| Revision as of 18:30, 16 February 2012 editBeetstra (talk | contribs)Edit filter managers, Administrators172,031 edits Saving copy of the {{chembox}} taken from revid 464539620 of page 5-Hydroxymethylcytosine for the Chem/Drugbox validation project (updated: 'CASNo'). |
Latest revision as of 06:20, 26 November 2024 edit Artoria2e5 (talk | contribs)Extended confirmed users, IP block exemptions34,481 edits list of methods |
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{{cs1 config|name-list-style=vanc}} |
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{{ambox | text = This page contains a copy of the infobox ({{tl|chembox}}) taken from revid of page ] with values updated to verified values.}} |
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{{chembox |
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{{chembox |
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| verifiedrevid = 450055821 |
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| verifiedrevid = 477224648 |
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|ImageFile=Hydroxymethylcytosine.png |
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| ImageFile=Hydroxymethylcytosine.png |
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|ImageSize=150px |
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| ImageSize=150px |
| ⚫ |
|IUPACName=6-Amino-5-(hydroxymethyl)-1''H''-pyrimidin-2-one |
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| ImageAlt = Skeletal formula of 5-hydroxymethylcytosine |
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|OtherNames= |
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| ImageFile1 = 5-Hydroxymethylcytosine-3D-balls.png |
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| ImageSize1 = 170 |
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| ImageAlt1 = Ball-and-stick model of the 5-hydroxymethylcytosine molecule |
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| PIN=4-Amino-5-(hydroxymethyl)pyrimidin-2(1''H'')-one |
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|Section1={{Chembox Identifiers |
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| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} |
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| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} |
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| ChemSpiderID = 63916 |
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| ChemSpiderID = 63916 |
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| InChI = 1/C5H7N3O2/c6-4-3(2-9)1-7-5(10)8-4/h1,9H,2H2,(H3,6,7,8,10) |
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| InChI = 1/C5H7N3O2/c6-4-3(2-9)1-7-5(10)8-4/h1,9H,2H2,(H3,6,7,8,10) |
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| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} |
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| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} |
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| StdInChIKey = RYVNIFSIEDRLSJ-UHFFFAOYSA-N |
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| StdInChIKey = RYVNIFSIEDRLSJ-UHFFFAOYSA-N |
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| CASNo_Ref = {{cascite|correct|??}} |
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| CASNo_Ref = {{cascite|correct|CAS}} |
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| CASNo = <!-- blanked - oldvalue: 1123-95-1 --> |
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| CASNo=1123-95-1 |
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| UNII_Ref = {{fdacite|correct|FDA}} |
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| PubChem=70751 |
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| UNII = 6CD2RLN1NK |
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| SMILES=C1=NC(=O)NC(=C1CO)N |
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| PubChem=70751 |
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| ChEBI = 76792 |
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| SMILES=C1=NC(=O)NC(=C1CO)N |
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|Section2={{Chembox Properties |
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|Section2={{Chembox Properties |
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| Formula=C<sub>5</sub>H<sub>7</sub>N<sub>3</sub>O<sub>2</sub> |
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| Formula=C<sub>5</sub>H<sub>7</sub>N<sub>3</sub>O<sub>2</sub> |
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| MolarMass=141.13 g/mol |
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| MolarMass=141.13 g/mol |
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'''5-Hydroxymethylcytosine''' (5hmC) is a ] ] ] derived from ]. It is potentially important in ], because the hydroxymethyl group on the cytosine can possibly switch a gene on and off. It was first seen in ] in 1952.<ref>{{cite journal |last=Warren |first=RA |title=Modified bases in bacteriophage DNAs |journal=Annu. Rev. Microbiol. |volume=34 |pages=137–158 |year=1980 |pmid=7002022 |doi=10.1146/annurev.mi.34.100180.001033}}</ref><ref>{{cite journal |last1=Wyatt |first1=GR |last2=Cohen |first2=SS |title=A new pyrimidine base from bacteriophage nucleic acids |journal=Nature |volume=170 |issue=4338 |pages=1072–1073 |date=December 1952 |pmid=13013321 |doi=10.1038/1701072a0|bibcode=1952Natur.170.1072W |s2cid=4277592 }}</ref> However, in 2009 it was found to be abundant in ] and ] brains,<ref>{{cite journal |last1=Kriaucionis |first1=S |last2=Heintz |first2=N |title=The nuclear DNA base 5-hydroxymethylcytosine is present in Purkinje neurons and the brain |journal=Science |volume=324 |issue=5929 |pages=929–930 |date=May 2009 |pmid=19372393 |doi=10.1126/science.1169786 |pmc=3263819|bibcode=2009Sci...324..929K }}</ref> as well as in ].<ref>{{cite journal |author=Tahiliani M |title=Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1 |journal=Science |volume=324 |issue=5929 |pages=930–935 |date=May 2009 |pmid=19372391 |doi=10.1126/science.1170116 |pmc=2715015|bibcode=2009Sci...324..930T |display-authors=etal|url=https://dash.harvard.edu/bitstream/handle/1/3415331/Tahiliani_Conversion5methylcytosine.pdf?sequence=2 }}</ref> In mammals, it can be generated by oxidation of ], a reaction mediated by ]. |
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==Localization== |
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Every mammalian cell seems to contain 5-Hydroxymethylcytosine, but the levels vary significantly depending on the cell type. The highest levels are found in neuronal cells of the ].<ref name="Münzel">{{cite journal |author=Münzel M |title=Quantification of the Sixth DNA Base Hydroxymethylcytosine in the Brain |journal=Angew. Chem. Int. Ed. |volume=49 |issue=31 |pages=5375–5377 |date=July 2010 |doi=10.1002/anie.201002033|pmid=20583021 |display-authors=etal}}</ref><ref>{{cite journal |author=Szwagierczak A |title=Sensitive Enzymatic Quantification of 5-Hydroxymethylcytosine in Genomic DNA |journal=Nucleic Acids Res. |volume=38 |issue=19 |pages=e181 |date=October 2010 |doi=10.1093/nar/gkq684 |pmid=20685817 |pmc=2965258|display-authors=etal}}</ref><ref name="Globisch">{{cite journal |author=Globisch D |title=Tissue Distribution of 5-Hydroxymethylcytosine and Search for Active Demethylation Intermediates |journal=PLOS ONE |volume=5 |issue=12 |pages=e15367 |date=December 2010 |doi=10.1371/journal.pone.0015367 |editor1-last=Croft |editor1-first=Anna Kristina |pmid=21203455 |pmc=3009720|bibcode=2010PLoSO...515367G |display-authors=etal|doi-access=free }}</ref> The amount of hydroxymethylcytosine increases with age, as shown in mouse ] and ].<ref name="Münzel"/><ref name="Song">{{cite journal |author=Song C-X |title=Selective chemical labeling reveals the genome-wide distribution of 5-hydroxymethylcytosine |journal=Nat. Biotechnol. |date=December 2010 |doi=10.1038/nbt.1732 |volume=29 |issue=1 |pages=68–72|display-authors=etal |pmid=21151123 |pmc=3107705}}</ref> |
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==Function== |
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The exact function of this nitrogen base is still not fully elucidated, but it is thought that it may regulate ] expression or prompt ]. This hypothesis is supported by the fact that artificial DNA that contains 5-hydroxymethylcytosines (5hmC) can be converted into unmodified cytosines once introduced into mammalian cells.<ref name=Guo>{{cite journal|last1=Guo|first1=Junjie U.|last2=Su |first2=Yijing |last3=Zhong |first3=Chun |last4=Ming | first4=Guo-li | last5=Song | first5=Hongjun|title=Hydroxylation of 5-Methylcytosine by TET1 Promotes Active DNA Demethylation in the Adult Brain|journal=Cell|date=1 April 2011|volume=145|issue=3|pages=423–434|doi=10.1016/j.cell.2011.03.022|pmid=21496894|pmc=3088758}}</ref> Moreover, 5hmC is highly enriched in ], where it apparently plays a role in global DNA demethylation.<ref>{{cite journal|last1=Hackett|first1=JA|last2=Sengupta |first2=R | last3=Zylicz | first3=JJ | last4=Murakami | first4=K | last5=Lee | first5=C | last6=Down | first6=T | last7=Surani | first7=MA|title=Germline DNA demethylation dynamics and imprint erasure through 5-hydroxymethylcytosine|journal=Science|date=2012-12-06|pmid=23223451|doi=10.1126/science.1229277|volume=339|issue=6118|pages=448–52|pmc=3847602}}</ref> Additionally, 5-Formylcytosine, an oxidation product of 5-Hydroxymethylcytosine and possible intermediate of an oxidative demethylation pathway was detected in DNA from embryonic stem cells,<ref name=Pfaffeneder>{{cite journal|last1=Pfaffeneder|first1=Toni|last2=Hackner | first2=Benjamin | last3=Truss | first3=Matthias | last4=Münzel | first4=Martin | last5=Müller | first5=Markus | last6=Deiml | first6=Christian A. | last7=Hagemeier | first7=Christian | last8=Carell | first8=Thomas|title=The Discovery of 5-Formylcytosine in Embryonic Stem Cell DNA|journal=Angew. Chem. Int. Ed.|date=30 June 2011|volume=50|issue=31|pages=7008–7012|doi= 10.1002/anie.201103899|pmid=21721093}}</ref> although no significant amounts of these putative demethylation intermediates could be detected in mouse tissue.<ref name="Globisch"/> 5-Hydroxymethylcytosine may be especially important in the ], as it is found in very high levels there.<ref name="Globisch"/> Reduction in the 5-Hydroxymethylcytosine levels have been found associated with impaired self-renewal in embryonic stem cells.<ref name=Freudenberg>{{cite journal|last1=Freudenberg | first1=JM | last2=Ghosh | first2=S | last3=Lackford | first3=BL | last4=Yellaboina | first4=S | last5=Zheng | first5=X | last6=Li | first6=R | last7=Cuddapah | first7=S | last8=Wade | first8=PA | last9=Hu | first9=G | last10=Jothi | first10=R|title=Acute depletion of Tet1-dependent 5-hydroxymethylcytosine levels impairs LIF/Stat3 signaling and results in loss of embryonic stem cell identity|journal=Nucleic Acids Research|date= April 2012|volume=40|issue=8|pages=3364–3377|doi=10.1093/nar/gkr1253|pmid=22210859|pmc=3333871}}</ref> 5-Hydroxymethylcytosine is also associated with labile, unstable nucleosomes which are frequently repositioned during cell differentiation.<ref name=Teif>{{cite journal|last1=Teif|first1=Vladimir|last2=Beshnova | first2=Daria A. | last3=Vainshtein | first3=Yevhen | last4=Marth | first4=Caroline | last5=Mallm | first5=Jan-Philipp | last6=Höfer | first6=Thomas | last7=Rippe | first7=Karsten|title=Nucleosome repositioning links DNA (de)methylation and differential CTCF binding during stem cell development|journal=Genome Research|date=8 May 2014|volume=24|issue=8|pages=1285–1295|doi= 10.1101/gr.164418.113|pmid=24812327 | pmc=4120082}}</ref> |
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The accumulation of 5-hydroxymethylcytosine (5hmC) in post-mitotic ]s is associated with “functional demethylation” that facilitates ] and ].<ref>{{cite journal | last1 = Mellén | first1 = M | last2 = Ayata | first2 = P | last3 = Heintz | first3 = N | date = Sep 2017 | title = 5-hydroxymethylcytosine accumulation in postmitotic neurons results in functional demethylation of expressed genes | journal = Proc Natl Acad Sci U S A | volume = 114 | issue = 37| pages = E7812–E7821 | doi = 10.1073/pnas.1708044114 | pmid = 28847947 | pmc=5604027| doi-access = free | bibcode = 2017PNAS..114E7812M }}</ref> The term “],” as applied to neurons, ordinarily refers to the replacement of ] (5mC) by ] in ] that can occur through a series of reactions involving a ] as well as enzymes of the DNA ] pathway (see ]). “Demethylation” of 5mC in DNA most often results in the promotion of expression of genes with neuronal activities. “Functional demethylation” refers to the replacement of 5mC by 5hmC, ordinarily a single-step TET-mediated reaction, that also facilitates gene expression, an effect similar to that of “demethylation.” |
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== Bacteria and phages == |
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Phages probably evolved to use 5hmC to avoid recognition by most restriction enzymes in bacteria. The ] uses 5hmC exclusively during replication, adding ] to the hydroxyl group to further complicate the moiety.<ref>{{cite journal |last1=Bryson |first1=Alexandra L. |last2=Hwang |first2=Young |last3=Sherrill-Mix |first3=Scott |last4=Wu |first4=Gary D. |last5=Lewis |first5=James D. |last6=Black |first6=Lindsay |last7=Clark |first7=Tyson A. |last8=Bushman |first8=Frederic D. |last9=Adhya |first9=Sankar |title=Covalent Modification of Bacteriophage T4 DNA Inhibits CRISPR-Cas9 |journal=mBio |date=16 June 2015 |volume=6 |issue=3 |pages=e00648 |doi=10.1128/mBio.00648-15|pmid=26081634 |pmc=4471564 }}</ref> Some bacteria have in turn evolved ] specific for sites containing 5hmC. One prominent example is PvuRts1I, originally identified in 1994.<ref>{{cite journal |last1=Borgaro |first1=JG |last2=Zhu |first2=Z |title=Characterization of the 5-hydroxymethylcytosine-specific DNA restriction endonucleases. |journal=Nucleic Acids Research |date=April 2013 |volume=41 |issue=7 |pages=4198–206 |doi=10.1093/nar/gkt102 |pmid=23482393 |pmc=3627594}}</ref> |
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5hmC in T4 is produced by genome protein 42, deoxycytidylate 5-hydroxymethyltransferase ({{UniProt|P08773}}; ]). The glycosylation reactions are known as ], ], and ]. |
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==History== |
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5-Hydroxymethylcytosine was observed by Skirmantas Kriaucionis, an associate at the Heintz lab, who was looking for levels of ] in two different neuron types. He discovered a significant amount of an unknown substance instead, and after conducting several tests, identified it as being 5-hydroxymethylcytosine.<ref>, popsci.com</ref> |
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The lab of L. Aravind used bioinformatic tools to predict that the Tet family of enzymes would likely oxidize 5-methylcytosine to 5-hydroxymethylcytosine.<ref>{{cite journal |author=Iyer LM |title=Prediction of novel families of enzymes involved in oxidative and other complex modifications of bases in nucleic acids |journal=Cell Cycle |volume=8 |issue=11 |pages=1698–1710 |date=June 2009|pmid=19411852 |doi=10.4161/cc.8.11.8580 |pmc=2995806|display-authors=etal}}</ref> This was demonstrated ] and in live human and mouse cells by scientists working in the labs of Anjana Rao and ]. |
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5-Hydroxymethylcytosine was originally observed in ] in 1972 by R. Yura,<ref>{{cite journal |last1=Penn | first1=NW | last2=Suwalski | first2=R | last3=O'Riley | first3=C | last4=Bojanowski | first4=K | last5=Yura | first5=R |title=The presence of 5-hydroxymethylcytosine in animal deoxyribonucleic acid |journal=Biochem. J. |volume=126 |issue=4 |pages=781–790 |date=February 1972 |pmid=4538516 |pmc=1178489 |doi= 10.1042/bj1260781}}</ref> but this initial finding is dubious. Yura found 5-hmC present at extremely high levels in rat brain and liver, completely supplanting 5-methylcytosine. This contradicts all research conducted on mammalian DNA composition conducted before and since, including the Heintz and Rao papers, and another group was unable to reproduce Yura's result.<ref>{{cite journal | pmid = 933178 |date=May 1976 | last1 = Kothari | first1=Rm | last2=Shankar | first2=V | title = 5-Methylcytosine content in the vertebrate deoxyribonucleic acids: species specificity | volume = 7 | issue = 4 | pages = 325–329 | issn = 0022-2844 | journal = Journal of Molecular Evolution | doi = 10.1007/BF01743628 |bibcode=1976JMolE...7..325K |s2cid=19957320 }}</ref> |
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With the discovery of 5-hydroxymethylcytosine some concerns have been raised regarding DNA methylation studies using the bisulfite sequencing technique.<ref>{{cite web |url=http://www.epigenie.com/Insights/5hmC-Analysis-Techniques.html |title=5 hydroxymethylcytosine analysis techniques |access-date=2011-01-14 |archive-url=https://web.archive.org/web/20110710194557/http://www.epigenie.com/Insights/5hmC-Analysis-Techniques.html |archive-date=2011-07-10 |url-status=dead}}</ref> 5-hydroxymethylcytosine has been shown to behave like its precursor, 5-methylcytosine, in ] experiments.<ref>Jin SG et al. (Jun 2010) "Examination of the specificity of DNA methylation profiling techniques towards 5-methylcytosine and 5-hydroxymethylcytosine." Nucleic Acids Res. 2010 Jun 1;38(11):e125</ref> Therefore, bisulfite sequencing data may need to be revisited to verify whether the detected modified base is 5-methylcytosine or 5-hydroxymethylcytosine. In 2012 the lab of ] discovered a method to solve the problems of 5-hydroxymethylcytosine being detected as 5-methylcytosine in normal bisulfite conversion experiments using the oxidative properties of the Tet-family of enzymes, this method has been termed ].<ref>{{cite journal |vauthors=Yu M, Hon GC, Szulwach KE, Song CX, Zhang L, Kim A, Li XK, Dai Q, Shen Y, Park B, Min JH, Jin P, Ren B, He C | title = Base-resolution analysis of 5-hydroxymethylcytosine in the mammalian genome. | journal = Cell | volume = 149 | issue = 6 | pages = 1368–1380 | date = June 2012 | doi = 10.1016/j.cell.2012.04.027 | pmc = 3589129 | pmid=22608086}}</ref><ref>{{cite journal |vauthors=Song CX, Szulwach KE, Fu Y, Dai Q, Yi C, Li X, Li Y, Chen CH, Zhang W, Jian X, Wang J, Zhang L, Looney TJ, Zhang B, Godley LA, Hicks LM, Lahn BT, Jin P, He C | title = Selective chemical labeling reveals the genome-wide distribution of 5-hydroxymethylcytosine | journal = Nat. Biotechnol. | volume = 29 | issue = 1 | pages = 68–72 | date = 2011 | doi = 10.1038/nbt.1732 | pmid=21151123 | pmc=3107705}}</ref> |
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In June 2020, Oxford Nanopore added a hydroxymethyl cytosine detection model to their research basecaller, rerio, allowing old signal-level data from any R9+ nanopore runs to be re-called to identify 5hmC. <ref>{{cite web |title=Added CpG (min, prom, and min 5mC+5hmC) models and some minor cleanup. |url=https://github.com/nanoporetech/rerio/commit/875a6f07b42486fa42bda7bfeda6f4525e556528 |website=nanoporetech / rerio |publisher=GitHub |access-date=18 June 2020}}</ref> |
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As of 2024, methods to characterize the presence of 5-hmC include:<ref>{{cite book |last1=Erlitzki |first1=Noa |last2=Kohli |first2=Rahul M. |chapter=An Overview of Global, Local, and Base-Resolution Methods for the Detection of 5-Hydroxymethylcytosine in Genomic DNA |title=Epigenome Editing |date=2024 |volume=2842 |pages=325–352 |doi=10.1007/978-1-0716-4051-7_17}}</ref> |
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* Enrichment: ] (hMeDIP, CMS-DIP); affinity pulldown (GLIB, hmC-Seal), oligotagging with near-base resolution (Jump-seq, TOP-seq); hmC-CATCH with base-resolution |
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* Sequencing: |
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** Bisulfide: oxBS-seq, TAB-seq, bACE-seq |
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** Non-bisulfide conversion: ACE-seq, CAPS(+), TAPS/TAPS-βsix-letter seq, six-letter seq |
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** Conversion-free: SMRT, Nanopore, Optical Mapping and Single-Molecule Epigenetic Imaging |
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==See also== |
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* ] |
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==References== |
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{{reflist|2}} |
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{{DEFAULTSORT:Hydroxymethylcytosine, 5-}} |
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] |
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] |