Advertisement

Epigenetics in amyotrophic lateral sclerosis: a role for histone post-translational modifications in neurodegenerative disease

  • Seth A. Bennett
    Affiliations
    Department of Chemistry, Brooklyn College, Brooklyn, NewYork

    Ph.D. Program in Biochemistry, The Graduate Center of the City University of New York, New York, New York
    Search for articles by this author
  • Royena Tanaz
    Affiliations
    Department of Chemistry, Brooklyn College, Brooklyn, NewYork
    Search for articles by this author
  • Samantha N. Cobos
    Affiliations
    Department of Chemistry, Brooklyn College, Brooklyn, NewYork

    Ph.D. Program in Chemistry, The Graduate Center of the City University of New York, New York, NY 10016
    Search for articles by this author
  • Author Footnotes
    1 Mariana P. Torrente, PhD, is an Assistant Professor in the Department of Chemistry at Brooklyn College. Dr. Torrente's research programs aims to integrate the different viewpoints of epigenetics, protein folding and molecular neurobiology to answer central questions underlying neurodegenerative and neuropsychiatric disease at the molecular level.
    Mariana P. Torrente
    Correspondence
    Reprint requests: Mariana P. Torrente, Department of chemistry, Brooklyn College, 2900 Bedford Ave., Brooklyn, NY 11210;
    Footnotes
    1 Mariana P. Torrente, PhD, is an Assistant Professor in the Department of Chemistry at Brooklyn College. Dr. Torrente's research programs aims to integrate the different viewpoints of epigenetics, protein folding and molecular neurobiology to answer central questions underlying neurodegenerative and neuropsychiatric disease at the molecular level.
    Affiliations
    Department of Chemistry, Brooklyn College, Brooklyn, NewYork

    Ph.D. Programs in Chemistry, Biochemistry, and Biology, The Graduate Center of the City University of New York, New York, New York
    Search for articles by this author
  • Author Footnotes
    1 Mariana P. Torrente, PhD, is an Assistant Professor in the Department of Chemistry at Brooklyn College. Dr. Torrente's research programs aims to integrate the different viewpoints of epigenetics, protein folding and molecular neurobiology to answer central questions underlying neurodegenerative and neuropsychiatric disease at the molecular level.
Published:October 11, 2018DOI:https://doi.org/10.1016/j.trsl.2018.10.002
      Amyotrophic lateral sclerosis (ALS) is the third most common adult onset neurodegenerative disorder worldwide. It is generally characterized by progressive paralysis starting at the limbs ultimately leading to death caused by respiratory failure. There is no cure and current treatments fail to slow the progression of the disease. As such, new treatment options are desperately needed. Epigenetic targets are an attractive possibility because they are reversible. Epigenetics refers to heritable changes in gene expression unrelated to changes in DNA sequence. Three main epigenetic mechanisms include the methylation of DNA, microRNAs and the post-translational modification of histone proteins. Histone modifications occur in many amino acid residues and include phosphorylation, acetylation, methylation as well as other chemical moieties. Recent evidence points to a possible role for epigenetic mechanisms in the etiology of ALS. Here, we review recent advances linking ALS and epigenetics, with a strong focus on histone modifications. Both local and global changes in histone modification profiles are associated with ALS drawing attention to potential targets for future diagnostic and treatment approaches.

      Abbreviations

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Translational Research
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Pang SY-Y
        • Hsu JS
        • Teo K-C
        • et al.
        Burden of rare variants in ALS genes influences survival in familial and sporadic ALS.
        Neurobiol Aging. 2017; 58 (e9-.e15): 238
        • Zarei S
        • Carr K
        • Reiley L
        • et al.
        A comprehensive review of amyotrophic lateral sclerosis.
        Surg Neurol Int. 2015; 6: 171
        • The Scottish Motor Neuron Disease
        Register: a prospective study of adult onset motor neuron disease in Scotland. Methodology, demography and clinical features of incident cases in 1989.
        J Neurol Neurosurg Psychiatry. 1992; 55: 536
        • Ferrari R
        • Kapogiannis D
        • Huey ED
        • et al.
        FTD and ALS: a tale of two diseases.
        Curr Alzheimer Res. 2011; 8: 273-294
        • Debove C
        • Zeisser P
        • Salzman PM
        • et al.
        The Rilutek (riluzole) global early access programme: an open-label safety evaluation in the treatment of amyotrophic lateral sclerosis.
        Amyotrophic Lateral Scler Other Motor Neuron Disord. 2001; 2: 153-158
      1. Brooks BR, Jorgenson JA, Newhouse BJ, et al. Edaravone in the treatment of amyotrophic lateral sclerosis: efficacy and access to therapy - a roundtable discussion. 2018. S175-S86 p.

        • Belzil VV
        • Katzman RB
        • Petrucelli L
        ALS and FTD: an epigenetic perspective.
        Acta Neuropathologica. 2016; 132: 487-502
        • Al-Chalabi A
        • Hardiman O
        The epidemiology of ALS: a conspiracy of genes, environment and time.
        Nat Rev Neurol. 2013; 9: 617
        • Ling S-C.
        Synaptic paths to neurodegeneration: the emerging role of TDP-43 and FUS in synaptic functions.
        Neural Plasticity. 2018; 20188413496
        • Arai T
        • Hasegawa M
        • Akiyama H
        • et al.
        TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis.
        Biochem Biophys Res Commun. 2006; 351: 602-611
        • Gonzalez DM
        • Gregory J
        • Brennand KJ
        The importance of non-neuronal cell types in hiPSC-based disease modeling and drug screening.
        Front Cell Dev Biol. 2017; 5: 117
        • Clement AM
        • Nguyen MD
        • Roberts EA
        • et al.
        Wild-type nonneuronal cells extend survival of SOD1 mutant motor neurons in ALS mice.
        Science. 2003; 302: 113
        • Yamanaka K
        • Chun SJ
        • Boillee S
        • et al.
        Astrocytes as determinants of disease progression in inherited ALS.
        Nat neurosci. 2008; 11: 251-253
        • Boillée S
        • Yamanaka K
        • Lobsiger CS
        • et al.
        Onset and Progression in Inherited ALS Determined by Motor Neurons and Microglia.
        Science. 2006; 312: 1389
        • Di Giorgio FP
        • Carrasco MA
        • Siao MC
        • et al.
        Non-cell autonomous effect of glia on motor neurons in an embryonic stem cell-based ALS model.
        Nat Neurosci. 2007; 10: 608
        • Di Giorgio FP
        • Boulting GL
        • Bobrowicz S
        • et al.
        Human embryonic stem cell-derived motor neurons are sensitive to the toxic effect of glial cells carrying an ALS-causing mutation.
        Cell Stem Cell. 2008; 3: 637-648
        • Paez-Colasante X
        • Figueroa-Romero C
        • Sakowski SA
        • et al.
        Amyotrophic lateral sclerosis: mechanisms and therapeutics in the epigenomic era.
        Nat Rev Neurol. 2015; 11: 266-279
        • Allis CD
        • Jenuwein T
        The molecular hallmarks of epigenetic control.
        Nat Rev Genet. 2016; 17: 487
        • Bird A
        DNA methylation patterns and epigenetic memory.
        Genes Dev. 2002; 16: 6-21
        • Ziller MJ
        • Ortega JA
        • Quinlan KA
        • et al.
        Dissecting the functional consequences of de novo DNA methylation dynamics in human motor neuron differentiation and physiology.
        Cell Stem Cell. 2018; 22 (e9): 559-574
        • Lu H
        • Liu X
        • Deng Y
        • et al.
        DNA methylation, a hand behind neurodegenerative diseases.
        Front Aging Neurosci. 2013; 5: 85
        • Cannell Ian G
        • Kong Yi W
        • Bushell M
        How do microRNAs regulate gene expression?.
        Biochem Soc Trans. 2008; 36: 1224
        • Luger K
        • Mäder AW
        • Richmond RK
        • et al.
        Crystal structure of the nucleosome core particle at 2.8 Å resolution.
        Nature. 1997; 389: 251
        • Mazzio EA
        • Soliman KFA
        Basic concepts of epigenetics.
        Epigenetics. 2012; 7: 119-130
        • Norton VG
        • Marvin KW
        • Yau P
        • et al.
        Nucleosome linking number change controlled by acetylation of histones H3 and H4.
        J Biol Chem. 1990; 265: 19848-19852
        • Lee DY
        • Hayes JJ
        • Pruss D
        • et al.
        A positive role for histone acetylation in transcription factor access to nucleosomal DNA.
        Cell. 1993; 72: 73-84
        • Hong L
        • Schroth GP
        • Matthews HR
        • et al.
        Studies of the DNA binding properties of histone H4 amino terminus. Thermal denaturation studies reveal that acetylation markedly reduces the binding constant of the H4 "tail" to DNA.
        J Biol Chem. 1993; 268: 305-314
        • Norton VG
        • Imai BS
        • Yau P
        • et al.
        Histone acetylation reduces nucleosome core particle linking number change.
        Cell. 1989; 57: 449-457
        • Garcia BA
        • Shabanowitz J
        • Hunt DF
        Characterization of histones and their post-translational modifications by mass spectrometry.
        Curr Opin Chem Biol. 2007; 11: 66-73
        • Strahl BD
        • Allis CD
        The language of covalent histone modifications.
        Nature. 2000; 403: 41
        • Latham JA
        • Dent SY
        Cross-regulation of histone modifications.
        Nat Struct Mol Biol. 2007; 14: 1017-1024
        • Zippo A
        • Serafini R
        • Rocchigiani M
        • et al.
        Histone crosstalk between H3S10ph and H4K16ac generates a histone code that mediates transcription elongation.
        Cell. 2009; 138: 1122-1136
        • Fischle W
        • Tseng BS
        • Dormann HL
        • et al.
        Regulation of HP1-chromatin binding by histone H3 methylation and phosphorylation.
        Nature. 2005; 438: 1116
        • Figueroa-Romero C
        • Hur J
        • Bender DE
        • et al.
        Identification of epigenetically altered genes in sporadic amyotrophic lateral sclerosis.
        PLOS One. 2012; 7: e52672
        • Nguyen S
        • Meletis K
        • Fu D
        • et al.
        Ablation of de novo DNA methyltransferase Dnmt3a in the nervous system leads to neuromuscular defects and shortened lifespan.
        Dev Dyn. 2007; 236: 1663-1676
        • Chestnut BA
        • Chang Q
        • Price A
        • et al.
        Epigenetic regulation of motor neuron cell death through DNA methylation.
        J Neurosci. 2011; 31: 16619
        • Wong M
        • Gertz B
        • Chestnut B
        • et al.
        Mitochondrial DNMT3A and DNA methylation in skeletal muscle and CNS of transgenic mouse models of ALS.
        Front Cell Neurosci. 2013; 7: 279
        • Taskesen E
        • Mishra A
        • van der Sluis S
        • et al.
        Susceptible genes and disease mechanisms identified in frontotemporal dementia and frontotemporal dementia with amyotrophic lateral sclerosis by DNA-methylation and GWAS.
        Sci Rep. 2017; 7: 8899
        • Meissner A
        • Mikkelsen TS
        • Gu H
        • et al.
        Genome-scale DNA methylation maps of pluripotent and differentiated cells.
        Nature. 2008; 454: 766-770
        • The N
        Pathway analysis subgroup of the psychiatric genomics C. Psychiatric genome-wide association study analyses implicate neuronal, immune, and histone pathways.
        Nat Neurosci. 2015; 18: 199
      2. J Martin L, Wong M. Aberrant regulation of DNA methylation in amyotrophic lateral sclerosis: a new target of disease mechanisms. 2013.

        • Tétreault N
        • De Guire V
        mirnas: their discovery, biogenesis and mechanism of action.
        Clin Biochem. 2013; 46: 842-845
        • Tolia NH
        • Joshua-Tor L
        Slicer and the argonautes.
        Nat Chem Biol. 2006; 3: 36
        • Brennecke J
        • Stark A
        • Russell RB
        • et al.
        Principles of microRNA-target recognition.
        PLOS Biol. 2005; 3: e85
        • Tomari Y
        • Zamore PD
        Perspective: machines for RNAi.
        Gene Dev. 2005; 19: 517-529
        • Valencia-Sanchez MA
        • Liu J
        • Hannon GJ
        • et al.
        Control of translation and mRNA degradation by miRNAs and siRNAs.
        Gene Deve. 2006; 20: 515-524
        • Basavaraju M
        • de Lencastre A
        Alzheimer's disease: presence and role of microRNAs.
        Biomol Concepts. 2016; 7: 241-252
        • Singh A
        • Sen D
        MicroRNAs in parkinson's disease.
        Exp Brain Res. 2017; 235: 2359-2374
        • Reed ER
        • Latourelle JC
        • Bockholt JH
        • et al.
        MicroRNAs in CSF as prodromal biomarkers for huntington disease in the PREDICT-HD study.
        Neurology. 2018; 90 (-e72): e264
        • Shah P
        • Cho SK
        • Thulstrup PW
        • et al.
        MicroRNA biomarkers in neurodegenerative diseases and emerging nanosensors technology.
        J Mov Disord. 2017; 10: 18-28
        • Figueroa-Romero C
        • Hur J
        • Lunn JS
        • et al.
        Expression of microRNAs in human post-mortem amyotrophic lateral sclerosis spinal cords provides insight into disease mechanisms.
        Mol Cell Neurosci. 2016; 71: 34-45
        • Tissir F
        • Goffinet AM
        Reelin and brain development.
        Nat Rev Neurosci. 2003; 4: 496
        • Winter J
        • Diederichs S
        Argonaute proteins regulate microRNA stability: increased microRNA abundance by argonaute proteins is due to microRNA stabilization.
        RNA Biol. 2011; 8: 1149-1157
        • Raman R
        • Allen Scott P
        • Goodall Emily F
        • et al.
        Gene expression signatures in motor neurone disease fibroblasts reveal dysregulation of metabolism, hypoxia-response, and RNA processing functions.
        Neuropathol Appl Neurobiol. 2014; 41: 201-226
        • Campos-Melo D
        • Droppelmann CA
        • He Z
        • et al.
        Altered microRNA expression profile in amyotrophic lateral sclerosis: a role in the regulation of NFL mRNA levels.
        Mol Brain. 2013; 6: 26
        • Gentil BJ
        • Minotti S
        • Beange M
        • et al.
        Normal role of the low-molecular-weight neurofilament protein in mitochondrial dynamics and disruption in Charcot-Marie-Tooth disease.
        FASEB J. 2011; 26: 1194-1203
        • Bergeron C
        • Beric-Maskarel K
        • Muntasser S
        • et al.
        Neurofilament light and polyadenylated mRNA levels are decreased in amyotrophic lateral sclerosis motor neurons.
        J Neuropathol Exp Neurol. 1994; 53: 221-230
        • Menzies Fiona M
        • Grierson Andrew J
        • Cookson Mark R
        • et al.
        Selective loss of neurofilament expression in Cu/Zn superoxide dismutase (SOD1) linked amyotrophic lateral sclerosis.
        J Neurochem. 2004; 82: 1118-1128
        • Wong NKY
        • He BP
        • Strong MJ
        Characterization of neuronal intermediate filament protein expression in cervical spinal motor neurons in sporadic amyotrophic lateral sclerosis (ALS).
        J Neuropathol Exp Neurol. 2000; 59: 972-982
        • Capauto D
        • Colantoni A
        • Lu L
        • et al.
        A regulatory circuitry between Gria2, miR-409, and miR-495 Is affected by ALS FUS mutation in ESC-derived motor neurons.
        Mol Neurobiol. 2018;
        • Takuma H
        • Kwak S
        • Yoshizawa T
        • et al.
        Reduction of GluR2 RNA editing, a molecular change that increases calcium influx through AMPA receptors, selective in the spinal ventral gray of patients with amyotrophic lateral sclerosis.
        Ann Neurol. 2001; 46: 806-815
        • Kawahara Y
        • Ito K
        • Sun H
        • et al.
        RNA editing and death of motor neurons.
        Nature. 2004; 427: 801
        • Hideyama T
        • Yamashita T
        • Aizawa H
        • et al.
        Profound downregulation of the RNA editing enzyme ADAR2 in ALS spinal motor neurons.
        Neurobiol Dis. 2012; 45: 1121-1128
        • De Felice B
        • Guida M
        • Guida M
        • et al.
        A miRNA signature in leukocytes from sporadic amyotrophic lateral sclerosis.
        Gene. 2012; 508: 35-40
        • Shioya M
        • Obayashi S
        • Tabunoki H
        • et al.
        Aberrant microRNA expression in the brains of neurodegenerative diseases: miR-29a decreased in Alzheimer disease brains targets neurone navigator 3.
        Neuropathol Appl Neurobiol. 2010; 36: 320-330
        • Toivonen JM
        • Manzano R
        • Oliván S
        • et al.
        MicroRNA-206: a potential circulating biomarker candidate for amyotrophic lateral sclerosis.
        PLOS One. 2014; 9: e89065
        • Takahashi I
        • Hama Y
        • Matsushima M
        • et al.
        Identification of plasma microRNAs as a biomarker of sporadic amyotrophic lateral sclerosis.
        Mol Brain. 2015; 8: 67
        • Van Hoecke A
        • Schoonaert L
        • Lemmens R
        • et al.
        EPHA4 is a disease modifier of amyotrophic lateral sclerosis in animal models and in humans.
        Nat Med. 2012; 18: 1418
        • Vrabec K
        • Boštjančič E
        • Koritnik B
        • et al.
        Differential expression of several miRNAs and the host genes AATK and DNM2 in leukocytes of sporadic ALS patients.
        Front Mol Neurosci. 2018; 11: 106
        • Ferrari R
        • Grassi M
        • Salvi E
        • et al.
        A genome-wide screening and SNPs-to-genes approach to identify novel genetic risk factors associated with frontotemporal dementia.
        Neurobiol Aging. 2015; 36 (e13-.e26): 2904
        • Sambuughin N
        • Goldfarb LG
        • Sivtseva TM
        • et al.
        Adult-onset autosomal dominant spastic paraplegia linked to a GTPase-effector domain mutation of dynamin 2.
        BMC Neurol. 2015; 15: 223
        • Chen K
        • Bennett SA
        • Rana N
        • et al.
        Neurodegenerative disease proteinopathies are connected to distinct histone post-translational modification landscapes.
        ACS Chem Neurosci. 2018;
        • AJMd Ruijter
        • AHv Gennip
        • Caron HN
        • et al.
        Histone deacetylases (HDACs): characterization of the classical HDAC family.
        Biochem J. 2003; 370: 737
        • Huang L
        Targeting histone deacetylases for the treatment of cancer and inflammatory diseases.
        J Cell Physiol. 2006; 209: 611-616
        • Ito K
        • Ito M
        • Elliott WM
        • et al.
        Decreased histone deacetylase activity in chronic obstructive pulmonary disease.
        N Engl J Med. 2005; 352: 1967
        • West AC
        • Johnstone RW
        New and emerging HDAC inhibitors for cancer treatment.
        J Clin Invest. 2014; 124: 30-39
        • Sawicka A
        • Seiser C
        Histone H3 phosphorylation - A versatile chromatin modification for different occasions.
        Biochimie. 2012; 94: 2193-2201
        • Wilson JR
        • Jing C
        • Walker PA
        • et al.
        Crystal structure and functional analysis of the histone methyltransferase SET7/9.
        Cell. 2002; 111: 105-115
        • Hyun K
        • Jeon J
        • Park K
        • et al.
        Writing, erasing, and reading histone lysine methylations.
        Exp Mol Med. 2017; 49: e324
        • Wang X
        • Arai S
        • Song X
        • et al.
        Induced ncRNAs allosterically modify RNA binding proteins in cis to inhibit transcription.
        Nature. 2008; 454: 126-130
        • Alao JP.
        The regulation of cyclin D1 degradation: roles in cancer development and the potential for therapeutic invention.
        Mol Cancer. 2007; 6: 24
        • Moller A
        • Bauer CS
        • Cohen RN
        • et al.
        Amyotrophic lateral sclerosis-associated mutant SOD1 inhibits anterograde axonal transport of mitochondria by reducing Miro1 levels.
        Hum Mol Genet. 2017; 26: 4668-4679
        • Kim SH
        • Shi Y
        • Hanson KA
        • et al.
        Potentiation of amyotrophic lateral sclerosis (ALS)-associated TDP-43 aggregation by the proteasome-targeting factor, ubiquilin 1.
        J Biol Chem. 2009; 284: 8083-8092
        • Kim SH
        • Shanware NP
        • Bowler MJ
        • et al.
        Amyotrophic Lateral Sclerosis-associated Proteins TDP-43 and FUS/TLS Function in a Common Biochemical Complex to Co-regulate HDAC6 mRNA.
        J Biol Chem. 2010; 285: 34097-34105
        • Simpson CL
        • Lemmens R
        • Miskiewicz K
        • et al.
        Variants of the elongator protein 3 (ELP3) gene are associated with motor neuron degeneration.
        Hum Mol Genet. 2009; 18: 472-481
        • Winkler GS
        • Kristjuhan A
        • Erdjument-Bromage H
        • et al.
        Elongator is a histone H3 and H4 acetyltransferase important for normal histone acetylation levels in vivo.
        Proc Natl Acad Sci. 2002; 99: 3517
        • Han Q
        • Lu J
        • Duan J
        • et al.
        Gcn5- and Elp3-induced histone H3 acetylation regulates Hsp70 gene transcription in yeast.
        Biochem J. 2008; 409: 779
        • Jovicic A
        • Mertens J
        • Boeynaems S
        • et al.
        Modifiers of C9orf72 dipeptide repeat toxicity connect nucleocytoplasmic transport defects to FTD/ALS.
        Nat Neurosci. 2015; 18: 1226-1229
        • Sanchez Y
        • Lindquist SL
        HSP104 required for induced thermotolerance.
        Science. 1990; 248: 1112
        • Johnson BS
        • Snead D
        • Lee JJ
        • et al.
        TDP-43 Is Intrinsically Aggregation-prone, and Amyotrophic Lateral Sclerosis-linked Mutations Accelerate Aggregation and Increase Toxicity.
        J Biol Chem. 2009; 284: 20329-20339
        • Sun Z
        • Diaz Z
        • Fang X
        • et al.
        Molecular determinants and genetic modifiers of aggregation and toxicity for the ALS disease protein FUS/TLS.
        PLOS Biol. 2011; 9e1000614
        • Elden AC
        • Kim H-J
        • Hart MP
        • et al.
        Ataxin-2 intermediate-length polyglutamine expansions are associated with increased risk for ALS.
        Nature. 2010; 466: 1069
        • Duan M-R
        • Smerdon MJ
        Histone H3 Lysine 14 (H3K14) acetylation facilitates dna repair in a positioned nucleosome by stabilizing the binding of the chromatin remodeler RSC (remodels structure of chromatin).
        J Biol Chem. 2014; 289: 8353-8363
        • Wang Y
        • Kallgren SP
        • Reddy BD
        • et al.
        Histone H3 Lysine 14 acetylation is required for activation of a DNA Damage Checkpoint in Fission yeast.
        J Biol Chemi. 2012; 287: 4386-4393
        • Chen C-C
        • Carson JJ
        • Feser J
        • et al.
        Acetylated Lysine 56 on Histone H3 drives chromatin assembly after repair and signals for the completion of repair.
        Cell. 2008; 134: 231-243
        • Karmodiya K
        • Krebs AR
        • Oulad-Abdelghani M
        • et al.
        H3K9 and H3K14 acetylation co-occur at many gene regulatory elements, while H3K14ac marks a subset of inactive inducible promoters in mouse embryonic stem cells.
        BMC Genom. 2012; 13: 424
        • Wang Z
        • Zang C
        • Rosenfeld JA
        • et al.
        Combinatorial patterns of histone acetylations and methylations in the human genome.
        Nat Genet. 2008; 40: 897-903
        • Blosser TR
        • Yang JG
        • Stone MD
        • et al.
        Dynamics of nucleosome remodelling by individual ACF complexes.
        Nature. 2009; 462: 1022
        • Zhou Y
        • Grummt I
        The PHD Finger/Bromodomain of NoRC interacts with acetylated histone H4K16 and is sufficient for rDNA silencing.
        Curr Biol. 2005; 15: 1434-1438
        • Lazo-Gomez R
        • Ramirez-Jarquin UN
        • Tovar YRLB
        • et al.
        Histone deacetylases and their role in motor neuron degeneration.
        Front Cell Neurosci. 2013; 7: 243
        • Armakola M
        • Higgins MJ
        • Figley MD
        • et al.
        Inhibition of RNA lariat debranching enzyme suppresses TDP-43 toxicity in ALS disease models.
        Nat Genet. 2012; 44: 1302
        • Janssen C
        • Schmalbach S
        • Boeselt S
        • et al.
        Differential histone deacetylase mRNA expression patterns in amyotrophic lateral sclerosis.
        J Neuropathol Exp Neurol. 2010; 69: 573-581
        • Scekic‐Zahirovic J
        • Sendscheid O
        • El Oussini H
        • et al.
        Toxic gain of function from mutant FUS protein is crucial to trigger cell autonomous motor neuron loss.
        EMBO J. 2016; 35: 1077-1097
        • Zhu Y
        • Vidaurre OG
        • Adula KP
        • et al.
        Subcellular distribution of HDAC1 in neurotoxic conditions is dependent on serine phosphorylation.
        J Neurosci. 2017; 37: 7547-7559
        • Valle C
        • Salvatori I
        • Gerbino V
        • et al.
        Tissue-specific deregulation of selected HDACs characterizes ALS progression in mouse models: pharmacological characterization of SIRT1 and SIRT2 pathways.
        Cell Death Dis. 2014; 5: e1296
        • Gal J
        • Chen J
        • Barnett KR
        • et al.
        HDAC6 regulates mutant SOD1 aggregation through two SMIR motifs and tubulin acetylation.
        J Biol Chem. 2013; 288: 15035-15045
        • Du Z-W
        • Chen H
        • Liu H
        • et al.
        Generation and expansion of highly pure motor neuron progenitors from human pluripotent stem cells.
        Nat Comm. 2015; 6: 6626
        • Hoogeveen RM
        • Nahrendorf M
        • Riksen NP
        • et al.
        Monocyte and haematopoietic progenitor reprogramming as common mechanism underlying chronic inflammatory and cardiovascular diseases.
        Eur Heart J. 2017; 39: 3521-3527
        • Dobbin MM
        • Madabhushi R
        • Pan L
        • et al.
        SIRT1 collaborates with ATM and HDAC1 to maintain genomic stability in neurons.
        Nat Neurosci. 2013; 16: 1008
        • Wang X
        • Zhang Q
        • Bao R
        • et al.
        Deletion of Nampt in projection neurons of adult mice leads to motor dysfunction, neurodegeneration, and death.
        Cell Rep. 2017; 20: 2184-2200
        • Hoch NC
        • Hanzlikova H
        • Rulten SL
        • et al.
        XRCC1 mutation is associated with PARP1 hyperactivation and cerebellar ataxia.
        Nature. 2016; 541: 87
        • Yoo Y-E
        • Ko C-P
        Treatment with trichostatin A initiated after disease onset delays disease progression and increases survival in a mouse model of amyotrophic lateral sclerosis.
        Exp Neurol. 2011; 231: 147-159
        • Guo W
        • Naujock M
        • Fumagalli L
        • et al.
        HDAC6 inhibition reverses axonal transport defects in motor neurons derived from FUS-ALS patients.
        Nat Commun. 2017; 8: 861
        • Corcoran LJ
        • Mitchison TJ
        • Liu Q
        A novel action of histone deacetylase inhibitors in a protein aggresome disease model.
        Curr Biol. 2004; 14: 488-492
        • Ryu H
        • Smith K
        • Camelo SI
        • et al.
        Sodium phenylbutyrate prolongs survival and regulates expression of anti-apoptotic genes in transgenic amyotrophic lateral sclerosis mice.
        J Neurochem. 2005; 93: 1087-1098
        • Petri S
        • Kiaei M
        • Kipiani K
        • et al.
        Additive neuroprotective effects of a histone deacetylase inhibitor and a catalytic antioxidant in a transgenic mouse model of amyotrophic lateral sclerosis.
        Neurobiol Dis. 2006; 22: 40-49
        • Del Signore SJ
        • Amante DJ
        • Kim J
        • et al.
        Combined riluzole and sodium phenylbutyrate therapy in transgenic amyotrophic lateral sclerosis mice.
        Amyotroph Lateral Scler. 2009; 10: 85-94
        • Cudkowicz ME
        • Andres PL
        • Macdonald SA
        • et al.
        Phase 2 study of sodium phenylbutyrate in ALS.
        Amyotroph Lateral Scler. 2009; 10: 99-106
        • Lachner M
        • Sullivan RJ
        • Jenuwein T
        An epigenetic road map for histone lysine methylation.
        J Cell Sci. 2003; 116: 2117
        • Belzil VV
        • Bauer PO
        • Prudencio M
        • et al.
        Reduced C9orf72 gene expression in c9FTD/ALS is caused by histone trimethylation, an epigenetic event detectable in blood.
        Acta Neuropathologica. 2013; 126: 895-905
        • Gary JD
        • Lin W-J
        • Yang MC
        • et al.
        The predominant protein-arginine methyltransferase from Saccharomyces cerevisiae.
        J Biol Chem. 1996; 271: 12585-12594
        • Carrozza MJ
        • Li B
        • Florens L
        • et al.
        Histone H3 methylation by set2 directs deacetylation of coding regions by Rpd3S to suppress spurious intragenic transcription.
        Cell. 2005; 123: 581-592
        • Joshi AA
        • Struhl K
        Eaf3 chromodomain interaction with methylated H3-K36 links histone deacetylation to Pol II elongation.
        Mol Cell. 2005; 20: 971-978
        • Huang S
        • Litt M
        • Felsenfeld G
        Methylation of histone H4 by arginine methyltransferase PRMT1 is essential in vivo for many subsequent histone modifications.
        Genes Dev. 2005; 19: 1885-1893
        • Litt M
        • Qiu Y
        • Huang S
        Histone arginine methylations: their roles in chromatin dynamics and transcriptional regulation.
        Biosci Rep. 2009; 29: 131-141
        • Jun MH
        • Ryu HH
        • Jun YW
        • et al.
        Sequestration of PRMT1 and Nd1-L mRNA into ALS-linked FUS mutant R521C-positive aggregates contributes to neurite degeneration upon oxidative stress.
        Sci Rep. 2017; 7: 40474
        • Tibshirani M
        • Tradewell ML
        • Mattina KR
        • et al.
        Cytoplasmic sequestration of FUS/TLS associated with ALS alters histone marks through loss of nuclear protein arginine methyltransferase 1.
        Hum Mol Genet. 2015; 24: 773-786
        • Kwon MJ
        • Kim S
        • Han MH
        • et al.
        Epigenetic changes in neurodegenerative diseases.
        Mol Cells. 2016; 39: 783-789
        • Ward CL
        • Boggio KJ
        • Johnson BN
        • et al.
        A loss of FUS/TLS function leads to impaired cellular proliferation.
        Cell Death Dis. 2014; 5: e1572
        • Kyriss MNM
        • Jin Y
        • Gallegos IJ
        • et al.
        Novel functional residues in the core domain of histone H2B regulate yeast gene expression and silencing and affect the response to DNA damage.
        Mol Cell Biol. 2010; 30: 3503-3518
        • Lo W-S
        • Duggan L
        • Tolga NC
        • et al.
        Snf1-a histone kinase that works in concert with the histone acetyltransferase Gcn5 to regulate transcription.
        Science. 2001; 293: 1142
        • Walker C
        • Herranz-Martin S
        • Karyka E
        • et al.
        C9orf72 expansion disrupts ATM-mediated chromosomal break repair.
        Nat Neurosci. 2017; 20: 1225
        • Wang Y
        • Zhang N
        • Zhang L
        • et al.
        Autophagy regulates chromatin ubiquitination in DNA damage response through elimination of SQSTM1/p62.
        Mol Cell. 2016; 63: 34-48
        • Maréchal A
        • Zou L
        DNA damage sensing by the ATM and ATR kinases.
        Cold Spring Harb Perspect Biol. 2013; 5a012716
      3. Henikoff S, Shilatifard A. Histone modification: cause or cog? trends in genetics. 2011;27:389-96.

        • Nowak SJ
        • Pai C-Y
        • Corces VG
        Protein phosphatase 2A activity affects histone H3 phosphorylation and transcription in drosophila melanogaster.
        Mol Cell Biol. 2003; 23: 6129-6138
        • Murnion ME
        • Adams RR
        • Callister DM
        • et al.
        Chromatin-associated protein phosphatase 1 regulates aurora-B and histone H3 phosphorylation.
        J Biol Chem. 2001; 276: 26656-26665
        • Chang B
        • Chen Y
        • Zhao Y
        • et al.
        JMJD6 Is a histone arginine demethylase.
        Science. 2007; 318: 444-447
        • Kouzarides T
        Chromatin modifications and their function.
        Cell. 2007; 128: 693-705
        • Grunstein M
        Histone acetylation in chromatin structure and transcription.
        Nature. 1997; 389: 349
        • Shogren-Knaak M
        • Ishii H
        • Sun J-M
        • et al.
        Histone H4-K16 acetylation controls chromatin structure and protein interactions.
        Science. 2006; 311: 844
        • Vaquero A
        • Scher M
        • Erdjument-Bromage H
        • et al.
        SIRT1 regulates the histone methyl-transferase SUV39H1 during heterochromatin formation.
        Nature. 2007; 450: 440
      4. You Jueng S, Jones Peter A. Cancer genetics and epigenetics: two sides of the same coin? Cancer Cell. 2012;22:9-20.

        • Teif VB
        • Rippe K
        Predicting nucleosome positions on the DNA: combining intrinsic sequence preferences and remodeler activities.
        Nucleic Acids Res. 2009; 37: 5641-5655
        • Berson A
        • Sartoris A
        • Nativio R
        • et al.
        TDP-43 promotes neurodegeneration by impairing chromatin remodeling.
        Curr Biol. 2017; 27 (e6): 3579-3590
        • Hansen JC.
        Conformational dynamics of the chromatin fiber in solution: determinants, mechanisms, and functions.
        Annu Rev Biophys Biomol Struct. 2002; 31: 361-392
        • Yanling Zhao D
        • Gish G
        • Braunschweig U
        • et al.
        SMN and symmetric arginine dimethylation of RNA polymerase II C-terminal domain control termination.
        Nature. 2015; 529: 48
        • Hirano M
        • Quinzii CM
        • Mitsumoto H
        • et al.
        Senataxin mutations and amyotrophic lateral sclerosis.
        Amyotroph Lateral Scler. 2011; 12: 223-227
        • Hill SJ
        • Mordes DA
        • Cameron LA
        • et al.
        Two familial ALS proteins function in prevention/repair of transcription-associated DNA damage.
        Proc Natl Acad Sci. 2016; 113: E7701
        • Kuo LJ
        • Yang L-X
        γ-H2AX - a novel biomarker for DNA double-strand breaks.
        In Vivo. 2008; 22: 305-309