Tet methylcytosine dioxygenase 3 is a protein that in humans is encoded by the TET3 gene. [5]
| TET3 | |||||||||||||||||||||||||||||||||||||||||||||||||||
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| Aliases | TET3, hCG_40738, tet methylcytosine dioxygenase 3, BEFAHRS | ||||||||||||||||||||||||||||||||||||||||||||||||||
| External IDs | OMIM: 613555; MGI: 2446229; HomoloGene: 35360; GeneCards: TET3; OMA:TET3 - orthologs | ||||||||||||||||||||||||||||||||||||||||||||||||||
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Function
editTet3 and its respective protein TET 3 are members of the TET (ten-eleven-translocation) family of genes and proteins that play a role in DNA demethylation.[6] DNA demethylation is the removal of suppressive methyl groups from the cytosine of DNA.[6] Demethylating the DNA and removing these markers is associated with increased transcription.[6] Since DNA methylation is a relatively strong and stable marker it is not often removed. However, there are important points in an organism’s life when these marks benefit from being removed so that certain genes can be accessed and transcribed.
One of which is right after an egg and sperm have come together to form a zygote. The methylation marks from the parent cells must be removed so that certain genes can be accessed and transcribed for the zygote to mature into a fully grown organism.[6] Tet3 plays an important role here. The TET3 protein works to demethylate the genome of the fertilized zygote to allow it to grow into a fully developed organism. It does this by starting a series of oxidation reactions that convert the methylated cytosine on the DNA from 5-methyl cytosine (5mC) into 5-hydroxymethylcytosine (5hmC).[6] This cytosine base then goes through a further series of reactions after which it can be removed either passively through replication-dependent dilution or actively by the enzyme thymidine DNA glycosylase and replaced with an unmethylated cytosine base.[6] Once this occurs the DNA is now more accessible for transcription.
There are certain tissues that rely heavily on Tet3 for their development. For example, TET3 is found in large quantities in neurons and is important for their development and maturation.[7] While there is not much work regarding the role of Tet3 in humans, studies have been done on model organisms such as mice, frogs, and rats. An experiment done by several researchers on mice showed that Tet3 is most active in NPC or Neuronal Progenitor Cells.[7] These cells are the progenitors of mature neurons and begin to develop shortly after a zygote is formed. Once an embryonic stem cell begins to differentiate into an NPC, Tet3 becomes upregulated.[7] The researchers speculate that this occurs in order to demethylate genes associated with neuronal maturation so they can be transcribed.[7] While Tet3 is not important for the commitment of an embryonic stem cell to turn into an NPC, it is important for maintaining the cell as an NPC and eventually turning it into a mature neuron. The complete absence or knockout of Tet3 in mouse cells leads to increased apoptosis of neurons, demonstrating how important the gene is to neuronal development.[7]
In addition, Tet3 is important for repair and upkeep in mature neurons. Epigenetic markers, especially ones that make the DNA more accessible, are important after cell damage because they can turn on genes that function in cell repair.[8] A recent study done in vivo in rats has shown that the TET3 protein is important in recovery after a stroke. The study shows that TET3 as well as its product, 5-hydroxymethylcytosine (5hmC), are expressed more after focal ischemia in order to demethylate and turn on genes associated with DNA repair in neurons.[8] Knockdown of the TET3 protein in these rats led to increased neuron damage after a stroke and a decreased expression of several genes that aid in neuron repair.[8] These results not only demonstrate the importance of Tet3 in neuronal repair but also suggest Tet3 and its protein as a possible therapeutic target for future studies that could aid patients in neuronal repair after a stroke.
In humans, less is known about the exact role of Tet3 in neurons. Current studies in humans are focusing on the effects of mutant Tet3 on an individual’s phenotype. While the complete knockout of Tet3 appears to be fatal to the developing zygote, the mutation of one or more alleles of Tet3 can result in viable offspring.[9] These mutations of Tet3 can greatly affect the TET3 protein and lead to a class of neurodevelopmental disorders in humans known as Beck–Fahrner syndrome.[9] Individuals with these mutations experience phenotypes such as developmental delay and growth abnormalities as well as features found in other neurodevelopmental disorders such as Sotos Syndrome and Autism Spectrum Disorder.[9]
Little is known about the exact mutations on Tet3 that cause Beck–Fahrner syndrome and their inheritance patterns. However, the mutations seem to follow a Mendelian pattern of inheritance.[9] In a recent study of affected individuals and their families, some were found to have autosomal-dominant patterns of inheritance while others were found to have autosomal-recessive patterns of inheritance.[9] Regardless of the inheritance pattern, all mutations in this gene were shown to be caused by either a missense variant in the region of the gene that codes for the catalytic domain of TET3 or a frameshift or nonsense variant in the same region.[9] The region in which this mutation occurs is highly conserved among species, especially mice and humans, which is why work done on model organisms may be useful in bettering our understanding of Tet3’s function in humans.[9]
In conclusion, the Tet3 gene is important in a variety of organisms including humans, rats, and mice. It functions mostly during the formation of a zygote, particularly in neurons. There it helps neurons mature and develop as well as aids them in repair.
Clinical
editMutations in this gene can result in Beck–Fahrner syndrome, which has been associated a number of abnormal phenotypic features including intellectual disability, developmental delay, hypotonia, autistic traits, movement disorders, growth abnormalities and facial dysmorphism.[9]
References
edit- ^ a b c GRCh38: Ensembl release 89: ENSG00000187605 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000034832 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Entrez Gene: Tet methylcytosine dioxygenase 3". Retrieved 2018-08-13.
- ^ a b c d e f Yang J, Bashkenova N, Zang R, Huang X, Wang J (January 2020). "The roles of TET family proteins in development and stem cells". Development. 147 (2). doi:10.1242/dev.183129. PMC 6983710. PMID 31941705.
- ^ a b c d e Li T, Yang D, Li J, Tang Y, Yang J, Le W (February 2015). "Critical role of Tet3 in neural progenitor cell maintenance and terminal differentiation". Molecular Neurobiology. 51 (1): 142–54. doi:10.1007/s12035-014-8734-5. PMID 24838624. S2CID 15337793.
- ^ a b c Morris-Blanco KC, Kim T, Lopez MS, Bertogliat MJ, Chelluboina B, Vemuganti R (September 2019). "Induction of DNA Hydroxymethylation Protects the Brain After Stroke". Stroke. 50 (9): 2513–2521. doi:10.1161/STROKEAHA.119.025665. PMC 6710106. PMID 31327315.
- ^ a b c d e f g h Beck DB, Petracovici A, He C, Moore HW, Louie RJ, Ansar M, et al. (February 2020). "Delineation of a Human Mendelian Disorder of the DNA Demethylation Machinery: TET3 Deficiency". American Journal of Human Genetics. 106 (2): 234–245. doi:10.1016/j.ajhg.2019.12.007. PMC 7010978. PMID 31928709.
Further reading
edit- Abdel-Wahab O, Mullally A, Hedvat C, Garcia-Manero G, Patel J, Wadleigh M, et al. (July 2009). "Genetic characterization of TET1, TET2, and TET3 alterations in myeloid malignancies". Blood. 114 (1): 144–7. doi:10.1182/blood-2009-03-210039. PMC 2710942. PMID 19420352.
- Abdel-Wahab O, Mullally A, Hedvat C, Garcia-Manero G, Patel J, Wadleigh M, et al. (July 2009). "Genetic characterization of TET1, TET2, and TET3 alterations in myeloid malignancies". Blood. 114 (1): 144–7. doi:10.1182/blood-2009-03-210039. PMC 2710942. PMID 19420352.
- Langemeijer SM, Aslanyan MG, Jansen JH (December 2009). "TET proteins in malignant hematopoiesis". Cell Cycle. 8 (24): 4044–8. doi:10.4161/cc.8.24.10239. PMID 19923888.
- Rose JE, Behm FM, Drgon T, Johnson C, Uhl GR (2010). "Personalized smoking cessation: interactions between nicotine dose, dependence and quit-success genotype score". Molecular Medicine. 16 (7–8): 247–53. doi:10.2119/molmed.2009.00159. PMC 2896464. PMID 20379614.
- Liu N, Wang M, Deng W, Schmidt CS, Qin W, Leonhardt H, Spada F (2013). "Intrinsic and extrinsic connections of Tet3 dioxygenase with CXXC zinc finger modules". PLOS ONE. 8 (5): e62755. Bibcode:2013PLoSO...862755L. doi:10.1371/journal.pone.0062755. PMC 3653909. PMID 23690950.
- Ponnaluri VK, Maciejewski JP, Mukherji M (June 2013). "A mechanistic overview of TET-mediated 5-methylcytosine oxidation". Biochemical and Biophysical Research Communications. 436 (2): 115–20. doi:10.1016/j.bbrc.2013.05.077. PMID 23727577.
- Zhang P, Huang B, Xu X, Sessa WC (August 2013). "Ten-eleven translocation (Tet) and thymine DNA glycosylase (TDG), components of the demethylation pathway, are direct targets of miRNA-29a". Biochemical and Biophysical Research Communications. 437 (3): 368–73. doi:10.1016/j.bbrc.2013.06.082. PMC 3767426. PMID 23820384.
- Ito R, Katsura S, Shimada H, Tsuchiya H, Hada M, Okumura T, et al. (January 2014). "TET3-OGT interaction increases the stability and the presence of OGT in chromatin". Genes to Cells. 19 (1): 52–65. doi:10.1111/gtc.12107. PMID 24304661. S2CID 21206974.
- Zhang Q, Liu X, Gao W, Li P, Hou J, Li J, Wong J (February 2014). "Differential regulation of the ten-eleven translocation (TET) family of dioxygenases by O-linked β-N-acetylglucosamine transferase (OGT)". The Journal of Biological Chemistry. 289 (9): 5986–96. doi:10.1074/jbc.M113.524140. PMC 3937666. PMID 24394411.
This article incorporates text from the United States National Library of Medicine, which is in the public domain.