New Insights into 5hmC DNA Modification: Generation, Distribution and Function

Dynamic DNA modifications, such as methylation/demethylation on cytosine, are major epigenetic mechanisms to modulate gene expression in both eukaryotes and prokaryotes. In addition to the common methylation on the 5th position of the pyrimidine ring of cytosine (5mC), other types of modifications at the same position, such as 5-hydroxymethyl (5hmC), 5-formyl (5fC), and 5-carboxyl (5caC), are also important. Recently, 5hmC, a product of 5mC demethylation by the Ten-Eleven Translocation family proteins, was shown to regulate many cellular and developmental processes, including the pluripotency of embryonic stem cells, neuron development, and tumorigenesis in mammals. Here, we review recent advances on the generation, distribution, and function of 5hmC modification in mammals and discuss its potential roles in plants.

[1]  A. Guidotti,et al.  Epigenetic modifications of GABAergic interneurons are associated with the schizophrenia-like phenotype induced by prenatal stress in mice , 2013, Neuropharmacology.

[2]  Markus Müller,et al.  The discovery of 5-formylcytosine in embryonic stem cell DNA. , 2011, Angewandte Chemie.

[3]  R. Lister,et al.  Highly Integrated Single-Base Resolution Maps of the Epigenome in Arabidopsis , 2008, Cell.

[4]  Andrew D. Johnson,et al.  Semi-quantitative immunohistochemical detection of 5-hydroxymethyl-cytosine reveals conservation of its tissue distribution between amphibians and mammals , 2012, Epigenetics.

[5]  D. Geschwind,et al.  Absence of CNTNAP2 Leads to Epilepsy, Neuronal Migration Abnormalities, and Core Autism-Related Deficits , 2011, Cell.

[6]  Peng Jin,et al.  5-hmC–mediated epigenetic dynamics during postnatal neurodevelopment and aging , 2011, Nature Neuroscience.

[7]  Gene W. Yeo,et al.  Blurred Boundaries: The RNA Binding Protein Lin28A Is Also an Epigenetic Regulator. , 2016, Molecular cell.

[8]  Jian-Kang Zhu,et al.  Regulation and function of DNA methylation in plants and animals , 2011, Cell Research.

[9]  W. Szybalski,et al.  The Cs2SO4 equilibrium density gradient and its application for the study of T-even phage DNA: Glucosylation and replication , 1964 .

[10]  J. Dunn,et al.  Heterologous expression and purification of Arabidopsis thaliana VIM1 protein: in vitro evidence for its inability to recognize hydroxymethylcytosine, a rare base in Arabidopsis DNA. , 2012, Protein expression and purification.

[11]  S. Nakagawa,et al.  De novo DNA methylation drives 5hmC accumulation in mouse zygotes , 2016, Nature Cell Biology.

[12]  S. Doublié,et al.  Genome and cancer single nucleotide polymorphisms of the human NEIL1 DNA glycosylase: activity, structure, and the effect of editing. , 2014, DNA repair.

[13]  Chuan He,et al.  A Highly Sensitive and Robust Method for Genome-wide 5hmC Profiling of Rare Cell Populations. , 2016, Molecular cell.

[14]  Fei Wang,et al.  Transcriptome-wide distribution and function of RNA hydroxymethylcytosine , 2016, Science.

[15]  Jikui Song,et al.  Effects of Tet-induced oxidation products of 5-methylcytosine on Dnmt1- and DNMT3a-mediated cytosine methylation. , 2014, Molecular bioSystems.

[16]  C. Levinthal,et al.  Protein synthesis by Escherichia coli infected with bacteriophage T4D. , 1968, Virology.

[17]  Saher Sue Hammoud,et al.  Chromatin and transcription transitions of mammalian adult germline stem cells and spermatogenesis. , 2014, Cell stem cell.

[18]  S. Hattman,et al.  HOST-INDUCED MODIFICATION OF T-EVEN PHAGES DUE TO DEFECTIVE GLUCOSYLATION OF THEIR DNA. , 1963, Proceedings of the National Academy of Sciences of the United States of America.

[19]  E. Kutter,et al.  Biological Effects of Substituting Cytosine for 5-Hydroxymethylcytosine in the Deoxyribonucleic Acid of Bacteriophage T4 , 1969, Journal of virology.

[20]  Huijue Jia,et al.  AID/APOBEC deaminases disfavor modified cytosines implicated in DNA demethylation , 2012, Nature chemical biology.

[21]  G. Ast,et al.  The alternative role of DNA methylation in splicing regulation. , 2015, Trends in genetics : TIG.

[22]  H. Kimura,et al.  Chromosome-wide regulation of euchromatin-specific 5mC to 5hmC conversion in mouse ES cells and female human somatic cells , 2012, Chromosome Research.

[23]  Colm E. Nestor,et al.  Tissue type is a major modifier of the 5-hydroxymethylcytosine content of human genes. , 2012, Genome research.

[24]  Ye Fu,et al.  Nucleic acid modifications with epigenetic significance. , 2012, Current opinion in chemical biology.

[25]  Increased 5-Methylcytosine and Decreased 5-Hydroxymethylcytosine Levels are Associated with Reduced Striatal A2AR Levels in Huntington’s Disease , 2013, NeuroMolecular Medicine.

[26]  K. Bojanowski,et al.  The presence of 5-hydroxymethylcytosine in animal deoxyribonucleic acid. , 1972, The Biochemical journal.

[27]  Chuan He,et al.  TET family proteins: oxidation activity, interacting molecules, and functions in diseases. , 2015, Chemical reviews.

[28]  J. Wong,et al.  Structural basis for hydroxymethylcytosine recognition by the SRA domain of UHRF2. , 2014, Molecular cell.

[29]  William A. Pastor,et al.  Distinct roles of the methylcytosine oxidases Tet1 and Tet2 in mouse embryonic stem cells , 2014, Proceedings of the National Academy of Sciences.

[30]  Thomas L. Dunwell,et al.  Genome-wide mapping of 5-hydroxymethylcytosine in three rice cultivars reveals its preferential localization in transcriptionally silent transposable element genes. , 2015, Journal of experimental botany.

[31]  Chuan He,et al.  Tet Proteins Can Convert 5-Methylcytosine to 5-Formylcytosine and 5-Carboxylcytosine , 2011, Science.

[32]  J. Wong,et al.  Structural basis for hydroxymethylcytosine recognition by the SRA domain of UHRF2 , 2014 .

[33]  J. Thomson,et al.  The application of genome-wide 5-hydroxymethylcytosine studies in cancer research. , 2017, Epigenomics.

[34]  Jiancheng Liu,et al.  Tet3 Reads 5-Carboxylcytosine through Its CXXC Domain and Is a Potential Guardian against Neurodegeneration. , 2016, Cell reports.

[35]  Andrew P. Feinberg,et al.  Epigenetic modulators, modifiers and mediators in cancer aetiology and progression , 2016, Nature Reviews Genetics.

[36]  Cheng-Sheng Chen,et al.  Age-associated decrease in global DNA methylation in patients with major depression , 2014, Neuropsychiatric disease and treatment.

[37]  K. Herrup,et al.  Alteration in 5-hydroxymethylcytosine-mediated epigenetic regulation leads to Purkinje cell vulnerability in ATM deficiency. , 2015, Brain : a journal of neurology.

[38]  J. Cadet,et al.  Deamination features of 5-hydroxymethylcytosine, a radical and enzymatic DNA oxidation product , 2014, Journal of Molecular Modeling.

[39]  J. Josse,et al.  ENZYMATIC SYNTHESIS OF DEOXYRIBONUCLEIC ACID. INFLUENCE OF BACTERIOPHAGE T2 ON THE SYNTHETIC PATHWAY IN HOST CELLS. , 1959, Proceedings of the National Academy of Sciences of the United States of America.

[40]  G. R. Wyatt,et al.  A New Pyrimidine Base from Bacteriophage Nucleic Acids , 1952, Nature.

[41]  R. Zecchina,et al.  Genome-wide analysis identifies a functional association of Tet 1 and Polycomb repressive complex 2 in mouse embryonic stem cells , 2013 .

[42]  L. Sowers,et al.  Endogenous cytosine damage products alter the site selectivity of human DNA maintenance methyltransferase DNMT1. , 2007, Cancer research.

[43]  Abraham J. Khorasani,et al.  Loss of 5-Hydroxymethylcytosine Is an Epigenetic Hallmark of Melanoma , 2012, Cell.

[44]  O. Kah,et al.  5‐hydroxymethylcytosine marks postmitotic neural cells in the adult and developing vertebrate central nervous system , 2017, The Journal of comparative neurology.

[45]  R. Hausinger,et al.  The protein that binds to DNA base J in trypanosomatids has features of a thymidine hydroxylase , 2007, Nucleic acids research.

[46]  D. Kintner,et al.  Hippocampal increase of 5-hmC in the glucocorticoid receptor gene following acute stress , 2015, Behavioural Brain Research.

[47]  P. Jin,et al.  Genome-wide alteration of 5-hydroxymenthylcytosine in a mouse model of Alzheimer’s disease , 2016, BMC Genomics.

[48]  A. Imberty,et al.  T4 phage beta-glucosyltransferase: substrate binding and proposed catalytic mechanism. , 1999, Journal of molecular biology.

[49]  B. Blencowe,et al.  5-hmC in the brain is abundant in synaptic genes and shows differences at the exon-intron boundary , 2012, Nature Structural &Molecular Biology.

[50]  Y. Osheim,et al.  Splice site selection, rate of splicing, and alternative splicing on nascent transcripts. , 1988, Genes & development.

[51]  S. Cohen,et al.  Virus-induced acquisition of metabolic function. I. Enzymatic formation of 5-hydroxymethyldeoxycytidylate. , 1959, The Journal of biological chemistry.

[52]  Z. Deng,et al.  The role of Tet3 DNA dioxygenase in epigenetic reprogramming by oocytes , 2011, Nature.

[53]  Karsten Rippe,et al.  HP1 is involved in regulating the global impact of DNA methylation on alternative splicing. , 2015, Cell reports.

[54]  Yi Zhang,et al.  Role of Tet proteins in 5mC to 5hmC conversion, ES-cell self-renewal and inner cell mass specification , 2010, Nature.

[55]  W. Reik,et al.  Dynamic regulation of 5-hydroxymethylcytosine in mouse ES cells and during differentiation , 2011, Nature.

[56]  P. Sætrom,et al.  Genome-wide profiling of DNA 5-hydroxymethylcytosine during rat Sertoli cell maturation , 2017, Cell Discovery.

[57]  Tin-Lap Lee,et al.  MicroRNA-29b/Tet1 regulatory axis epigenetically modulates mesendoderm differentiation in mouse embryonic stem cells , 2015, Nucleic acids research.

[58]  A. Maiti,et al.  Thymine DNA Glycosylase Can Rapidly Excise 5-Formylcytosine and 5-Carboxylcytosine , 2011, The Journal of Biological Chemistry.

[59]  John D. Davis,et al.  Upregulation of TET1 and downregulation of APOBEC3A and APOBEC3C in the parietal cortex of psychotic patients , 2012, Translational Psychiatry.

[60]  G. Schackert,et al.  5-Hydroxymethylcytosine is strongly depleted in human cancers but its levels do not correlate with IDH1 mutations. , 2011, Cancer research.

[61]  S. Quake,et al.  Simultaneous single-molecule epigenetic imaging of DNA methylation and hydroxymethylation , 2016, Proceedings of the National Academy of Sciences.

[62]  D. Wion,et al.  N6-methyl-adenine: an epigenetic signal for DNA–protein interactions , 2006, Nature Reviews Microbiology.

[63]  R. R. Ariza,et al.  DEMETER and REPRESSOR OF SILENCING 1 encode 5-methylcytosine DNA glycosylases. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[64]  Cheng Luo,et al.  Structural insight into substrate preference for TET-mediated oxidation , 2015, Nature.

[65]  Bing Ren,et al.  Tet-assisted bisulfite sequencing of 5-hydroxymethylcytosine , 2012, Nature Protocols.

[66]  Kairong Cui,et al.  Intragenic DNA methylation modulates alternative splicing by recruiting MeCP2 to promote exon recognition , 2013, Cell Research.

[67]  R. Zecchina,et al.  Genome-wide analysis identifies a functional association of Tet1 and Polycomb repressive complex 2 in mouse embryonic stem cells , 2013, Genome Biology.

[68]  Tin-Lap Lee,et al.  MicroRNA-29b/Tet1 regulatory axis epigenetically modulates mesendoderm differentiation in mouse embryonic stem cells , 2015, Nucleic acids research.

[69]  Y. Hayashi,et al.  LCX, leukemia-associated protein with a CXXC domain, is fused to MLL in acute myeloid leukemia with trilineage dysplasia having t(10;11)(q22;q23). , 2002, Cancer research.

[70]  James A. Cuff,et al.  A Bivalent Chromatin Structure Marks Key Developmental Genes in Embryonic Stem Cells , 2006, Cell.

[71]  B. Horsthemke,et al.  Altering TET dioxygenase levels within physiological range affects DNA methylation dynamics of HEK293 cells , 2015, Epigenetics.

[72]  R. Pérez,et al.  Global DNA cytosine methylation as an evolving trait: phylogenetic signal and correlated evolution with genome size in angiosperms , 2015, Front. Genet..

[73]  J. Valcárcel,et al.  Chromatin’s thread to alternative splicing regulation , 2013, Chromosoma.

[74]  Jon Penterman,et al.  DEMETER DNA Glycosylase Establishes MEDEA Polycomb Gene Self-Imprinting by Allele-Specific Demethylation , 2006, Cell.

[75]  S. Brenner,et al.  A CHEMICAL BASIS FOR THE HOST-INDUCED MODIFICATION OF T-EVEN BACTERIOPHAGES. , 1963, Proceedings of the National Academy of Sciences of the United States of America.

[76]  M. Fraga,et al.  The role of 5-hydroxymethylcytosine in development, aging and age-related diseases , 2017, Ageing Research Reviews.

[77]  Jian‐Kang Zhu Active DNA demethylation mediated by DNA glycosylases. , 2009, Annual review of genetics.

[78]  P. Jin,et al.  Genome-wide alteration of 5-hydroxymethylcytosine in a mouse model of fragile X-associated tremor/ataxia syndrome. , 2014, Human molecular genetics.

[79]  H. Blom,et al.  Cytosine DNA Methylation Is Found in Drosophila melanogaster but Absent in Saccharomyces cerevisiae, Schizosaccharomyces pombe, and Other Yeast Species , 2014, Analytical chemistry.

[80]  A. Bird,et al.  The thymine glycosylase MBD4 can bind to the product of deamination at methylated CpG sites , 1999, Nature.

[81]  Zachary D. Smith,et al.  DNA methylation: roles in mammalian development , 2013, Nature Reviews Genetics.

[82]  P. Jin,et al.  Selective chemical labeling reveals the genome-wide distribution of 5-hydroxymethylcytosine , 2011, Nature Biotechnology.

[83]  M. Marshall,et al.  JBP1 and JBP2 are two distinct thymidine hydroxylases involved in J biosynthesis in genomic DNA of African trypanosomes , 2009, Nucleic acids research.

[84]  P. Jin,et al.  5-Hydroxymethylcytosine-mediated alteration of transposon activity associated with the exposure to adverse in utero environments in human. , 2016, Human molecular genetics.

[85]  M. Biel,et al.  Quantification of the sixth DNA base hydroxymethylcytosine in the brain. , 2010, Angewandte Chemie.

[86]  N. Heintz,et al.  MeCP2 binds to 5hmc enriched within active genes and accessible chromatin in the nervous system , 2012, Cell.

[87]  B. Ren,et al.  Integrating 5-Hydroxymethylcytosine into the Epigenomic Landscape of Human Embryonic Stem Cells , 2011, PLoS genetics.

[88]  H. Leonhardt,et al.  TET-mediated oxidation of methylcytosine causes TDG or NEIL glycosylase dependent gene reactivation , 2014, Nucleic acids research.

[89]  C. Niehrs,et al.  Neil DNA glycosylases promote substrate turnover by Tdg during DNA demethylation , 2016, Nature Structural &Molecular Biology.

[90]  Yang Shi,et al.  Genome-wide comparison of DNA hydroxymethylation in mouse embryonic stem cells and neural progenitor cells by a new comparative hMeDIP-seq method , 2013, Nucleic acids research.

[91]  G. R. Wyatt,et al.  The bases of the nucleic acids of some bacterial and animal viruses: the occurrence of 5-hydroxymethylcytosine. , 1953, The Biochemical journal.

[92]  Keji Zhao,et al.  Genome-wide analysis of 5-hydroxymethylcytosine distribution reveals its dual function in transcriptional regulation in mouse embryonic stem cells. , 2011, Genes & development.

[93]  V. Ondřej,et al.  Changes of DNA methylation and hydroxymethylation in plant protoplast cultures. , 2013, Acta biochimica Polonica.

[94]  Q. Dong,et al.  Effects of intracerebral hemorrhage on 5-hydroxymethylcytosine modification in mouse brains , 2016, Neuropsychiatric disease and treatment.

[95]  David R. Liu,et al.  Conversion of 5-Methylcytosine to 5- Hydroxymethylcytosine in Mammalian DNA by the MLL Partner TET1 , 2009 .

[96]  Yun-Gui Yang,et al.  Genome-wide loss of 5-hmC is a novel epigenetic feature of Huntington's disease. , 2013, Human molecular genetics.

[97]  R. F. Luco,et al.  Epigenetics in Alternative Pre-mRNA Splicing , 2011, Cell.

[98]  D. Wenzel,et al.  Epigenetics in C. elegans: Facts and challenges , 2011, Genesis.

[99]  S. Keleş,et al.  Genome-wide alterations in hippocampal 5-hydroxymethylcytosine links plasticity genes to acute stress , 2016, Neurobiology of Disease.

[100]  Philipp Kapranov,et al.  Genome-wide mapping of 5-hydroxymethylcytosine in embryonic stem cells , 2011, Nature.

[101]  J. Bitinaite,et al.  Biochemical Characterization of Recombinant β-Glucosyltransferase and Analysis of Global 5-Hydroxymethylcytosine in Unique Genomes , 2012, Biochemistry.

[102]  M. Pook,et al.  Friedreich Ataxia Patient Tissues Exhibit Increased 5-Hydroxymethylcytosine Modification and Decreased CTCF Binding at the FXN Locus , 2013, PloS one.

[103]  P. Hof,et al.  Consistent decrease in global DNA methylation and hydroxymethylation in the hippocampus of Alzheimer's disease patients , 2013, Neurobiology of Aging.

[104]  N. Heintz,et al.  The Nuclear DNA Base 5-Hydroxymethylcytosine Is Present in Purkinje Neurons and the Brain , 2009, Science.

[105]  Yang Wang,et al.  Tet-Mediated Formation of 5-Carboxylcytosine and Its Excision by TDG in Mammalian DNA , 2011, Science.

[106]  B. Eichman,et al.  Excision of 5-hydroxymethylcytosine by DEMETER family DNA glycosylases. , 2014, Biochemical and biophysical research communications.

[107]  R. Alisch,et al.  Early-life stress links 5-hydroxymethylcytosine to anxiety-related behaviors , 2017, Epigenetics.

[108]  Epigenetics: judge, jury and executioner of stem cell fate. , 2012, Epigenetics.

[109]  R. Hotchkiss The quantitative separation of purines, pyrimidines, and nucleosides by paper chromatography. , 1948, The Journal of biological chemistry.

[110]  Eric T. Wang,et al.  Alternative Isoform Regulation in Human Tissue Transcriptomes , 2008, Nature.

[111]  A. Riggs,et al.  DNA Methylation and Demethylation in Mammals* , 2011, The Journal of Biological Chemistry.

[112]  Robert J. Schmitz,et al.  Widespread natural variation of DNA methylation within angiosperms , 2016, Genome Biology.

[113]  D. Zivkovic,et al.  Methylome evolution in plants , 2016, Genome Biology.

[114]  I. O. Torres,et al.  Functional coupling between writers, erasers and readers of histone and DNA methylation. , 2015, Current opinion in structural biology.

[115]  Lei Zhang,et al.  A primary role of TET proteins in establishment and maintenance of De Novo bivalency at CpG islands , 2016, Nucleic acids research.

[116]  H. Schöler,et al.  Dynamic link of DNA demethylation, DNA strand breaks and repair in mouse zygotes , 2010, The EMBO journal.

[117]  Chuan He,et al.  Abundant DNA 6mA methylation during early embryogenesis of zebrafish and pig , 2016, Nature Communications.

[118]  Thomas L. Dunwell,et al.  Detection of Oxidation Products of 5-Methyl-2′-Deoxycytidine in Arabidopsis DNA , 2013, PloS one.

[119]  Jian-Kang Zhu,et al.  Active DNA demethylation by oxidation and repair , 2011, Cell Research.

[120]  A. H. Smits,et al.  Dynamic Readers for 5-(Hydroxy)Methylcytosine and Its Oxidized Derivatives , 2013, Cell.

[121]  M. Biel,et al.  Tissue Distribution of 5-Hydroxymethylcytosine and Search for Active Demethylation Intermediates , 2010, PloS one.

[122]  J. M. Buchanan,et al.  Deoxycytidine triphosphatase, an enzyme induced by bacteriophage infection. , 1960, The Journal of biological chemistry.

[123]  W. Reik,et al.  Uncovering the role of 5-hydroxymethylcytosine in the epigenome , 2011, Nature Reviews Genetics.

[124]  Heng Zhu,et al.  Lin28A Binds Active Promoters and Recruits Tet1 to Regulate Gene Expression. , 2016, Molecular cell.