Abstract
5-Methylcytosine (5mC) is an epigenetic mark known to contribute to the regulation of gene expression in a wide range of biological systems. Ten Eleven Translocation (TET) dioxygenases oxidize 5mC to 5-hydroxymethylcytosine, 5-formylcytosine, and 5-carboxylcytosine in metazoans and fungi. Moreover, two recent reports imply the existence of other species of modified cytosine in unicellular alga Chlamydomonas reinhardtii and malaria parasite Plasmodium falciparum. Here we provide an overview of the spectrum of cytosine modifications and their roles in demethylation of DNA and regulation of gene expression in different eukaryotic organisms.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Moore LD, Le T, Fan G (2012) DNA Methylation and its basic function. Neuropsychopharmacology 38:23–38. https://doi.org/10.1038/npp.2012.112
Johnson TB, Coghill RD (1925) Researches on pyrimidines. C111. The discovery of 5-methyl-cytosine in tuberculinic acid, the nucleic acid of the tubercle bacillus. J Am Chem Soc 47:2838–2844. https://doi.org/10.1021/ja01688a030
Bickle TA, Kruger DH (1993) Biology of DNA restriction. Microbiol Rev 57:434–450
Holliday R, Pugh J (1975) DNA modification mechanisms and gene activity during development. Science 187:226–232. https://doi.org/10.1126/science.1111098
Compere SJ, Palmiter RD (1981) DNA methylation controls the inducibility of the mouse metallothionein-I gene in lymphoid cells. Cell 25:233–240. https://doi.org/10.1016/0092-8674(81)90248-8
Kumar S, Chinnusamy V, Mohapatra T (2018) Epigenetics of modified DNA bases: 5-methylcytosine and beyond. Front Genet 9:1–14. https://doi.org/10.3389/fgene.2018.00640
Lister R, Pelizzola M, Dowen RH et al (2009) Human DNA methylomes at base resolution show widespread epigenomic differences. Nature 462:315–322. https://doi.org/10.1038/nature08514
Ramsahoye BH, Biniszkiewicz D, Lyko F et al (2000) Non-CpG methylation is prevalent in embryonic stem cells and may be mediated by DNA methyltransferase 3a. Proc Natl Acad Sci U S A 97:5237–5242. https://doi.org/10.1073/pnas.97.10.5237
Price AJ, Collado-torres L, Ivanov NA et al (2019) Divergent neuronal DNA methylation patterns across human cortical development reveal critical periods and a unique role of CpH methylation. Genome Biol 20:1–20
Methylation TDNA, Clemens AW, Wu DY et al (2020) MeCP2 represses enhancers through chromosome article MeCP2 represses enhancers through. Mol Cell 77:279–293.e8. https://doi.org/10.1016/j.molcel.2019.10.033
Li E, Zhang Y (2014) DNA methylation in mammals. Cold Spring Harb Perspect Biol 6. https://doi.org/10.1101/cshperspect.a019133
Moarefi AH, Chédin F (2011) ICF syndrome mutations cause a broad spectrum of biochemical defects in DNMT3B-mediated de novo DNA methylation. J Mol Biol 409:758–772. https://doi.org/10.1016/j.jmb.2011.04.050
Traynor S, Møllegaard NE, Jørgensen MG et al (2019) Remodeling and destabilization of chromosome 1 pericentromeric heterochromatin by SSX proteins. Nucleic Acids Res 47:6668–6684. https://doi.org/10.1093/nar/gkz396
Charlet J, Duymich CE, Lay FD et al (2016) Bivalent regions of cytosine methylation and H3K27 acetylation suggest an active role for DNA methylation at enhancers. Mol Cell 62:422–431. https://doi.org/10.1016/j.molcel.2016.03.033
Buck-Koehntop BA, Defossez PA (2013) On how mammalian transcription factors recognize methylated DNA. Epigenetics 8:131–137. https://doi.org/10.4161/epi.23632
Spruijt CG, Vermeulen M (2014) DNA methylation: old dog, new tricks? Nat Struct Mol Biol 21:949–954. https://doi.org/10.1038/nsmb.2910
Laurent L, Wong E, Li G et al (2010) Dynamic changes in the human methylome during differentiation. Genome Res 20:320–331. https://doi.org/10.1101/gr.101907.109
Lewis S, Ross L, Bain SA et al (2020) Widespread conservation and lineage-specific diversification of genome-wide DNA methylation patterns across athropods. biorxiv
Chodavarapu RK, Feng S, Bernatavichute YV et al (2010) Relationship between nucleosome positioning and DNA methylation. Nature 466:388–392. https://doi.org/10.1038/nature09147.Relationship
Schwartz S, Meshorer E, Ast G (2009) Chromatin organization marks exon-intron structure. Nat Struct Mol Biol 16:990–995. https://doi.org/10.1038/nsmb.1659
Tilgner H, Nikolaou C, Althammer S et al (2009) Nucleosome positioning as a determinant of exon recognition. Nat Struct Mol Biol 16. https://doi.org/10.1038/nsmb.1658
Finnegan EJ, Peacock WJ, Dennis ES (2000) DNA methylation, a key regulator of plant development and other processes. Genet Dev 10:217–223
Bartels A, Han Q, Nair P et al (2018) Dynamic DNA Methylation in plant growth and development. Int J Mol Sci 19. https://doi.org/10.3390/ijms19072144
Feng S, Jacobsen SE, Reik W (2010) Epigenetic reprogramming in plant and animal development. Science 330:622–627. https://doi.org/10.1126/science.1190614.Epigenetic
Pradhan S, Bacolla A, Larson JE et al (1999) Recombinant human DNA (cytosine-5) methyltransferase. J Biol Chem 274:33002–33010. https://doi.org/10.1074/jbc.m100404200
Goll MG, Bestor TH (2005) Eukaryotic cytosine Methyltransferases. Annu Rev Biochem 74:481–514. https://doi.org/10.1146/annurev.biochem.74.010904.153721
Kishikawa S, Murata T, Ugai H et al (2003) Control elements of Dnmt1 gene are regulated in cell-cycle dependent manner. Nucleic Acids Res Suppl 307–308
Leonhardt H, Page AW, Weier HU, Bestor TH (1992) A targeting sequence directs DNA methyltransferase to sites of DNA replication in mammalian nuclei. Cell 71:865–873. https://doi.org/10.1016/0092-8674(92)90561-P
Hermann A, Goyal R, Jeltsch A (2004) The Dnmt1 DNA-(cytosine-C5)-methyltransferase methylates DNA processively with high preference for hemimethylated target sites. J Biol Chem 279:48350–48359. https://doi.org/10.1074/jbc.M403427200
Achour M, Jacq X, Rondé P et al (2008) The interaction of the SRA domain of ICBP90 with a novel domain of DNMT1 is involved in the regulation of VEGF gene expression. Oncogene 27:2187–2197. https://doi.org/10.1038/sj.onc.1210855
Bostick M, Kim Kyong J, Pierre-Olivier E, Amander C et al (2007) UHRF1 plays a role in maintaining DNA Methylation in mammalian cells. Science (80- ) 317:1760–1764. https://doi.org/10.1017/CBO9781107415324.004
Li E, Bestor TH, Jaenisch R (1992) Targeted mutation of the DNA methyltransferase gene results in embryonic lethality. Cell 69:915–926. https://doi.org/10.1016/0092-8674(92)90611-F
Okano M, Bell DW, Haber DA, Li E (1999) DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell 99:247–257. https://doi.org/10.1016/S0092-8674(00)81656-6
Xie S, Wang Z, Okano M et al (1999) Cloning, expression and chromosome locations of the human DNMT3 gene family. Gene 236:87–95. https://doi.org/10.1016/S0378-1119(99)00252-8
Hata K, Okano M, Lei H, Li E (2002) Dnmt3L cooperates with the Dnmt3 family of de novo DNA methyltransferases to establish maternal imprints in mice. Development 129:1983–1993
Kim JK, Samaranayake M, Pradhan S (2009) Epigenetic mechanisms in mammals. Cell Mol Life Sci 66:596–612. https://doi.org/10.1007/s00018-008-8432-4
Aapola U, Shibuya K, Scott HS et al (2000) Isolation and initial characterization of a novel zinc finger gene, DNMT3L, on 21q22.3, related to the cytosine-5-methyltransferase 3 gene family. Genomics 65:293–298. https://doi.org/10.1006/geno.2000.6168
Kaneda M, Okano M, Hata K et al (2004) Essential role for de novo DNA methyltransferase Dnmt3a in paternal and maternal imprinting. Nature 429:900–903. https://doi.org/10.1038/nature02633
Bourc’his D, Xu GL, Lin CS et al (2001) Dnmt3L and the establishment of maternal genomic imprints. Science 294:2536–2539. https://doi.org/10.1126/science.1065848
Bourc’his D, Bestor TH (2004) Meiotic catastrophe and retrotransposon reactivation in male germ cells lacking Dnmt3L. Nature 431:96–99. https://doi.org/10.1038/nature02886
Neri F, Krepelova A, Incarnato D et al (2013) Dnmt3L antagonizes DNA methylation at bivalent promoters and favors DNA methylation at gene bodies in ESCs. Cell 155:121. https://doi.org/10.1016/j.cell.2013.08.056
Zeng Y, Chen T (2019) DNA methylation reprogramming during mammalian development. Genes (Basel) 10:257. https://doi.org/10.3390/genes10040257
De CDD, You JS, Jones PA (2011) DNA methylation and cellular reprogramming. Trends Cell Biol 20:609–617. https://doi.org/10.1016/j.tcb.2010.08.003.DNA
Messerschmidt DM, Knowles BB, Solter D (2014) DNA methylation dynamics during epigenetic reprogramming in the germline and preimplantation embryos. Genes Dev 28:812–828. https://doi.org/10.1101/gad.234294.113.process
Morales-ruiz T, García-ortiz MV, Devesa-guerra I et al (2018) DNA methylation reprogramming of human cancer cells by expression of a plant 5- methylcytosine DNA glycosylase. Epigenetics 13:95–107. https://doi.org/10.1080/15592294.2017.1414128
Poli V, Fagnocchi L, Zippo A (2018) Tumorigenic cell reprogramming and cancer plasticity: interplay between signaling, microenvironment, and epigenetics. Stem Cells Int 2018
Saitou M, Kagiwada S, Kurimoto K (2012) Epigenetic reprogramming in mouse pre-implantation development and primordial germ cells. Development 139:15–31. https://doi.org/10.1242/dev.050849
Lee HJ, Hore TA, Reik W (2014) Reprogramming the methylome: erasing memory and creating diversity. Cell Stem Cell 14:710–719. https://doi.org/10.1016/j.stem.2014.05.008
Bagci H, Fisher AG (2013) Dna demethylation in pluripotency and reprogramming: the role of Tet proteins and cell division. Cell Stem Cell 13:265–269. https://doi.org/10.1016/j.stem.2013.08.005
Bochtler M, Kolano A, Xu G (2016) DNA demethylation pathways: additional players and regulators. BioEssays 1600178:1–13. https://doi.org/10.1002/bies.201600178
Wu X, Zhang Y (2017) TET-mediated active DNA demethylation: mechanism, function and beyond. Nat Rev Genet 18:517–534. https://doi.org/10.1038/nrg.2017.33
Deleris A, Halter T, Navarro L (2016) DNA methylation and demethylation in plant immunity. Annu Rev Phytopathol 54:579–603. https://doi.org/10.1146/annurev-phyto-080615-100308
Tahiliani M, Koh KP, Shen Y et al (2009) Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science 324:930–935. https://doi.org/10.1126/science.1170116
He Y-F, Li B-Z, Li Z et al (2011) TET-mediated formation of 5-carboxylcytosine and its excision by TDG in mammalian DNA. Science 333:1303–1307. https://doi.org/10.1016/b978-0-408-01434-2.50020-6
Ito S, Shen L, Dai Q et al (2011) Tet proteins can convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine. Science 333:1300–1303. https://doi.org/10.1126/science.1210597
Maiti A, Drohat AC (2011) Thymine DNA glycosylase can rapidly excise 5-formylcytosine and 5-carboxylcytosine: potential implications for active demethylation of CpG sites. J Biol Chem 286:35334–35338. https://doi.org/10.1074/jbc.C111.284620
Zhang L, Lu X, Lu J et al (2012) Thymine DNA glycosylase specifically recognizes 5-carboxylcytosine-modified DNA. Nat Chem Biol 8:328–330. https://doi.org/10.1038/nchembio.914
Weber AR, Krawczyk C, Robertson AB et al (2016) Biochemical reconstitution of TET1–TDG–BER-dependent active DNA demethylation reveals a highly coordinated mechanism. Nat Commun 7:10806. https://doi.org/10.1038/ncomms10806
Schomacher L, Han D, Musheev MU et al (2016) Neil DNA glycosylases promote substrate turnover by Tdg during DNA demethylation. Nat Struct Mol Biol 23:116–124. https://doi.org/10.1038/nsmb.3151
Mellen M, Ayata P, Dewell S et al (2012) MeCP2 binds to 5hmC enriched within active genes and accessible chromatin in the nervous system. Cell 151:1417–1430. https://doi.org/10.1016/j.cell.2012.11.022.MeCP2
Klungland A, Robertson AB (2017) Oxidized C5-methyl cytosine bases in DNA: 5-hydroxymethylcytosine; 5-carboxycytosine. Free Radic Biol Med 107:62–68. https://doi.org/10.1016/j.freeradbiomed.2016.11.038
Hashimoto H, Liu Y, Upadhyay AK et al (2012) Recognition and potential mechanisms for replication and erasure of cytosine hydroxymethylation. Nucleic Acids Res 40:4841–4849. https://doi.org/10.1093/nar/gks155
Wheldon LM, Abakir A, Ferjentsik Z et al (2014) Transient accumulation of 5-carboxylcytosine indicates involvement of active demethylation in lineage specification of neural stem cells. Cell Rep 7:1353–1361. https://doi.org/10.1016/j.celrep.2014.05.003
Lewis LC, Cho P, Lo K et al (2017) Dynamics of 5-carboxylcytosine during hepatic differentiation: potential general role for active demethylation by DNA repair in lineage specification. Epigenetics 12:277–286. https://doi.org/10.1080/15592294.2017.1292189
Guo F, Li X, Liang D et al (2014) Active and passive demethylation of male and female pronuclear DNA in the mammalian zygote. Cell Stem Cell 15:447–459. https://doi.org/10.1016/j.stem.2014.08.003
Schiesser S, Hackner B, Pfaffeneder T et al (2012) Mechanism and stem-cell activity of 5-carboxycytosine decarboxylation determined by isotope tracing. Angew Chemie Int Ed Engl 51:6516–6520. https://doi.org/10.1002/anie.201202583
Lee HJ, Dean W, Arand J et al (2013) FGF signaling inhibition in ESCs drives rapid genome-wide demethylation to the epigenetic ground state of pluripotency. Cell Stem Cell 13:351–359. https://doi.org/10.1016/j.stem.2013.06.004
Shen L, Wu H, Diep D et al (2013) Genome-wide analysis reveals TET- and TDG-dependent 5-methylcytosine oxidation dynamics. Cell 153:692–706. https://doi.org/10.1016/j.cell.2013.04.002
Dawlaty MM, Breiling A, Le T et al (2014) Loss of Tet enzymes compromises proper differentiation of embryonic stem cells. Dev Cell 20:102–111. https://doi.org/10.1016/j.devcel.2014.03.003
Dai H, Wang B, Yang L et al (2016) TET-mediated DNA demethylation controls gastrulation by regulating lefty – nodal signalling. Nature 538:528–532. https://doi.org/10.1038/nature20095
Dawlaty MM, Ganz K, Powell BE et al (2011) Tet1 is dispensable for maintaining pluripotency and its loss is compatible with embryonic and postnatal development. Stem Cell 9:166–175. https://doi.org/10.1016/j.stem.2011.07.010
Li Z, Cai X, Cai C et al (2011) Deletion of Tet2 in mice leads to dysregulated hematopoietic stem cells and subsequent development of myeloid malignancies. Am Soc Hematol 118:4509–4518. https://doi.org/10.1182/blood-2010-12-325241.An
Moran-crusio K, Reavie L, Shih A et al (2011) Article Tet2 loss leads to increased hematopoietic stem cell self-renewal and myeloid transformation. Cancer Cell 20:11–24. https://doi.org/10.1016/j.ccr.2011.06.001
Gu T-P, Guo F, Yang H et al (2011) The role of Tet3 DNA dioxygenase in epigenetic reprogramming by oocytes. Nature 477:606–610. https://doi.org/10.1038/nature10443
Zhang R, Cui Q, Murai K et al (2013) Short article Tet1 regulates adult hippocampal neurogenesis and cognition. Stem Cell 13:237–245. https://doi.org/10.1016/j.stem.2013.05.006
Rudenko A, Dawlaty MM, Seo J et al (2015) Tet1 is critical for neuronal activity-regulated gene expression and memory extinction. Neuron 79:1109–1122. https://doi.org/10.1016/j.neuron.2013.08.003.Tet1
Ko M, Bandukwala HS, An J et al (2011) Ten-eleven-translocation 2 (TET2) negatively regulates homeostasis and differentiation of hematopoietic stem cells in mice. PNAS 108:14566–14571. https://doi.org/10.1073/pnas.1112317108
Quivoron C, Couronne L, Wagner-ballon O et al (2011) Article TET2 inactivation results in pleiotropic hematopoietic abnormalities in mouse and is a recurrent event during human lymphomagenesis. Cancer Cell 20:25–38. https://doi.org/10.1016/j.ccr.2011.06.003
Dawlaty MM, Breiling A, Le T et al (2013) Combined deficiency of Tet1 and Tet2 causes epigenetic abnormalities but is compatible with postnatal development. Dev Cell 3:310–323. https://doi.org/10.1016/j.devcel.2012.12.015
Xu Y, Xu C, Kato A et al (2012) Tet3 CXXC domain and Dioxygenase activity cooperatively regulate key genes for Xenopus eye and neural development. Cell 151:1200–1213. https://doi.org/10.1016/j.cell.2012.11.014.Tet3
Tamanaha E, Guan S, Marks K, Saleh L (2016) Distributive processing by the iron(II)/α -ketoglutarate-dependent catalytic domains of the TET enzymes is consistent with epigenetic roles for oxidized 5 - methylcytosine bases. J Am Chem Soc 9345–9348. https://doi.org/10.1021/jacs.6b03243
Spruijt CG, Gnerlich F, Smits AH et al (2013) Resource dynamic readers for 5- (Hydroxy) methylcytosine and its oxidized derivatives. Cell 152:1146–1159. https://doi.org/10.1016/j.cell.2013.02.004
Bachman M, Uribe-lewis S, Yang X et al (2015) 5-Formylcytosine can be a stable DNA modification in mammals. Nat Chem Biol 11:3–6. https://doi.org/10.1038/nchembio.1848
Su M, Kirchner A, Stazzoni S et al (2016) 5-Formylcytosine could be a semipermanent base in specific genome sites. Angew Chemie Int Ed Engl 55:11797–11800. https://doi.org/10.1002/anie.201605994
Iurlaro M, Mcinroy GR, Burgess HE et al (2016) In vivo genome-wide profiling reveals a tissue-specific role for 5-formylcytosine. Genome Biol 1(9). https://doi.org/10.1186/s13059-016-1001-5
Li F, Zhang Y, Bai J et al (2017) 5 - Formylcytosine yields DNA − protein cross-links in nucleosome core particles. J Am Chem Soc 139:10617–10620. https://doi.org/10.1021/jacs.7b05495
Raiber E, Portella G, Cuesta SM et al (2018) 5-Formylcytosine organizes nucleosomes and forms Schiff base interactions with histones in mouse embryonic stem cells. Nat Chem 10. https://doi.org/10.1038/s41557-018-0149-x
Ji S, Fu I, Naldiga S et al (2018) 5-Formylcytosine mediated DNA – protein cross-links block DNA replication and induce mutations in human cells. Nucleic Acids Res 46:6455–6469. https://doi.org/10.1093/nar/gky444
Ji XS, Park D, Kropachev K et al (2019) 5-Formylcytosine-induced DNA – peptide cross-links reduce transcription efficiency, but do not cause transcription errors in human cells. J Biol Chem 294:18387–18397. https://doi.org/10.1074/jbc.RA119.009834
Kellinger MW, Song C, Chong J et al (2012) 5-formylcytosine and 5-carboxylcytosine reduce rate and substrate specificity of RNA polymerase II transcription. Nat Struct Mol Biol 19:831–834. https://doi.org/10.1038/nsmb.2346
Wang L, Zhou Y, Xu L et al (2015) Molecular basis for 5-carboxycytosine recognition by RNA polymerase II elongation complex. Nature 523. https://doi.org/10.1038/nature14482
Spruijt CG, Gnerlich F, Smits AH et al (2013) Dynamic readers for 5-(Hydroxy)methylcytosine and its oxidized derivatives. Cell 152:1146–1159. https://doi.org/10.1016/j.cell.2013.02.004
Pfeifer GP, Szabó PE, Song J (2019) Protein interactions at oxidized 5-Methylcytosine bases. J Mol Biol 2–14. https://doi.org/10.1016/j.jmb.2019.07.039
Song J, Pfeifer GP, Rapids G (2016) Are there specific readers of oxidized 5-methylcytosine bases. BioEssays 38:1038–1047. https://doi.org/10.1002/bies.201600126.Are
Nanan KK, Sturgill DM, Prigge MF et al (2019) TET-catalyzed 5-carboxylcytosine promotes CTCF binding to suboptimal sequences genome- wide promotes CTCF binding to suboptimal sequences genome-wide. iScience 19:326–339. https://doi.org/10.1016/j.isci.2019.07.041
Inoue A, Shen L, Dai Q et al (2011) Generation and replication-dependent dilution of 5fC and 5caC during mouse preimplantation development. Cell Res 21:1670–1676. https://doi.org/10.1038/cr.2011.189
Hashimoto H, Olanrewaju YO, Zheng Y et al (2014) Wilms tumor protein recognizes 5-carboxylcytosine within a specific DNA sequence. Genes Dev 4:2304–2313. https://doi.org/10.1101/gad.250746.114
Wang Y, Xiao M, Chen X et al (2015) WT1 recruits TET2 to regulate its target gene expression and suppress leukemia cell article WT1 recruits TET2 to regulate its target gene expression and suppress leukemia cell proliferation. Mol Cell 57:662–673. https://doi.org/10.1016/j.molcel.2014.12.023
Ji D, Lin K, Song J, Wang Y (2014) Effects of Tet-induced oxidation products of 5-methylcytosine on Dnmt1- and DNMT3a-mediated cytosine methylation. Mol BioSyst 10:1749. https://doi.org/10.1039/c4mb00150h
Nabel CS, Manning SA, Kohli RM (2012) The curious chemical biology of cytosine: deamination, Methylation, and oxidation as modulators of genomic potential. ACS Chem Biol 7:20–30. https://doi.org/10.1021/cb2002895
Zhang L, Chen W, Iyer LM et al (2014) A TET homologue protein from Coprinopsis cinerea (CcTET) that biochemically converts 5 - methylcytosine to 5 - hydroxymethylcytosine, 5 - formylcytosine, and 5 - carboxylcytosine. J Am Chem Soc 136:4801–4804. https://doi.org/10.1021/ja500979k
Iyer LM, Zhang D, De Souza RF et al (2014) Lineage-specific expansions of TET/JBP genes and a new class of DNA transposons shape fungal genomic and epigenetic landscapes. PNAS 111. https://doi.org/10.1073/pnas.1321818111
Mahmood AM, Dunwell JM (2019) Evidence for novel epigenetic marks within plants. Genetics 6:70–87. https://doi.org/10.3934/genet.2019.4.70
Tang Y, Xiong J, Jiang H et al (2014) Determination of oxidation products of 5 - methylcytosine in plants by chemical derivatization coupled with liquid chromatography/tandem mass spectrometry analysis. Anal Chem 86:7764–7777. https://doi.org/10.1021/ac5016886
Wang X, Song S, Wu Y et al (2015) Genome-wide mapping of 5-hydroxymethylcytosine in three rice cultivars reveals its preferential localization in transcriptionally silent transposable element genes. J Exp Bot 66:6651–6663. https://doi.org/10.1093/jxb/erv372
Yakovlev IA, Gackowski D, Abakir A et al (2019) Mass spectrometry reveals the presence of specific set of epigenetic DNA modifications in the Norway spruce genome. Sci Rep 1–7. doi:https://doi.org/10.1038/s41598-019-55826-z
Bian K, Lenz SAP, Tang Q et al (2019) DNA repair enzymes ALKBH, ALKBH3, and AlkB oxidize 5-methylcytosine to 5-hydroxymethylcytosine, 5-formylcytosine and 5-carboxylcytosine in vitro. Nucleic Acids Res 47:5522–5529. https://doi.org/10.1093/nar/gkz395
Jang H, Shin H, Eichman BF, Hoe J (2014) Biochemical and biophysical research communications excision of 5-hydroxymethylcytosine by DEMETER family DNA glycosylases. Biochem Biophys Res Commun 446:1067–1072. https://doi.org/10.1016/j.bbrc.2014.03.060
Kriaucionis S, Heintz N (2009) The nuclear DNA Base 5-Hydroxymethylcytosine is present in Purkinje neurons and the brain. Science 324:929–931
Globisch D, Münzel M, Müller M et al (2010) Tissue distribution of 5-hydroxymethylcytosine and search for active demethylation intermediates. PLoS One 5:1–9. https://doi.org/10.1371/journal.pone.0015367
Wu YC, Ling Z (2014) The role of TET family proteins and 5-hydroxymethylcytosine in human tumors. Histol Histopathol 29(8):991–997
Ko M, Huang Y, Jankowska AM et al (2010) Impaired hydroxylation of 5-methylcytosine in myeloid cancers with mutant TET2. Nature 468:839–843. https://doi.org/10.1038/nature09586
Kraus TFJ, Globisch D, Wagner M et al (2012) Low values of 5-hydroxymethylcytosine (5hmC), the “sixth base,” are associated with anaplasia in human brain tumors. Int J Cancer 131:1577–1590. https://doi.org/10.1002/ijc.27429
Xue J, Chen G, Hao F et al (2019) A vitamin-C-derived DNA modification catalysed by an algal TET homologue. Nature 569. https://doi.org/10.1038/s41586-019-1160-0
Hammam E, Ananda G, Sinha A et al (2020) Discovery of a new predominant cytosine DNA modification that is linked to gene expression in malaria parasites. Nucleic Acids Res 48:184–199. https://doi.org/10.1093/nar/gkz1093
Acknowledgments
A.R.’s lab is supported by Biotechnology and Biological Sciences Research Council [grant number BB/N005759/1] to A.R.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2021 The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature
About this protocol
Cite this protocol
Eleftheriou, M., Ruzov, A. (2021). Modified Forms of Cytosine in Eukaryotes: DNA (De)methylation and Beyond. In: Ruzov, A., Gering, M. (eds) DNA Modifications. Methods in Molecular Biology, vol 2198. Humana, New York, NY. https://doi.org/10.1007/978-1-0716-0876-0_1
Download citation
DOI: https://doi.org/10.1007/978-1-0716-0876-0_1
Published:
Publisher Name: Humana, New York, NY
Print ISBN: 978-1-0716-0875-3
Online ISBN: 978-1-0716-0876-0
eBook Packages: Springer Protocols