5-Hydroxymethylcytosine

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5-Hydroxymethylcytosine
Skeletal formula of 5-hydroxymethylcytosine
Ball-and-stick model of the 5-hydroxymethylcytosine molecule
Names
Preferred IUPAC name
4-Amino-5-(hydroxymethyl)pyrimidin-2(1H)-one
Identifiers
3D model (
JSmol
)
ChEBI
ChemSpider
UNII
  • InChI=1S/C5H7N3O2/c6-4-3(2-9)1-7-5(10)8-4/h1,9H,2H2,(H3,6,7,8,10) checkY
    Key: RYVNIFSIEDRLSJ-UHFFFAOYSA-N checkY
  • InChI=1/C5H7N3O2/c6-4-3(2-9)1-7-5(10)8-4/h1,9H,2H2,(H3,6,7,8,10)
    Key: RYVNIFSIEDRLSJ-UHFFFAOYAT
  • C1=NC(=O)NC(=C1CO)N
  • O=C1/N=C\C(=C(\N)N1)CO
Properties
C5H7N3O2
Molar mass 141.13 g/mol
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
☒N verify (what is checkY☒N ?)

5-Hydroxymethylcytosine (5hmC) is a

5-methylcytosine, a reaction mediated by TET enzymes. Its molecular formula is C5H7N3O2.[5]

Localization

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 central nervous system.[6][7][8] The amount of hydroxymethylcytosine increases with age, as shown in mouse hippocampus and cerebellum.[6][9]

Function

The exact function of this nitrogen base is still not fully elucidated, but it is thought that it may regulate

primordial germ cells, where it apparently plays a role in global DNA demethylation.[11] 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,[12] although no significant amounts of these putative demethylation intermediates could be detected in mouse tissue.[8] 5-Hydroxymethylcytosine may be especially important in the central nervous system, as it is found in very high levels there.[8] Reduction in the 5-Hydroxymethylcytosine levels have been found associated with impaired self-renewal in embryonic stem cells.[13] 5-Hydroxymethylcytosine is also associated with labile, unstable nucleosomes which are frequently repositioned during cell differentiation.[14]

The accumulation of 5-hydroxymethylcytosine (5hmC) in post-mitotic

5-methylcytosine (5mC) by cytosine in DNA that can occur through a series of reactions involving a TET enzyme as well as enzymes of the DNA base excision repair pathway (see Epigenetics in learning and memory
). “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.”

Bacteria and phages

Phages probably evolved to use 5hmC to avoid recognition by most restriction enzymes in bacteria. The

restriction enzymes specific for sites containing 5hmC. One prominent example is PvuRts1I, originally identified in 1994.[17]

5hmC in T4 is produced by genome protein 42, deoxycytidylate 5-hydroxymethyltransferase (P08773;

EC 2.4.1.28
.

History

5-Hydroxymethylcytosine was observed by Skirmantas Kriaucionis, an associate at the Heintz lab, who was looking for levels of 5-methylcytosine 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.[18]

The lab of L. Aravind used bioinformatic tools to predict that the Tet family of enzymes would likely oxidize 5-methylcytosine to 5-hydroxymethylcytosine.[19] This was demonstrated in vitro and in live human and mouse cells by scientists working in the labs of Anjana Rao and David R. Liu.

5-Hydroxymethylcytosine was originally observed in

mammals in 1972 by R. Yura,[20] 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.[21]

With the discovery of 5-hydroxymethylcytosine some concerns have been raised regarding DNA methylation studies using the bisulfite sequencing technique.[22] 5-hydroxymethylcytosine has been shown to behave like its precursor, 5-methylcytosine, in bisulfite conversion experiments.[23] 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 Chuan He 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 TAB-seq.[24][25]

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. [26]

References

  1. PMID 7002022
    .
  2. S2CID 4277592
    .
  3. PMID 19372393
    .
  4. PMID 19372391
    .
  5. ^ 5-Hydroxymethylcytosine Archived 2017-09-04 at the Wayback Machine, nextbio.com
  6. ^
    PMID 20583021
    .
  7. PMID 20685817
    .
  8. ^
    PMID 21203455
    .
  9. PMID 21151123
    .
  10. PMID 21496894
    .
  11. PMID 23223451
    .
  12. PMID 21721093
    .
  13. PMID 22210859
    .
  14. PMID 24812327
    .
  15. PMID 28847947
    .
  16. PMID 26081634
    .
  17. PMID 23482393
    .
  18. ^ A, T, G, C and What?, popsci.com
  19. PMID 19411852
    .
  20. PMID 4538516
    .
  21. S2CID 19957320
    .
  22. ^ "5 hydroxymethylcytosine analysis techniques". Archived from the original on 2011-07-10. Retrieved 2011-01-14.
  23. ^ 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
  24. PMID 22608086
    .
  25. PMID 21151123
    .
  26. ^ "Added CpG (min, prom, and min 5mC+5hmC) models and some minor cleanup". nanoporetech / rerio. GitHub. Retrieved 18 June 2020.

See also

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