hongjun Song (2009) DNA excision repair proteins and Gadd45 as molecular players for active DNA demethylation, Cell Cycle, 8:10, 1526-1531, DOI: 10.4161/cc.8.10.8500 To link to this article: http://dx.doi.org/10.4161/cc.8.10.8500 Published online: 15 May 2009. Submit your article to this journal Article views: 135 View related articles Citing articles: 92 View citing articles Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=kccy20 Download by: [University of Pennsylvania] Date: 27 April 2017, At: 12:48 [Cell Cycle 8:10, 1526-1531; 15 May 2009]; ©2009 Landes Bioscience Perspective DNA excision repair proteins and Gadd45 as molecular players for active DNA demethylation Dengke K. Ma,1,2,* Junjie U. Guo,1,3 Guo-li Ming1-3 and Hongjun Song1-3 1Institute for Cell Engineering; 2Department of Neurology; and 3The Solomon Snyder Department of Neuroscience; Johns Hopkins University School of Medicine; Baltimore, MD USA Abbreviations: DNMT, DNA methyltransferases; PGCs, primordial germ cells; MBD, methyl-CpG binding protein; NER, nucleotide excision repair; BER, base excision repair; AP, apurinic/apyrimidinic; SAM, S-adenosyl methionine Key words: DNA demethylation, Gadd45, Gadd45a, Gadd45b, Gadd45g, 5-methylcytosine, deaminase, glycosylase, base excision repair, nucleotide excision repair DNA cytosine methylation represents an intrinsic modifica- silencing of gene activity or parasitic genetic elements (Fig. -
The Role of Active DNA Demethylation and Tet Enzyme Function in Memory Formation and Cocaine Action
Accepted Manuscript Title: The role of active DNA demethylation and Tet enzyme function in memory formation and cocaine action Author: Yasaman Alaghband Timothy W. Bredy Marcelo A. Wood PII: S0304-3940(16)30022-2 DOI: http://dx.doi.org/doi:10.1016/j.neulet.2016.01.023 Reference: NSL 31781 To appear in: Neuroscience Letters Received date: 15-8-2015 Revised date: 29-11-2015 Accepted date: 14-1-2016 Please cite this article as: Yasaman Alaghband, Timothy W.Bredy, Marcelo A.Wood, The role of active DNA demethylation and Tet enzyme function in memory formation and cocaine action, Neuroscience Letters http://dx.doi.org/10.1016/j.neulet.2016.01.023 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. The role of active DNA demethylation and Tet enzyme function in memory formation and cocaine action Yasaman Alaghband1,2, Timothy W. Bredy1,2,3, and Marcelo A. Wood1,2 1. Department of Neurobiology & Behavior, UC Irvine 2. Center for the Neurobiology of Learning and Memory, UC Irvine 3. Queensland Brain Institute, The University of Queensland, Brisbane, Australia Corresponding Author: Dr. Marcelo A Wood University of California Irvine Department of Neurobiology & Behavior 301 Qureshey Research Lab Irvine, CA 92697 [email protected] 949-824-2259 1 Abstract Active DNA modification is a major epigenetic mechanism that regulates gene expression in an experience-dependent manner, which is thought to establish stable changes in neuronal function and behavior. -
Synaptic Control of DNA Methylation Involves Activity-Dependent
www.nature.com/npp ARTICLE OPEN Synaptic control of DNA methylation involves activity- dependent degradation of DNMT3A1 in the nucleus Gonca Bayraktar 1,11, PingAn Yuanxiang 1, Alessandro D. Confettura1, Guilherme M. Gomes 1,2, Syed A. Raza3, Oliver Stork2,3, Shoji Tajima4, Isao Suetake 5,6,7, Anna Karpova1,2, Ferah Yildirim8 and Michael R. Kreutz 1,2,9,10 DNA methylation is a crucial epigenetic mark for activity-dependent gene expression in neurons. Very little is known about how synaptic signals impact promoter methylation in neuronal nuclei. In this study we show that protein levels of the principal de novo DNA-methyltransferase in neurons, DNMT3A1, are tightly controlled by activation of N-methyl-D-aspartate receptors (NMDAR) containing the GluN2A subunit. Interestingly, synaptic NMDARs drive degradation of the methyltransferase in a neddylation- dependent manner. Inhibition of neddylation, the conjugation of the small ubiquitin-like protein NEDD8 to lysine residues, interrupts degradation of DNMT3A1. This results in deficits in promoter methylation of activity-dependent genes, as well as synaptic plasticity and memory formation. In turn, the underlying molecular pathway is triggered by the induction of synaptic plasticity and in response to object location learning. Collectively, the data show that plasticity-relevant signals from GluN2A-containing NMDARs control activity-dependent DNA-methylation involved in memory formation. Neuropsychopharmacology (2020) 45:2120–2130; https://doi.org/10.1038/s41386-020-0780-2 1234567890();,: INTRODUCTION de novo DNA methyltransferase in the brain and plays a It is widely believed that rapid and reversible DNA methylation is documented role in activity-dependent DNA methylation essential for the stability of long-term memory but very little is [15, 16]. -
Strand Breaks for P53 Exon 6 and 8 Among Different Time Course of Folate Depletion Or Repletion in the Rectosigmoid Mucosa
SUPPLEMENTAL FIGURE COLON p53 EXONIC STRAND BREAKS DURING FOLATE DEPLETION-REPLETION INTERVENTION Supplemental Figure Legend Strand breaks for p53 exon 6 and 8 among different time course of folate depletion or repletion in the rectosigmoid mucosa. The input of DNA was controlled by GAPDH. The data is shown as ΔCt after normalized to GAPDH. The higher ΔCt the more strand breaks. The P value is shown in the figure. SUPPLEMENT S1 Genes that were significantly UPREGULATED after folate intervention (by unadjusted paired t-test), list is sorted by P value Gene Symbol Nucleotide P VALUE Description OLFM4 NM_006418 0.0000 Homo sapiens differentially expressed in hematopoietic lineages (GW112) mRNA. FMR1NB NM_152578 0.0000 Homo sapiens hypothetical protein FLJ25736 (FLJ25736) mRNA. IFI6 NM_002038 0.0001 Homo sapiens interferon alpha-inducible protein (clone IFI-6-16) (G1P3) transcript variant 1 mRNA. Homo sapiens UDP-N-acetyl-alpha-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase 15 GALNTL5 NM_145292 0.0001 (GALNT15) mRNA. STIM2 NM_020860 0.0001 Homo sapiens stromal interaction molecule 2 (STIM2) mRNA. ZNF645 NM_152577 0.0002 Homo sapiens hypothetical protein FLJ25735 (FLJ25735) mRNA. ATP12A NM_001676 0.0002 Homo sapiens ATPase H+/K+ transporting nongastric alpha polypeptide (ATP12A) mRNA. U1SNRNPBP NM_007020 0.0003 Homo sapiens U1-snRNP binding protein homolog (U1SNRNPBP) transcript variant 1 mRNA. RNF125 NM_017831 0.0004 Homo sapiens ring finger protein 125 (RNF125) mRNA. FMNL1 NM_005892 0.0004 Homo sapiens formin-like (FMNL) mRNA. ISG15 NM_005101 0.0005 Homo sapiens interferon alpha-inducible protein (clone IFI-15K) (G1P2) mRNA. SLC6A14 NM_007231 0.0005 Homo sapiens solute carrier family 6 (neurotransmitter transporter) member 14 (SLC6A14) mRNA. -
UC San Diego UC San Diego Electronic Theses and Dissertations
UC San Diego UC San Diego Electronic Theses and Dissertations Title Insights from reconstructing cellular networks in transcription, stress, and cancer Permalink https://escholarship.org/uc/item/6s97497m Authors Ke, Eugene Yunghung Ke, Eugene Yunghung Publication Date 2012 Peer reviewed|Thesis/dissertation eScholarship.org Powered by the California Digital Library University of California UNIVERSITY OF CALIFORNIA, SAN DIEGO Insights from Reconstructing Cellular Networks in Transcription, Stress, and Cancer A dissertation submitted in the partial satisfaction of the requirements for the degree Doctor of Philosophy in Bioinformatics and Systems Biology by Eugene Yunghung Ke Committee in charge: Professor Shankar Subramaniam, Chair Professor Inder Verma, Co-Chair Professor Web Cavenee Professor Alexander Hoffmann Professor Bing Ren 2012 The Dissertation of Eugene Yunghung Ke is approved, and it is acceptable in quality and form for the publication on microfilm and electronically ________________________________________________________________ ________________________________________________________________ ________________________________________________________________ ________________________________________________________________ Co-Chair ________________________________________________________________ Chair University of California, San Diego 2012 iii DEDICATION To my parents, Victor and Tai-Lee Ke iv EPIGRAPH [T]here are known knowns; there are things we know we know. We also know there are known unknowns; that is to say we know there -
DNA Methylation Alterations in Ipsc- and Hesc-Derived Neurons
de Boni et al. Clinical Epigenetics (2018) 10:13 DOI 10.1186/s13148-018-0440-0 RESEARCH Open Access DNA methylation alterations in iPSC- and hESC-derived neurons: potential implications for neurological disease modeling Laura de Boni1,2† , Gilles Gasparoni3†, Carolin Haubenreich2†, Sascha Tierling3, Ina Schmitt1,4, Michael Peitz2,4, Philipp Koch2, Jörn Walter3*, Ullrich Wüllner1,4* and Oliver Brüstle2* Abstract Background: Genetic predisposition and epigenetic alterations are both considered to contribute to sporadic neurodegenerative diseases (NDDs) such as Parkinson’s disease (PD). Since cell reprogramming and the generation of induced pluripotent stem cells (iPSCs) are themselves associated with major epigenetic remodeling, it remains unclear to what extent iPSC-derived neurons lend themselves to model epigenetic disease-associated changes. A key question to be addressed in this context is whether iPSC-derived neurons exhibit epigenetic signatures typically observed in neurons derived from non-reprogrammed human embryonic stem cells (hESCs). Results: Here, we compare mature neurons derived from hESC and isogenic human iPSC generated from hESC-derived neural stem cells. Genome-wide 450 K-based DNA methylation and HT12v4 gene array expression analyses were complemented by a deep analysis of selected genes known to be involved in NDD. Our studies show that DNA methylation and gene expression patterns of isogenic hESC- and iPSC-derived neurons are markedly preserved on a genome-wide and single gene level. Conclusions: Overall, iPSC-derived neurons exhibit similar DNA methylation patterns compared to isogenic hESC-derived neurons. Further studies will be required to explore whether the epigenetic patterns observed in iPSC-derived neurons correspond to those detectable in native brain neurons.