349:
211:. The isoforms of TET3 are the full length form TET3FL, a short form splice variant TET3s, and a form that occurs in oocytes designated TET3o. TET3o is created by alternative promoter use and contains an additional first N-terminal exon coding for 11 amino acids. TET3o only occurs in oocytes and the one cell stage of the zygote and is not expressed in embryonic stem cells or in any other cell type or adult mouse tissue tested. Whereas TET1 expression can barely be detected in oocytes and zygotes, and TET2 is only moderately expressed, the TET3 variant TET3o shows extremely high levels of expression in oocytes and zygotes, but is nearly absent at the 2-cell stage. It appears that TET3o, high in oocytes and zygotes at the one cell stage, is the major TET enzyme utilized when almost 100% rapid demethylation occurs in the paternal genome just after fertilization and before DNA replication begins (see
228:
335:
the same DNA molecule, indicating that TET is not physically processive. Chemical processivity refers to the ability of TET to catalyze the oxidation of 5mC iteratively to 5caC without releasing its substrate. It appears that TET can work through both chemically processive and non‑processive mechanisms depending on reaction conditions. Genetic processivity refers to the genetic outcome of TET‑mediated oxidation in the genome, as shown by mapping of the oxidized bases. In mouse embryonic stem cells, many genomic regions or
98:
573:
446:
51:
612:(ILPFC) neuron samples derived from mice trained to fear an auditory cue and extinction-trained mice revealed dramatic experience-dependent genome-wide differences in the accumulation of 5-hmC in the ILPFC in response to learning. Extinction training led to a significant increase in TET3 messenger RNA levels within cortical neurons. TET3 was selectively activated within the adult
593:
conditioning, but rats retain a considerable amount of contextual fear when hippocampectomy is delayed by four weeks. 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
207:(PGCs). The dominant TET1 isoform in most somatic tissues, at least in the mouse, arises from alternative promoter usage which gives rise to a short transcript and a truncated protein designated TET1s. The three isoforms of TET2 arise from different promoters. They are expressed and active in embryogenesis and differentiation of
640:
564:(TDG). One particular TET enzyme, TET1, and TDG are present at high levels from embryo day 9.5 to 13.5, and are employed in active TET-dependent demethylation during gametogenesis. PGC genomes display the lowest levels of DNA methylation of any cells in the entire life cycle of the mouse by embryonic day 13.5.
753:
or Tet3-siRNA for three consecutive days before formalin injection alleviated the mouse perception of pain. On the other hand, forced overexpression of TET1 or TET3 for 2 consecutive days significantly produced pain-like behavior as evidenced by a decrease in the mouse of the thermal pain threshold.
537:
of the cell cycle while they migrate toward the hindgut during embryo days 7.5 to 8.5. Then demethylation of the PGCs takes place in two waves. There is both passive and active, TET-dependent demethylation of the primordial germ cells. At day 9.5 the primordial germ cells begin to rapidly replicate
334:
TET processivity can be viewed at three levels, the physical, chemical and genetic levels. Physical processivity refers to the ability of a TET protein to slide along the DNA from one CpG site to another. An in vitro study showed that DNA-bound TET does not preferentially oxidize other CpG sites on
597:
neurons during memory maintenance. There were 1,223 differentially methylated genes in the anterior cingulate cortex (see Figure) of mice four weeks after contextual fear conditioning. Thus, while there were many methylations in the hippocampus shortly after memory was formed, all these hippocampus
744:
injection of 5% formalin into the dorsal surface of the mouse hindpaw and measured time of licking of the hindpaw as a measure of induced pain. Protein expression of TET1 and TET3 increased by 152% and 160%, respectively, by 2 hours after formalin injection. Forced reduction of expression of TET1
580:
Learning and memory have levels of permanence, differing from other mental processes such as thought, language, and consciousness, which are temporary in nature. Learning and memory can be either accumulated slowly (multiplication tables) or rapidly (touching a hot stove), but once attained, can be
379:
The first step involves the binding of α-KG and 5-methylcytosine to the TET enzyme active site. The TET enzymes each harbor a core catalytic domain with a double-stranded β-helix fold that contains the crucial metal-binding residues found in the family of Fe(II)/α-KG- dependent oxygenases. α-KG
223:
Many different proteins bind to particular TET enzymes and recruit the TETs to specific genomic locations. In some studies, further analysis is needed to determine whether the interaction per se mediates the recruitment or instead the interacting partner helps to establish a favourable chromatin
321:
is rapidly and selectively up-regulated in subsets of neurons in specific brain regions associated with learning and memory formation. TET1s is the predominant isoform of TET1 that is expressed in neurons. When EGR1 proteins are expressed, they appear to bring TET1s to about 600 sites in the
592:
The hippocampus region of the brain is where contextual fear memories are first stored (see Figure), but this storage is transient and does not remain in the hippocampus. In rats contextual fear conditioning is abolished when the hippocampus is subjected to hippocampectomy just one day after
2177:
Feng J, Shao N, Szulwach KE, Vialou V, Huynh J, Zhong C, Le T, Ferguson D, Cahill ME, Li Y, Koo JW, Ribeiro E, Labonte B, Laitman BM, Estey D, Stockman V, Kennedy P, Couroussé T, Mensah I, Turecki G, Faull KF, Ming GL, Song H, Fan G, Casaccia P, Shen L, Jin P, Nestler EJ (April 2015).
147:
code respectively for three related mammalian proteins TET1, TET2, and TET3. All three proteins possess 5mC oxidase activity, but they differ in terms of domain architecture. TET proteins are large (~180- to 230-kDa) multidomain enzymes. All TET proteins contain a conserved
559:
In addition, from embryo day 9.5 to 13.5 there is an active form of demethylation. As indicated in the Figure of the demethylation pathway above, two enzymes are central to active demethylation. These are a ten-eleven translocation (TET) methylcytosine dioxygenase and
589:. This included more than 2,000 differentially methylated genes at 24 hours after training, with over 500 genes being demethylated. Similar results to that in the rat hippocampus were also obtained in mice with contextual fear conditioning.
339:
are modified so that 5mC is changed to 5hmC but not to 5fC or 5caC, whereas at many otherCpG sites 5mCs are modified to 5fC or 5caC but not 5hmC, suggesting that 5mC is processed to different states at different genomic regions or CpG sites.
2013:
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 (January 2016).
520:
The newly formed primordial germ cells (PGC) in the implanted embryo devolve from the somatic cells at about day 7 of embryogenesis in the mouse. At this point the PGCs have high levels of methylation. These cells migrate from the
224:
environment for TET binding. TET1‑depleted and TET2‑depleted cells revealed distinct target preferences of these two enzymes, with TET1‑preferring promoters and TET2‑preferring gene bodies of highly expressed genes and enhancers.
499:
designated DNMT1o. It appears that demethylation of the maternal chromosomes largely takes place by blockage of the methylating enzyme DNMT1o from entering the nucleus except briefly at the 8 cell stage (see
348:
697:. Conditioned place preference can measure the amount of time an animal spends in an area that has been associated with cocaine exposure, and this can indicate an addiction to cocaine. Reduced
556:) is repressed and UHRF1 is an essential protein needed to recruit DNMT1 to replication foci where maintenance DNA methylation takes place. This is a passive, dilution form of demethylation.
372:) into its substrate, 5-methylcytosine in DNA (5mC), to produce the product 5-hydroxymethylcytosine in DNA. This conversion is coupled with the oxidation of the co-substrate α-KG to
183:
gene, that's a neighbor of the TET2 gene, encodes a CXXC4 protein. IDAX is thought to play a role in regulating TET2 activity by facilitating its recruitment to unmethylated CpGs.
62:. The image shows a cytosine single ring base and a methyl group added on to the 5 carbon. In mammals, DNA methylation occurs almost exclusively at a cytosine that is followed by a
1259:
Zhou X, Zhuang Z, Wang W, He L, Wu H, Cao Y, Pan F, Zhao J, Hu Z, Sekhar C, Guo Z (September 2016). "OGG1 is essential in oxidative stress induced DNA demethylation".
757:
They further showed that the nociceptive pain effects occurred through TET mediated conversion of 5-methylcytosine to 5-hydroxymethylcytosine in the promoter of a
203:
genes are expressed in different cells and tissues. The full-length canonical TET1 isoform appears virtually restricted to early embryos, embryonic stem cells and
1299:
Sun Z, Xu X, He J, Murray A, Sun MA, Wei X, Wang X, McCoig E, Xie E, Jiang X, Li L, Zhu J, Chen J, Morozov A, Pickrell AM, Theus MH, Xie H (August 2019).
504:). The maternal-origin DNA thus undergoes passive demethylation by dilution of the methylated maternal DNA during replication (red line in Figure). The
361:
740:
Work by Pan et al. first showed that TET1 and TET3 proteins are normally present in the spinal cords of mice. They used a pain inducing model of intra
585:
create an especially strong long-term memory. At 24 hours after training, 9.17% of the genes in the genomes of rat hippocampus neurons were found to be
546:
are repressed and DNMT1 is present in the nucleus at a high level. But DNMT1 is unable to methylate cytosines during days 9.5 to 12.5 because the
791:. Forced decrease in expression of TET1 or TET3 through pre-injection of siRNA reversed the decrease of KCNH2 protein in formalin-treated mice.
445:
717:
response to harmful stimuli, such as a toxic chemical applied to a tissue. In nociception, chemical stimulation of sensory nerve cells called
2245:
392:
in close proximity. The TET active site contains a highly conserved triad motif, in which the catalytically-essential Fe(II) is held by two
404:(see Figure). TET then acts to convert 5-methylcytosine to 5-hydroxymethylcytosine while α-ketoglutarate is converted to succinate and CO
310:
is another example of a protein that recruits a TET enzyme. EGR1 has an important role in learning and memory. When a new event such as
1159:
Ziller MJ, MĂĽller F, Liao J, Zhang Y, Gu H, Bock C, Boyle P, Epstein CB, Bernstein BE, Lengauer T, Gnirke A, Meissner A (December 2011).
267:
110:
416:
The TET proteins also have activities that are independent of DNA demethylation. These include, for instance, TET2 interaction with
1732:
762:
1507:
Greer CB, Wright J, Weiss JD, Lazarenko RM, Moran SP, Zhu J, Chronister KS, Jin AY, Kennedy AJ, Sweatt JD, Kaas GA (January 2021).
1714:
964:
Jin SG, Zhang ZM, Dunwell TL, Harter MR, Wu X, Johnson J, Li Z, Liu J, SzabĂł PE, Lu Q, Xu GL, Song J, Pfeifer GP (January 2016).
586:
301:
143:
137:
131:
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residue (see Figure). The triad binds to one face of the Fe center, leaving three labile sites available for binding α-KG and O
368:(α-KG) dependent dioxygenase that catalyses an oxidation reaction by incorporating a single oxygen atom from molecular oxygen (O
729:. Nociception triggers a variety of physiological and behavioral responses and usually results in a subjective experience, or
292:(8-OHdG or its tautomer 8-oxo-dG), resulting in a 5mCp-8-OHdG dinucleotide (see Figure). After formation of 5mCp-8-OHdG, the
601:
Li et al. reported one example of the relationship between expression of a TET protein, demethylation and memory while using
289:
70:
Demethylation by TET enzymes (see second Figure), can alter the regulation of transcription. The TET enzymes catalyze the
609:
694:
300:
binds to the 8-OHdG lesion without immediate excision (see Figure). Adherence of OGG1 to the 5mCp-8-OHdG site recruits
227:
1064:"The Human TET2 Gene Contains Three Distinct Promoter Regions With Differing Tissue and Developmental Specificities"
605:. Extinction training is the disappearance of a previously learned behavior when the behavior is not reinforced.
746:
149:
1713:
Bernstein, Carol; Bernstein, Harris (2 December 2019). "Demethylation in Early
Embryonic Development and Memory".
631:. Mice trained in the presence of TET3-targeted shRNA showed a significant impairment in fear extinction memory.
572:
1509:"Tet1 Isoforms Differentially Regulate Gene Expression, Synaptic Transmission, and Memory in the Mammalian Brain"
594:
488:
2264:
44:
966:"Tet3 Reads 5-Carboxylcytosine through Its CXXC Domain and Is a Potential Guardian against Neurodegeneration"
807:
Wu, Xiaoji; Zhang, Yi (2017-05-30). "TET-mediated active DNA demethylation: mechanism, function and beyond".
352:
The conversion of 5-methylcytosine to 5-hydroxymethylcytosine by TET enzyme plus a-ketoglutarate & Fe(II)
765:, thus increasing its expression. This microRNA, in turn, ordinarily targets (decreases expression of) the
602:
561:
365:
285:
153:
79:
2115:
Li X, Wei W, Zhao QY, Widagdo J, Baker-Andresen D, Flavell CR, D'Alessio A, Zhang Y, Bredy TW (May 2014).
788:
297:
281:
1458:"Role of Immediate-Early Genes in Synaptic Plasticity and Neuronal Ensembles Underlying the Memory Trace"
1116:
Wu X, Zhang Y (September 2017). "TET-mediated active DNA demethylation: mechanism, function and beyond".
2117:"Neocortical Tet3-mediated accumulation of 5-hydroxymethylcytosine promotes rapid behavioral adaptation"
750:
473:
243:
1062:
Lou H, Li H, Ho KJ, Cai LL, Huang AS, Shank TR, Verneris MR, Nickerson ML, Dean M, Anderson SK (2019).
538:
going from about 200 PGCs at embryo day 9.5 to about 10,000 PGCs at day 12.5. During days 9.5 to 12.5
199:, including at least two isoforms of TET1, three of TET2 and three of TET3. Different isoforms of the
86:(5fC) and then to 5-carboxycytosine (5caC). 5fC and 5caC can be removed from the DNA base sequence by
1812:"DNA methylation dynamics during epigenetic reprogramming in the germline and preimplantation embryos"
480:
in six hours by an active TET-dependent process, before DNA replication begins (blue line in Figure).
97:
2269:
2128:
1669:
1569:
1312:
714:
389:
293:
204:
87:
284:(OGG1) is one example of a protein that recruits a TET enzyme. TET1 is able to act on 5mCpG if an
304:, allowing TET1 to oxidize the 5mC adjacent to 8-OHdG. This initiates the demethylation pathway.
1787:
1738:
1638:
1141:
840:
208:
1161:"Genomic distribution and inter-sample variation of non-CpG methylation across human cell types"
274:). This forms a 5mCpG site. More than 98% of DNA methylation occurs at CpG sites in mammalian
2016:"DNA methylation changes in plasticity genes accompany the formation and maintenance of memory"
1301:"EGR1 recruits TET1 to shape the brain methylome during development and upon neuronal activity"
701:
expression caused by shRNA injected into the NAc robustly enhanced cocaine place conditioning.
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Howell CY, Bestor TH, Ding F, Latham KE, Mertineit C, Trasler JM, Chaillet JR (March 2001).
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and thereby activating the expression of genes downstream of the EGR1 binding sites in DNA.
168:
83:
75:
24:
2065:"Neural circuits and mechanisms involved in Pavlovian fear conditioning: a critical review"
2237:
1866:"Replication-coupled passive DNA demethylation for the erasure of genome imprints in mice"
915:
Pan Z, Zhang M, Ma T, Xue ZY, Li GF, Hao LY, Zhu LJ, Li YQ, Ding HL, Cao JL (March 2016).
780:
677:
molecule with a tight hairpin turn that can be used to silence target gene expression via
627:
molecule with a tight hairpin turn that can be used to silence target gene expression via
509:
196:
101:
Demethylation of 5-methylcytosine. Demethylation of 5-methylcytosine (5mC) in neuron DNA.
2132:
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2015:
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1533:
1508:
1484:
1457:
1433:
1407:"Immediate Early Genes, Memory and Psychiatric Disorders: Focus on c-Fos, Egr1 and Arc"
1406:
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1333:
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862:
741:
160:
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Ross SE, Bogdanovic O (June 2019). "TET enzymes, DNA demethylation and pluripotency".
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1642:
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469:
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318:
71:
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expression with cocaine exposure. They then used an indirect measure of addiction,
662:(mRNA) and reduced TET1 protein expression. Similarly, there was a ~40% decrease in
1524:
1145:
932:
844:
655:. In the nucleus accumbens of mice, repeated cocaine exposure resulted in reduced
483:
Demethylation of the maternal genome occurs by a different process. In the mature
275:
259:
1272:
2231:
1177:
981:
917:"Hydroxymethylation of microRNA-365-3p Regulates Nociceptive Behaviors via Kcnh2"
722:
710:
581:
recalled into conscious use for a long time. Rats subjected to one instance of
529:. As reviewed by Messerschmidt et al., the majority of PGCs are arrested in the
357:
246:(DNMTs) show a strong preference for adding a methyl group to the 5 carbon of a
176:
114:
32:
1324:
1758:"Genomic imprinting disrupted by a maternal effect mutation in the Dnmt1 gene"
1373:
730:
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50:
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1227:
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1981:
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1716:
Demethylation in Early
Embryonic Development and Memory | IntechOpen
758:
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385:
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271:
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domain that can bind DNA. The TET2 protein lacks a CXXC domain, but the
91:
59:
40:
1681:
1626:
1581:
1129:
820:
495:
stage (see Figure), the only methyltransferase present is an isoform of
1212:"DNA methylation: superior or subordinate in the epigenetic hierarchy?"
429:
255:
63:
1864:
Kagiwada S, Kurimoto K, Hirota T, Yamaji M, Saitou M (February 2013).
721:
produces a signal that travels along a chain of nerve fibers via the
543:
539:
505:
484:
457:
381:
156:
55:
2195:
2031:
1966:"Experience-dependent epigenomic reorganization in the hippocampus"
278:. Thus TET enzymes largely initiate demethylation at 5mCpG sites.
726:
639:
548:
496:
454:
1658:"TET2 promotes histone O-GlcNAcylation during gene transcription"
1015:"Role of TET enzymes in DNA methylation, development, and cancer"
152:(DSBH) domain, a cysteine-rich domain, and binding sites for the
770:
734:
487:, about 40% of its CpG sites in DNA are methylated. In the pre-
307:
1405:
Gallo FT, Katche C, Morici JF, Medina JH, Weisstaub NV (2018).
468:
in DNA, amounting to about 20 million methylated sites. After
1964:
Duke CG, Kennedy AJ, Gavin CF, Day JJ, Sweatt JD (July 2017).
861:
Melamed P, Yosefzon Y, David C, Tsukerman A, Pnueli L (2018).
674:
666:
mRNA in the NAc of human cocaine addicts examined postmortem.
624:
36:
863:"Tet Enzymes, Variants, and Differential Effects on Function"
2180:"Role of Tet1 and 5-hydroxymethylcytosine in cocaine action"
1915:"DNA Methylation Reprogramming during Mammalian Development"
598:
methylations were demethylated as soon as four weeks later.
449:
Methylation levels during mouse early embryonic development.
163:(2-OG) that together form the core catalytic region in the
432:
O-GlcN acylation to affect transcription of target genes.
322:
neuron genome. Then EGR1 and TET1 appear to cooperate in
2233:
TET Proteins and DNA Demethylation: Methods and
Protocols
2236:. Methods in Molecular Biology. Vol. 2272. London:
1558:"TET enzymes, TDG and the dynamics of DNA demethylation"
1656:
Chen Q, Chen Y, Bian C, Fujiki R, Yu X (January 2013).
82:(5hmC), and can further catalyse oxidation of 5hmC to
1810:
Messerschmidt DM, Knowles BB, Solter D (April 2014).
2230:
Bogdanovic, Ozren; Vermeulen, Michiel, eds. (2021).
508:(at the 16 cell stage), has only a small amount of
16:
Family of translocation methylcytosine dioxygenases
476:, the paternal chromosomes are almost completely
47:and has several other functions in the genome.
1805:
1803:
1801:
23:are a family of ten-eleven translocation (TET)
1111:
1109:
910:
908:
689:expression in the same manner as reduction of
109:required during embryogenesis, gametogenesis,
669:As indicated above in learning and memory, a
171:, full-length TET1 and TET3 proteins have an
8:
31:. 5-Methylcytosine (see first Figure) is a
1859:
1857:
1855:
1456:Minatohara K, Akiyoshi M, Okuno H (2015).
681:. Feng et al. injected shRNA targeted to
576:Brain regions involved in memory formation
362:alpha-ketoglutarate-dependent hydroxylases
2203:
2150:
2140:
2088:
2039:
1989:
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1930:
1889:
1835:
1773:
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1483:
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1432:
1422:
1381:
1358:"DNA Methylation and Establishing Memory"
1332:
1235:
1186:
1176:
1089:
1079:
1038:
989:
940:
888:
878:
856:
854:
643:. Brain structures connected to addiction
638:
571:
444:
347:
288:has first acted on the guanine to form
226:
96:
49:
2172:
2170:
1210:Jin B, Li Y, Robertson KD (June 2011).
799:
685:in the NAc of mice. This could reduce
388:(see Figure), while the 5mC is held by
27:dioxygenases. They are instrumental in
1294:
1292:
1290:
2110:
2108:
775:, that codes for a protein known as K
616:in an experience-dependent manner.
54:DNA methylation is the addition of a
7:
1013:Rasmussen KD, Helin K (April 2016).
1556:Kohli RM, Zhang Y (October 2013).
779:11.1 or KCNH2. KCNH2 is the alpha
105:TET enzymes have central roles in
14:
376:and carbon dioxide (see Figure).
195:genes are expressed as different
58:group to the DNA that happens at
651:(NAc) has a significant role in
2081:10.1016/j.neubiorev.2005.06.005
1525:10.1523/JNEUROSCI.1821-20.2020
933:10.1523/JNEUROSCI.3474-15.2016
314:causes a memory to be formed,
43:(C) that often regulates gene
1:
1913:Zeng Y, Chen T (March 2019).
1775:10.1016/s0092-8674(01)00280-x
1273:10.1016/j.cellsig.2016.05.021
610:infralimbic prefrontal cortex
384:(connected at two points) to
2121:Proc. Natl. Acad. Sci. U.S.A
1178:10.1371/journal.pgen.1002389
982:10.1016/j.celrep.2015.12.044
709:As described in the article
695:conditioned place preference
583:contextual fear conditioning
472:, early in the first day of
290:8-hydroxy-2'-deoxyguanosine
2286:
1325:10.1038/s41467-019-11905-3
1374:10.1177/25168657211072499
673:(shRNA) is an artificial
623:(shRNA) is an artificial
587:differentially methylated
428:) transferase to promote
258:nucleotide in the linear
2063:Kim JJ, Jung MW (2006).
1725:10.5772/intechopen.90306
1475:10.3389/fnmol.2015.00078
1424:10.3389/fnbeh.2018.00079
1228:10.1177/1947601910393957
1081:10.3389/fcell.2019.00099
880:10.3389/fcell.2018.00022
715:sensory nervous system's
512:(black line in Figure).
412:Alternate TET activities
167:. In addition to their
2142:10.1073/pnas.1318906111
809:Nature Reviews Genetics
562:thymine-DNA glycosylase
150:double-stranded β-helix
80:5-hydroxymethylcytosine
1882:10.1038/emboj.2012.331
1828:10.1101/gad.234294.113
1031:10.1101/gad.276568.115
789:central nervous system
644:
577:
450:
364:. A TET enzyme is an
353:
282:Oxoguanine glycosylase
244:DNA methyltransferases
239:
102:
94:in the base sequence.
67:
2069:Neurosci Biobehav Rev
1982:10.1101/lm.045112.117
1932:10.3390/genes10040257
1368:: 25168657211072499.
785:potassium ion channel
713:, nociception is the
642:
608:A comparison between
575:
448:
351:
230:
205:primordial germ cells
100:
53:
1411:Front Behav Neurosci
1356:Bernstein C (2022).
552:gene (also known as
424:-acetylglucosamine (
294:base excision repair
242:The three mammalian
88:base excision repair
2133:2014PNAS..111.7120L
1682:10.1038/nature11742
1674:2013Natur.493..561C
1627:10.1042/BST20180606
1615:Biochem. Soc. Trans
1582:10.1038/nature12750
1574:2013Natur.502..472K
1317:2019NatCo..10.3892S
1130:10.1038/nrg.2017.33
1068:Front Cell Dev Biol
867:Front Cell Dev Biol
821:10.1038/nrg.2017.33
603:extinction training
568:Learning and memory
441:Early embryogenesis
390:a noncovalent force
366:alpha-ketoglutarate
344:TET enzyme activity
209:hematopoietic cells
1462:Front Mol Neurosci
705:Pain (nociception)
645:
578:
451:
354:
240:
125:The three related
103:
68:
2247:978-1-0716-1293-4
1362:Epigenet Insights
671:short hairpin RNA
649:nucleus accumbens
621:short hairpin RNA
502:DNA demethylation
491:embryo up to the
396:residues and one
380:coordinates as a
360:in the family of
312:fear conditioning
268:5' → 3' direction
254:is followed by a
250:where a cytosine
233:DNA demethylation
213:DNA demethylation
107:DNA demethylation
29:DNA demethylation
2277:
2251:
2218:
2217:
2207:
2174:
2165:
2164:
2154:
2144:
2112:
2103:
2102:
2092:
2060:
2054:
2053:
2043:
2010:
2004:
2003:
1993:
1961:
1955:
1954:
1944:
1934:
1910:
1904:
1903:
1893:
1861:
1850:
1849:
1839:
1807:
1796:
1795:
1777:
1753:
1747:
1746:
1710:
1704:
1703:
1693:
1653:
1647:
1646:
1610:
1604:
1603:
1593:
1553:
1547:
1546:
1536:
1504:
1498:
1497:
1487:
1477:
1453:
1447:
1446:
1436:
1426:
1402:
1396:
1395:
1385:
1353:
1347:
1346:
1336:
1296:
1285:
1284:
1256:
1250:
1249:
1239:
1207:
1201:
1200:
1190:
1180:
1171:(12): e1002389.
1156:
1150:
1149:
1113:
1104:
1103:
1093:
1083:
1059:
1053:
1052:
1042:
1010:
1004:
1003:
993:
961:
955:
954:
944:
912:
903:
902:
892:
882:
858:
849:
848:
804:
679:RNA interference
629:RNA interference
382:bidentate ligand
356:TET enzymes are
330:TET processivity
169:catalytic domain
113:, addiction and
111:memory, learning
90:and replaced by
84:5-formylcytosine
76:5-methylcytosine
2285:
2284:
2280:
2279:
2278:
2276:
2275:
2274:
2265:Gene expression
2255:
2254:
2248:
2238:Springer Nature
2229:
2226:
2224:Further reading
2221:
2196:10.1038/nn.3976
2176:
2175:
2168:
2114:
2113:
2106:
2062:
2061:
2057:
2032:10.1038/nn.4194
2012:
2011:
2007:
1963:
1962:
1958:
1912:
1911:
1907:
1863:
1862:
1853:
1809:
1808:
1799:
1755:
1754:
1750:
1735:
1712:
1711:
1707:
1668:(7433): 561–4.
1655:
1654:
1650:
1612:
1611:
1607:
1568:(7472): 472–9.
1555:
1554:
1550:
1506:
1505:
1501:
1455:
1454:
1450:
1404:
1403:
1399:
1355:
1354:
1350:
1298:
1297:
1288:
1258:
1257:
1253:
1209:
1208:
1204:
1158:
1157:
1153:
1118:Nat. Rev. Genet
1115:
1114:
1107:
1061:
1060:
1056:
1012:
1011:
1007:
963:
962:
958:
914:
913:
906:
860:
859:
852:
806:
805:
801:
797:
778:
707:
637:
570:
534:
518:
510:DNA methylation
443:
438:
414:
407:
403:
371:
346:
332:
221:
219:TET specificity
189:
123:
115:pain perception
17:
12:
11:
5:
2283:
2281:
2273:
2272:
2267:
2257:
2256:
2253:
2252:
2246:
2225:
2222:
2220:
2219:
2166:
2127:(19): 7120–5.
2104:
2075:(2): 188–202.
2055:
2005:
1976:(7): 278–288.
1956:
1905:
1851:
1797:
1748:
1733:
1719:. IntechOpen.
1705:
1648:
1621:(3): 875–885.
1605:
1548:
1519:(4): 578–593.
1499:
1448:
1397:
1348:
1286:
1267:(9): 1163–71.
1251:
1202:
1151:
1124:(9): 517–534.
1105:
1054:
1005:
976:(3): 493–505.
956:
927:(9): 2769–81.
904:
850:
815:(9): 517–534.
798:
796:
793:
776:
706:
703:
636:
633:
569:
566:
532:
517:
514:
442:
439:
437:
434:
413:
410:
405:
401:
369:
345:
342:
331:
328:
231:Initiation of
220:
217:
188:
185:
161:2-oxoglutarate
122:
119:
25:methylcytosine
15:
13:
10:
9:
6:
4:
3:
2:
2282:
2271:
2268:
2266:
2263:
2262:
2260:
2249:
2243:
2239:
2235:
2234:
2228:
2227:
2223:
2215:
2211:
2206:
2201:
2197:
2193:
2190:(4): 536–44.
2189:
2185:
2184:Nat. Neurosci
2181:
2173:
2171:
2167:
2162:
2158:
2153:
2148:
2143:
2138:
2134:
2130:
2126:
2122:
2118:
2111:
2109:
2105:
2100:
2096:
2091:
2086:
2082:
2078:
2074:
2070:
2066:
2059:
2056:
2051:
2047:
2042:
2037:
2033:
2029:
2026:(1): 102–10.
2025:
2021:
2020:Nat. Neurosci
2017:
2009:
2006:
2001:
1997:
1992:
1987:
1983:
1979:
1975:
1971:
1967:
1960:
1957:
1952:
1948:
1943:
1938:
1933:
1928:
1924:
1920:
1919:Genes (Basel)
1916:
1909:
1906:
1901:
1897:
1892:
1887:
1883:
1879:
1876:(3): 340–53.
1875:
1871:
1867:
1860:
1858:
1856:
1852:
1847:
1843:
1838:
1833:
1829:
1825:
1822:(8): 812–28.
1821:
1817:
1813:
1806:
1804:
1802:
1798:
1793:
1789:
1785:
1781:
1776:
1771:
1768:(6): 829–38.
1767:
1763:
1759:
1752:
1749:
1744:
1740:
1736:
1734:9781838808181
1730:
1726:
1722:
1718:
1717:
1709:
1706:
1701:
1697:
1692:
1687:
1683:
1679:
1675:
1671:
1667:
1663:
1659:
1652:
1649:
1644:
1640:
1636:
1632:
1628:
1624:
1620:
1616:
1609:
1606:
1601:
1597:
1592:
1587:
1583:
1579:
1575:
1571:
1567:
1563:
1559:
1552:
1549:
1544:
1540:
1535:
1530:
1526:
1522:
1518:
1514:
1510:
1503:
1500:
1495:
1491:
1486:
1481:
1476:
1471:
1467:
1463:
1459:
1452:
1449:
1444:
1440:
1435:
1430:
1425:
1420:
1416:
1412:
1408:
1401:
1398:
1393:
1389:
1384:
1379:
1375:
1371:
1367:
1363:
1359:
1352:
1349:
1344:
1340:
1335:
1330:
1326:
1322:
1318:
1314:
1310:
1306:
1302:
1295:
1293:
1291:
1287:
1282:
1278:
1274:
1270:
1266:
1262:
1255:
1252:
1247:
1243:
1238:
1233:
1229:
1225:
1222:(6): 607–17.
1221:
1217:
1213:
1206:
1203:
1198:
1194:
1189:
1184:
1179:
1174:
1170:
1166:
1162:
1155:
1152:
1147:
1143:
1139:
1135:
1131:
1127:
1123:
1119:
1112:
1110:
1106:
1101:
1097:
1092:
1087:
1082:
1077:
1073:
1069:
1065:
1058:
1055:
1050:
1046:
1041:
1036:
1032:
1028:
1025:(7): 733–50.
1024:
1020:
1016:
1009:
1006:
1001:
997:
992:
987:
983:
979:
975:
971:
967:
960:
957:
952:
948:
943:
938:
934:
930:
926:
922:
918:
911:
909:
905:
900:
896:
891:
886:
881:
876:
872:
868:
864:
857:
855:
851:
846:
842:
838:
834:
830:
826:
822:
818:
814:
810:
803:
800:
794:
792:
790:
786:
782:
774:
773:
768:
767:messenger RNA
764:
760:
755:
752:
749:injection of
748:
743:
738:
736:
732:
728:
724:
720:
716:
712:
704:
702:
700:
696:
692:
688:
684:
680:
676:
672:
667:
665:
661:
660:messenger RNA
658:
654:
650:
641:
634:
632:
630:
626:
622:
617:
615:
611:
606:
604:
599:
596:
590:
588:
584:
574:
567:
565:
563:
557:
555:
551:
550:
545:
541:
536:
528:
527:gonadal ridge
524:
516:Gametogenesis
515:
513:
511:
507:
503:
498:
494:
490:
486:
481:
479:
475:
474:embryogenesis
471:
470:fertilization
467:
463:
459:
456:
447:
440:
436:TET functions
435:
433:
431:
427:
423:
419:
411:
409:
399:
398:aspartic acid
395:
391:
387:
383:
377:
375:
367:
363:
359:
350:
343:
341:
338:
329:
327:
325:
324:demethylating
320:
319:messenger RNA
317:
313:
309:
305:
303:
299:
295:
291:
287:
283:
279:
277:
276:somatic cells
273:
269:
265:
261:
257:
253:
249:
245:
238:
234:
229:
225:
218:
216:
214:
210:
206:
202:
198:
194:
186:
184:
182:
178:
174:
170:
166:
162:
158:
155:
151:
146:
145:
140:
139:
134:
133:
128:
120:
118:
116:
112:
108:
99:
95:
93:
89:
85:
81:
77:
73:
72:hydroxylation
65:
61:
57:
52:
48:
46:
45:transcription
42:
38:
34:
30:
26:
22:
2232:
2187:
2183:
2124:
2120:
2072:
2068:
2058:
2023:
2019:
2008:
1973:
1969:
1959:
1922:
1918:
1908:
1873:
1869:
1819:
1815:
1765:
1761:
1751:
1715:
1708:
1665:
1661:
1651:
1618:
1614:
1608:
1565:
1561:
1551:
1516:
1512:
1502:
1465:
1461:
1451:
1414:
1410:
1400:
1365:
1361:
1351:
1308:
1304:
1264:
1261:Cell. Signal
1260:
1254:
1219:
1216:Genes Cancer
1215:
1205:
1168:
1164:
1154:
1121:
1117:
1071:
1067:
1057:
1022:
1018:
1008:
973:
969:
959:
924:
920:
870:
866:
812:
808:
802:
771:
756:
739:
708:
698:
690:
686:
682:
668:
663:
656:
646:
618:
607:
600:
591:
579:
558:
553:
547:
519:
489:implantation
482:
478:demethylated
452:
421:
417:
415:
378:
358:dioxygenases
355:
333:
315:
306:
280:
241:
222:
200:
192:
190:
187:TET isoforms
180:
142:
136:
130:
126:
124:
121:TET proteins
104:
69:
35:form of the
20:
18:
2270:Epigenetics
1311:(1): 3892.
921:J. Neurosci
761:designated
745:or TET3 by
723:spinal cord
719:nociceptors
711:Nociception
525:toward the
177:zinc finger
21:TET enzymes
2259:Categories
1970:Learn. Mem
1925:(4): 257.
1513:J Neurosci
1305:Nat Commun
1165:PLOS Genet
795:References
763:miR-365-3p
751:Tet1-siRNA
731:perception
614:neo-cortex
493:blastocyst
462:methylated
460:is 80–90%
453:The mouse
266:along its
252:nucleotide
191:The three
173:N-terminal
165:C terminus
33:methylated
1816:Genes Dev
1743:213761365
1643:190516439
1019:Genes Dev
829:1471-0056
653:addiction
635:Addiction
466:CpG sites
394:histidine
374:succinate
337:CpG sites
272:CpG sites
154:cofactors
78:(5mC) to
2214:25774451
2161:24757058
2099:16120461
2050:26656643
2000:28620075
1951:30934924
1900:23241950
1846:24736841
1792:11233153
1784:11290321
1700:23222540
1635:31209155
1600:24153300
1543:33262245
1494:26778955
1443:29755331
1392:35098021
1343:31467272
1281:27251462
1246:21941617
1197:22174693
1138:28555658
1100:31231651
1049:27036965
1000:26774490
970:Cell Rep
951:26937014
899:29556496
837:28555658
759:microRNA
595:cortical
523:epiblast
426:O-GlcNAc
420:-linked
260:sequence
248:cytosine
237:CpG site
197:isoforms
92:cytosine
60:cytosine
41:cytosine
2205:4617315
2152:4024925
2129:Bibcode
2090:4342048
2041:4700510
1991:5473107
1942:6523607
1891:3567490
1837:4003274
1691:3684361
1670:Bibcode
1591:4046508
1570:Bibcode
1534:7842754
1485:4700275
1434:5932360
1383:8793415
1334:6715719
1313:Bibcode
1237:3174260
1188:3234221
1146:3393814
1091:6566030
1040:4826392
991:4731272
942:6604871
890:5844914
845:3393814
787:in the
781:subunit
742:plantar
725:to the
464:at its
430:histone
296:enzyme
256:guanine
129:genes,
74:of DNA
64:guanine
2244:
2212:
2202:
2159:
2149:
2097:
2087:
2048:
2038:
1998:
1988:
1949:
1939:
1898:
1888:
1870:EMBO J
1844:
1834:
1790:
1782:
1741:
1731:
1698:
1688:
1662:Nature
1641:
1633:
1598:
1588:
1562:Nature
1541:
1531:
1492:
1482:
1468:: 78.
1441:
1431:
1417:: 79.
1390:
1380:
1341:
1331:
1279:
1244:
1234:
1195:
1185:
1144:
1136:
1098:
1088:
1074:: 99.
1047:
1037:
998:
988:
949:
939:
897:
887:
873:: 22.
843:
835:
827:
747:spinal
544:DNMT3b
540:DNMT3a
506:morula
485:oocyte
458:genome
386:Fe(II)
157:Fe(II)
56:methyl
1788:S2CID
1739:S2CID
1639:S2CID
1142:S2CID
841:S2CID
783:of a
772:Kcnh2
733:, of
727:brain
549:UHRF1
535:phase
497:DNMT1
455:sperm
264:bases
235:at a
175:CXXC
39:base
2242:ISBN
2210:PMID
2157:PMID
2095:PMID
2046:PMID
1996:PMID
1947:PMID
1896:PMID
1842:PMID
1780:PMID
1762:Cell
1729:ISBN
1696:PMID
1631:PMID
1596:PMID
1539:PMID
1490:PMID
1439:PMID
1388:PMID
1339:PMID
1277:PMID
1242:PMID
1193:PMID
1134:PMID
1096:PMID
1045:PMID
996:PMID
947:PMID
895:PMID
833:PMID
825:ISSN
735:pain
699:Tet1
691:TET1
687:TET1
683:TET1
664:TET1
657:TET1
647:The
554:NP95
542:and
316:EGR1
308:EGR1
302:TET1
298:OGG1
270:(at
181:IDAX
159:and
144:TET3
141:and
138:TET2
132:TET1
19:The
2200:PMC
2192:doi
2147:PMC
2137:doi
2125:111
2085:PMC
2077:doi
2036:PMC
2028:doi
1986:PMC
1978:doi
1937:PMC
1927:doi
1886:PMC
1878:doi
1832:PMC
1824:doi
1770:doi
1766:104
1721:doi
1686:PMC
1678:doi
1666:493
1623:doi
1586:PMC
1578:doi
1566:502
1529:PMC
1521:doi
1480:PMC
1470:doi
1429:PMC
1419:doi
1378:PMC
1370:doi
1329:PMC
1321:doi
1269:doi
1232:PMC
1224:doi
1183:PMC
1173:doi
1126:doi
1086:PMC
1076:doi
1035:PMC
1027:doi
986:PMC
978:doi
937:PMC
929:doi
885:PMC
875:doi
817:doi
769:of
675:RNA
625:RNA
286:ROS
262:of
215:).
201:TET
193:TET
127:TET
37:DNA
2261::
2240:.
2208:.
2198:.
2188:18
2186:.
2182:.
2169:^
2155:.
2145:.
2135:.
2123:.
2119:.
2107:^
2093:.
2083:.
2073:30
2071:.
2067:.
2044:.
2034:.
2024:19
2022:.
2018:.
1994:.
1984:.
1974:24
1972:.
1968:.
1945:.
1935:.
1923:10
1921:.
1917:.
1894:.
1884:.
1874:32
1872:.
1868:.
1854:^
1840:.
1830:.
1820:28
1818:.
1814:.
1800:^
1786:.
1778:.
1764:.
1760:.
1737:.
1727:.
1694:.
1684:.
1676:.
1664:.
1660:.
1637:.
1629:.
1619:47
1617:.
1594:.
1584:.
1576:.
1564:.
1560:.
1537:.
1527:.
1517:41
1515:.
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