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词条 DNA demethylation
释义

  1. Passive and active demethylation

  2. Examples DNA Demethylation

  3. Possible mechanisms of active DNA demethylation

  4. DNA hydroxymethylation

  5. Cognition

     Demethylations after excercise 

  6. Peripheral sensory neuron regeneration

  7. See also

  8. References

  9. External links

{{multiple issues|{{technical|date=May 2017}}{{context|date=September 2014}}
}}DNA demethylation is the process of removal of a methyl group from nucleotides in DNA. Both DNA demethylation and methylation play important roles in mammalian development and differentiation, as well as in cognition and neuroregeneration (after injury to peripheral nerves in mammals). DNA methylation on cytosine at CpG sites on a gene promoter leads to the silencing of gene expression, while DNA demethylation of a gene promoter is linked to transcriptional activation and gene expression. These are called epigenetic changes. The DNA methylation status that controls gene expression is copied during DNA replication and is transmitted to daughter cells along with the DNA sequence. This area is currently being investigated for its role in disease progression and for potential treatments, such as cancer therapy.[1]

Passive and active demethylation

DNA demethylation can occur through passive or active mechanisms. The passive process takes place in the absence of methylation of newly synthesised DNA strands by DNMT1 during several replication rounds (for example, upon 5-Azacytidine treatment), leading to dilution of the methylation signal. Active DNA demethylation is mediated by multiple enzymes and can occur independent of DNA replication.

Examples DNA Demethylation

All the cases of DNA demethylation can be classified as global (genome wide) or locus-specific (when just specific sequences are demethylated).

The genome-wide DNA demethylation occurs:

  1. In mammals:
    1. In the male pronucleus of zygote immediately after fertilization;
    2. In mouse primordial germ cells (PGCs) between E8.5-11.5 day old embryos;&91;2&93;
  2. Possibly in amphibia - during midblastula transition.

Examples of specific DNA demethylation:

  1. Genomic imprinting during plant reproduction;
  2. Electroconvulsive stimulation-induced demethylation of neurotrophic factor genes in dentate gyrus neurons in the mouse brain.&91;3&93;&91;4&93;

Possible mechanisms of active DNA demethylation

There are several proposed hypothetical mechanisms of active DNA demethylation:

A Direct removal of 5-methylcytosine

  1. Direct removal of methyl group. This process has quite low thermodynamic probability.
  2. Removal of methylated bases (either by direct removal of methylcytosine, or through cytosine deamination followed by removal of thymine from thymine/guanosine mismatch), followed by insertion of unmethylated one using base excision repair machinery (BER).
  3. Removal of entire DNA patch and following filling it with new nucleotides by nucleotide excision repair (NER) or mismatch repair (MMR).&91;5&93;

B Removal of 5-methylcytosine via further modified cytosine bases

Oxidation of the methyl group generates 5-Hydroxymethylcytosine. Several mechanisms have been proposed to mediate demethylation of 5-hydroxymethylcytosines.[6][7] This base can be either deaminated by AID/Apobec enzymes to give 5-Hydroxymethyluracil.[4] Alternatively, TET enzymes can further oxidize 5-hydroxymethylcytosine to 5-Formylcytosine and 5-Carboxylcytosine.[8][9][10]

  1. Both the deamination and the oxidation products have been shown to be repaired by TDG, a glycosylase which is involved in base excision repair.&91;9&93;&91;11&93;&91;12&93; A base excision mediated demethylation mechanism would yield double strand breaks if it occurs on large scale in CpG islands.
  2. The carboxyl and formyl groups of 5-Formylcytosine and 5-Carboxylcytosine could be enzymatically removed without excision of the base.&91;6&93;&91;7&93;&91;8&93;&91;10&93; Precedent for similar reactions is found in biosynthetic pathways.

DNA hydroxymethylation

DNA hydroxymethylation has been proposed to act as a specific epigenetic mark opposing DNA methylation, rather than a passive intermediate in the de-methylation pathway. DNA hydroxymethylation in vivo is sometimes associated with labile nucleosomes, which are more easy to disassemble and to be out-competed by transcription factors during cell development.[13] Hydroxymethylation has been associated with pluripotency of stem cells. Furthermore, changes in hydroxymethylation have been associated with cancer.[14]

Cognition

In mammals, DNA methyltransferases (which add methyl groups to DNA bases) exhibit a strong sequence preference for cytosines within the particular DNA sequence cytosine-phosphate-guanine (CpG sites).[17] Methylation of cytosines occurs at 60–90% of CpG sites depending on the tissue type.[18] In the mammalian brain, ~62% of CpGs are methylated.[18] Methylation of CpG sites tends to stably silence genes.[19]

Active DNA methylation and demethylation is required for the cognition process of memory formation and maintenance.[20] In rats, contextual fear conditioning can trigger lifelong memory for the event with a single trial, and methylation changes appear to be correlated with triggering particularly long-lived memories.[20] With contextual fear conditioning, after 24 hours, DNA isolated from the rat brain hippocampus region had 2097 differentially methylated genes, with a portion being demethylated.[20] Similar results in the hippocampus were obtained with contextual fear conditioning in mice.[21] As shown with the rats, 9.2% of the genes in the rat hippocampus neurons are differentially methylated 24 hours after contextual fear conditioning. In mice, examined at 4 weeks after conditioning, the hippocampus methylations and demethylations were reversed (the hippocampus is needed to form memories but memories are not stored there) while substantial differential CpG methylation and demethylation occurred in cortical neurons during memory maintenance. There were 1,223 differentially methylated genes in the anterior cingulate cortex of mice four weeks after contextual fear conditioning. Thus, where there were many methylations in the hippocampus shortly after memory was formed, all these hippocampus methylations were demethylated as soon as 4 weeks later.

The process of demethylation is illustrated in the two figures shown in this section. First, the guanine in the CpG site is oxidized to form 8-oxo-dG (or its tautomer 8-OHdG) (see first figure).[15] TET1 is a key enzyme involved in demethylating 5mCpG. However, TET1 is only able to act on 5mCpG if the guanine has first been oxidized (presumably by an ROS) to form 8-OHdG, resulting in a 5mCp-8-OHdG dinucleotide (see first figure).[15] After formation of 5mCp-8-OHdG, the base excision repair enzyme OGG1 binds to the 8-OHdG lesion without immediate excision. Adherence of OGG1 to the 5mCp-8-OHdG site recruits TET1, allowing TET1 to oxidize the 5mC adjacent to 8-OHdG, as shown in the second figure. As reviewed by Bayraktar and Kreutz,[16] in the brain, further reactions in DNA demethylation are primarily dependent upon TET enzymes in the steps indicated in the second figure. The formation of the final product, unmethylated cytosine, depends on base excision repair (BER) as the terminal step.

Altered protein expression in neurons, (likely initiated by 8-oxo-dG-dependent demethylation of CpG sites in gene promoters within neuron DNA), is central to memory formation.[22]

Demethylations after excercise

Physical exercise has well established beneficial effects on learning and memory (see Neurobiological effects of physical exercise). BDNF is a particularly important regulator of learning and memory.[23] As reviewed by Fernandes et al.,[24] in rats, exercise enhances the hippocampus expression of the gene Bdnf, which has an essential role in memory formation. Enhanced expression of Bdnf occurs through demethylation of its CpG island promoter at exon IV[24] and this demethylation depends on steps illustrated in the two figures.[16]

Peripheral sensory neuron regeneration

After injury, neurons in the adult peripheral nervous system can switch from a dormant state with little axonal growth to robust axon regeneration. DNA demethylation in mature mammalian neurons removes barriers to axonal regeneration.[25] This demethylation, in regenerating mouse peripheral neurons, depends upon TET3 to generate 5-hydroxymethylcytosine (5hmC) in DNA.[25][26] 5hmC was altered in a large set of regeneration-associated genes (RAGs), including well-known RAGs such as Atf3, Bdnf, and Smad1, that regulate the axon growth potential of neurons.[26]

See also

  • DNA methylation
  • Demethylating agent

References

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6. ^1 {{cite journal|last=Wu|first=SC|author2=Zhang, Y|title=Active DNA demethylation: many roads lead to Rome|journal=Nature Reviews Molecular Cell Biology|date=Sep 2010|volume=11|issue=9|pages=607–20|pmid=20683471|doi=10.1038/nrm2950|pmc=3711520}}
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11. ^{{cite journal|last=Maiti|first=A|author2=Drohat, AC|title=Thymine DNA Glycosylase Can Rapidly Excise 5-Formylcytosine and 5-Carboxylcytosine|journal=J. Biol. Chem.|date=23 August 2011|volume=286|issue=41|pages=35334–8|pmid=21862836|doi=10.1074/jbc.C111.284620|pmc=3195571}}
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13. ^{{cite journal|last=Teif|first=Vladimir|author2=Beshnova, Daria A. |author3=Vainshtein, Yevhen |author4=Marth, Caroline |author5=Mallm, Jan-Philipp |author6=Höfer, Thomas |author7= Rippe, 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}}
14. ^http://www.ks.uiuc.edu/Research/methylation/
15. ^1 2 {{cite journal |vauthors=Zhou X, Zhuang Z, Wang W, He L, Wu H, Cao Y, Pan F, Zhao J, Hu Z, Sekhar C, Guo Z |title=OGG1 is essential in oxidative stress induced DNA demethylation |journal=Cell. Signal. |volume=28 |issue=9 |pages=1163–71 |date=September 2016 |pmid=27251462 |doi=10.1016/j.cellsig.2016.05.021 |url=}}
16. ^1 2 {{cite journal |vauthors=Bayraktar G, Kreutz MR |title=The Role of Activity-Dependent DNA Demethylation in the Adult Brain and in Neurological Disorders |journal=Front Mol Neurosci |volume=11 |issue= |pages=169 |date=2018 |pmid=29875631 |pmc=5975432 |doi=10.3389/fnmol.2018.00169 |url=}}
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18. ^1 {{cite journal |vauthors=Fasolino M, Zhou Z |title=The Crucial Role of DNA Methylation and MeCP2 in Neuronal Function |journal=Genes (Basel) |volume=8 |issue=5 |pages= |date=May 2017 |pmid=28505093 |pmc=5448015 |doi=10.3390/genes8050141 |url=}}
19. ^{{cite journal |vauthors=Bird A |title=DNA methylation patterns and epigenetic memory |journal=Genes Dev. |volume=16 |issue=1 |pages=6–21 |date=January 2002 |pmid=11782440 |doi=10.1101/gad.947102 |url=}}
20. ^1 2 {{cite journal |vauthors=Duke CG, Kennedy AJ, Gavin CF, Day JJ, Sweatt JD |title=Experience-dependent epigenomic reorganization in the hippocampus |journal=Learn. Mem. |volume=24 |issue=7 |pages=278–288 |date=July 2017 |pmid=28620075 |pmc=5473107 |doi=10.1101/lm.045112.117 |url=}}
21. ^{{cite journal |vauthors=Halder R, Hennion M, Vidal RO, Shomroni O, Rahman RU, Rajput A, Centeno TP, van Bebber F, Capece V, Garcia Vizcaino JC, Schuetz AL, Burkhardt S, Benito E, Navarro Sala M, Javan SB, Haass C, Schmid B, Fischer A, Bonn S |title=DNA methylation changes in plasticity genes accompany the formation and maintenance of memory |journal=Nat. Neurosci. |volume=19 |issue=1 |pages=102–10 |date=January 2016 |pmid=26656643 |doi=10.1038/nn.4194 |url=}}
22. ^{{cite journal |vauthors=Day JJ, Sweatt JD |title=DNA methylation and memory formation |journal=Nat. Neurosci. |volume=13 |issue=11 |pages=1319–23 |date=November 2010 |pmid=20975755 |pmc=3130618 |doi=10.1038/nn.2666 |url=}}
23. ^{{cite journal |vauthors=Karpova NN |title=Role of BDNF epigenetics in activity-dependent neuronal plasticity |journal=Neuropharmacology |volume=76 Pt C |issue= |pages=709–18 |date=January 2014 |pmid=23587647 |doi=10.1016/j.neuropharm.2013.04.002 |url=}}
24. ^1 {{cite journal |vauthors=Fernandes J, Arida RM, Gomez-Pinilla F |title=Physical exercise as an epigenetic modulator of brain plasticity and cognition |journal=Neurosci Biobehav Rev |volume=80 |issue= |pages=443–456 |date=September 2017 |pmid=28666827 |pmc=5705447 |doi=10.1016/j.neubiorev.2017.06.012 |url=}}
25. ^1 {{cite journal |vauthors=Weng YL, An R, Cassin J, Joseph J, Mi R, Wang C, Zhong C, Jin SG, Pfeifer GP, Bellacosa A, Dong X, Hoke A, He Z, Song H, Ming GL |title=An Intrinsic Epigenetic Barrier for Functional Axon Regeneration |journal=Neuron |volume=94 |issue=2 |pages=337–346.e6 |date=April 2017 |pmid=28426967 |pmc=6007997 |doi=10.1016/j.neuron.2017.03.034 |url=}}
26. ^1 {{cite journal |vauthors=Loh YE, Koemeter-Cox A, Finelli MJ, Shen L, Friedel RH, Zou H |title=Comprehensive mapping of 5-hydroxymethylcytosine epigenetic dynamics in axon regeneration |journal=Epigenetics |volume=12 |issue=2 |pages=77–92 |date=February 2017 |pmid=27918235 |pmc=5330438 |doi=10.1080/15592294.2016.1264560 |url=}}

External links

  • Cell Research (Nature) for 5-fC and 5-caC antibodies.
{{DEFAULTSORT:Dna Demethylation}}

1 : Molecular biology
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