TET enzymes: Difference between revisions
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[[File:DNA methylation.png|thumb|300px|DNA methylation is the addition of a [[methyl]] group to the DNA that happens at [[cytosine]]. 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 [[guanine]].]] |
[[File:DNA methylation.png|thumb|300px|DNA methylation is the addition of a [[methyl]] group to the DNA that happens at [[cytosine]]. 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 [[guanine]].]] |
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The TET enzymes, causing demethylation (see second Figure), alter the regulation of transcription. The TET enzymes catalyze the [[hydroxylation]] of DNA [[5-Methylcytosine]] (5mC) into [[5-hydroxymethylcytosine]] (5hmC), and can further oxidize 5hmC to 5-formylcytosine (5fC) and 5-carboxycytosine (5caC).<ref name= |
The TET enzymes, causing demethylation (see second Figure), alter the regulation of transcription. The TET enzymes catalyze the [[hydroxylation]] of DNA [[5-Methylcytosine]] (5mC) into [[5-hydroxymethylcytosine]] (5hmC), and can further oxidize 5hmC to 5-formylcytosine (5fC) and 5-carboxycytosine (5caC).<ref name=Melamed>{{cite journal |vauthors=Melamed P, Yosefzon Y, David C, Tsukerman A, Pnueli L |title=Tet Enzymes, Variants, and Differential Effects on Function |journal=Front Cell Dev Biol |volume=6 |issue= |pages=22 |date=2018 |pmid=29556496 |pmc=5844914 |doi=10.3389/fcell.2018.00022 |url=}}</ref> The intermediates 5fC and 5caC can be replaced in DNA by [[base excision repair]] with [[cytosine]] in the base sequence. |
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[[File:Demethylation of 5-methylcytosine.svg|thumb|259x259px|Demethylation of 5-methylcytosine. Demethylation of 5-methylcytosine (5mC) in neuron DNA.|alt=]] |
[[File:Demethylation of 5-methylcytosine.svg|thumb|259x259px|Demethylation of 5-methylcytosine. Demethylation of 5-methylcytosine (5mC) in neuron DNA.|alt=]] |
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As reviewed in 2018, in brain neurons, 5mC is oxidized by a TET dioxygenase to generate 5-hydroxymethylcytosine(5hmC). In successive steps a TET enzyme further hydroxylates 5hmC to generate 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC). Thymine-DNA glycosylase (TDG) recognizes the intermediate bases 5fC and 5caC and cleaves the glycosidic bond resulting in an apyrimidinic site (AP site). In an alternative oxidative deamination pathway, 5hmC can be oxidatively deaminated by activity-induced cytidine deaminase/apolipoprotein B mRNA editing complex (AID/APOBEC) to form 5-hydroxymethyluracil (5hmU). 5mC can also be converted to thymine (Thy). 5hmU can be cleaved by TDG, single-strand-selective monofunctional uracil-DNA glycosylase 1 (SMUG1), Nei-Like DNA glycosylase 1 (NEIL1), or methyl-CpG binding protein 4 (MBD4). AP sites and T:G mismatches are then repaired by base excision repair (BER) enzymes to yield cytosine (Cyt). |
As reviewed in 2018, in brain neurons, 5mC is oxidized by a TET dioxygenase to generate 5-hydroxymethylcytosine(5hmC). In successive steps a TET enzyme further hydroxylates 5hmC to generate 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC). Thymine-DNA glycosylase (TDG) recognizes the intermediate bases 5fC and 5caC and cleaves the glycosidic bond resulting in an apyrimidinic site (AP site). In an alternative oxidative deamination pathway, 5hmC can be oxidatively deaminated by activity-induced cytidine deaminase/apolipoprotein B mRNA editing complex (AID/APOBEC) to form 5-hydroxymethyluracil (5hmU). 5mC can also be converted to thymine (Thy). 5hmU can be cleaved by TDG, single-strand-selective monofunctional uracil-DNA glycosylase 1 (SMUG1), Nei-Like DNA glycosylase 1 (NEIL1), or methyl-CpG binding protein 4 (MBD4). AP sites and T:G mismatches are then repaired by base excision repair (BER) enzymes to yield cytosine (Cyt). |
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==TET proteins== |
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There are three related TET genes, ''[[Tet methylcytosine dioxygenase 1|TET1]]'', ''TET2'' and ''TET3''. They code for three related mammalian proteins Tet1, Tet2, and Tet3. All three proteins possess 5mC oxidase activity, but they differ in terms of domain architecture.<ref name="pmid26774490">{{cite journal |vauthors=Jin SG, Zhang ZM, Dunwell TL, Harter MR, Wu X, Johnson J, Li Z, Liu J, Szabó PE, Lu Q, Xu GL, Song J, Pfeifer GP |title=Tet3 Reads 5-Carboxylcytosine through Its CXXC Domain and Is a Potential Guardian against Neurodegeneration |journal=Cell Rep |volume=14 |issue=3 |pages=493–505 |date=January 2016 |pmid=26774490 |pmc=4731272 |doi=10.1016/j.celrep.2015.12.044 |url=}}</ref> TET proteins are large (∼180- to 230-kDa) multidomain enzymes. All TET proteins contain a conserved double-stranded β-helix (DSBH) domain, a cysteine-rich domain, and binding sites for the cofactors Fe(II) and 2-oxoglutarate (2-OG) that together form the core catalytic region in the C terminus. In addition to their catalytic domain, full-length TET1 and TET3 proteins have an N-terminal CXXC zinc finger domain that can bind DNA.<ref name="pmid27036965">{{cite journal |vauthors=Rasmussen KD, Helin K |title=Role of TET enzymes in DNA methylation, development, and cancer |journal=Genes Dev. |volume=30 |issue=7 |pages=733–50 |date=April 2016 |pmid=27036965 |pmc=4826392 |doi=10.1101/gad.276568.115 |url=}}</ref> TET2, which lacks a CXXC domain has a neighboring gene, IDAX, which encodes a CXXC4 protein. IDAX is thought to play a role in regulating TET2 activity by facilitating its recruitment to unmethylated CpGs. |
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==TET isoforms== |
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The three TET genes are expressed as different [[protein isoform|isoforms]], including at least two isoforms of TET1, three of TET2 and three of TET3.<ref name=Melamed /><ref name="pmid31231651">{{cite journal |vauthors=Lou H, Li H, Ho KJ, Cai LL, Huang AS, Shank TR, Verneris MR, Nickerson ML, Dean M, Anderson SK |title=The Human TET2 Gene Contains Three Distinct Promoter Regions With Differing Tissue and Developmental Specificities |journal=Front Cell Dev Biol |volume=7 |issue= |pages=99 |date=2019 |pmid=31231651 |pmc=6566030 |doi=10.3389/fcell.2019.00099 |url=}}</ref> Different isoforms of the TET genes are expressed in different cells and tissues. The full-length canonical TET1 isoform appears virtually restricted to early embryos, embryonic stem cells and primordial germ cells (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 hematopoietic cells. The isoforms of TET3 are the full length form TET3FL, a short form splice variant TET3s, and a form that occurs in oocytes and neurons 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 [[DNA demethylation]]). |
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==TET specificity== |
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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 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.<ref name="pmid28555658">{{cite journal |vauthors=Wu X, Zhang Y |title=TET-mediated active DNA demethylation: mechanism, function and beyond |journal=Nat. Rev. Genet. |volume=18 |issue=9 |pages=517–534 |date=September 2017 |pmid=28555658 |doi=10.1038/nrg.2017.33 |url=}}</ref> |
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== References == |
== References == |
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Revision as of 21:39, 27 May 2020
The TET enzymes are a family of ten-eleven translocation (TET) methylcytosine dioxygenases. They are instrumental in DNA demethylation. 5-Methylcytosine (see first Figure) is a methylated form of the DNA base cytosine (C) that regulates gene transcription and has several other functions in the genome.[1]
The TET enzymes, causing demethylation (see second Figure), alter the regulation of transcription. The TET enzymes catalyze the hydroxylation of DNA 5-Methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC), and can further oxidize 5hmC to 5-formylcytosine (5fC) and 5-carboxycytosine (5caC).[2] The intermediates 5fC and 5caC can be replaced in DNA by base excision repair with cytosine in the base sequence.
TET proteins
There are three related TET genes, TET1, TET2 and TET3. They code for three related mammalian proteins Tet1, Tet2, and Tet3. All three proteins possess 5mC oxidase activity, but they differ in terms of domain architecture.[3] TET proteins are large (∼180- to 230-kDa) multidomain enzymes. All TET proteins contain a conserved double-stranded β-helix (DSBH) domain, a cysteine-rich domain, and binding sites for the cofactors Fe(II) and 2-oxoglutarate (2-OG) that together form the core catalytic region in the C terminus. In addition to their catalytic domain, full-length TET1 and TET3 proteins have an N-terminal CXXC zinc finger domain that can bind DNA.[4] TET2, which lacks a CXXC domain has a neighboring gene, IDAX, which encodes a CXXC4 protein. IDAX is thought to play a role in regulating TET2 activity by facilitating its recruitment to unmethylated CpGs.
TET isoforms
The three TET genes are expressed as different isoforms, including at least two isoforms of TET1, three of TET2 and three of TET3.[2][5] Different isoforms of the TET genes are expressed in different cells and tissues. The full-length canonical TET1 isoform appears virtually restricted to early embryos, embryonic stem cells and primordial germ cells (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 hematopoietic cells. The isoforms of TET3 are the full length form TET3FL, a short form splice variant TET3s, and a form that occurs in oocytes and neurons 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 DNA demethylation).
TET specificity
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 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.[6]
References
- ^ Wu, Xiaoji; Zhang, Yi (2017-05-30). "TET-mediated active DNA demethylation: mechanism, function and beyond". Nature Reviews Genetics. 18 (9): 517–534. doi:10.1038/nrg.2017.33. ISSN 1471-0056. PMID 28555658.
- ^ a b Melamed P, Yosefzon Y, David C, Tsukerman A, Pnueli L (2018). "Tet Enzymes, Variants, and Differential Effects on Function". Front Cell Dev Biol. 6: 22. doi:10.3389/fcell.2018.00022. PMC 5844914. PMID 29556496.
{{cite journal}}: CS1 maint: unflagged free DOI (link) - ^ Jin SG, Zhang ZM, Dunwell TL, Harter MR, Wu X, Johnson J, Li Z, Liu J, Szabó PE, Lu Q, Xu GL, Song J, Pfeifer GP (January 2016). "Tet3 Reads 5-Carboxylcytosine through Its CXXC Domain and Is a Potential Guardian against Neurodegeneration". Cell Rep. 14 (3): 493–505. doi:10.1016/j.celrep.2015.12.044. PMC 4731272. PMID 26774490.
- ^ Rasmussen KD, Helin K (April 2016). "Role of TET enzymes in DNA methylation, development, and cancer". Genes Dev. 30 (7): 733–50. doi:10.1101/gad.276568.115. PMC 4826392. PMID 27036965.
- ^ Lou H, Li H, Ho KJ, Cai LL, Huang AS, Shank TR, Verneris MR, Nickerson ML, Dean M, Anderson SK (2019). "The Human TET2 Gene Contains Three Distinct Promoter Regions With Differing Tissue and Developmental Specificities". Front Cell Dev Biol. 7: 99. doi:10.3389/fcell.2019.00099. PMC 6566030. PMID 31231651.
{{cite journal}}: CS1 maint: unflagged free DOI (link) - ^ Wu X, Zhang Y (September 2017). "TET-mediated active DNA demethylation: mechanism, function and beyond". Nat. Rev. Genet. 18 (9): 517–534. doi:10.1038/nrg.2017.33. PMID 28555658.