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      TET-mediated active DNA demethylation: mechanism, function and beyond

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      Journal: Nature Reviews Genetics
      Publisher: Springer Nature

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          Abstract

          A key mode of regulating DNA methylation is through active demethylation driven by TET-mediated oxidation of 5-methylcytosine (5mC). This Review discusses our latest understanding of the mechanisms and regulation of active DNA demethylation, and the roles of active demethylation (and the oxidized 5mC intermediates) in gene regulation, genome stability, development and disease.

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          TET enzymes, TDG and the dynamics of DNA demethylation.

          Rahul M. Kohli, Yi Zhang (2013)
          DNA methylation has a profound impact on genome stability, transcription and development. Although enzymes that catalyse DNA methylation have been well characterized, those that are involved in methyl group removal have remained elusive, until recently. The transformative discovery that ten-eleven translocation (TET) family enzymes can oxidize 5-methylcytosine has greatly advanced our understanding of DNA demethylation. 5-Hydroxymethylcytosine is a key nexus in demethylation that can either be passively depleted through DNA replication or actively reverted to cytosine through iterative oxidation and thymine DNA glycosylase (TDG)-mediated base excision repair. Methylation, oxidation and repair now offer a model for a complete cycle of dynamic cytosine modification, with mounting evidence for its significance in the biological processes known to involve active demethylation.
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            Hydroxylation of 5-methylcytosine by TET1 promotes active DNA demethylation in the adult brain.

            Junjie U. Guo, Yijing Su, Chun Zhong … (2011)
            Cytosine methylation is the major covalent modification of mammalian genomic DNA and plays important roles in transcriptional regulation. The molecular mechanism underlying the enzymatic removal of this epigenetic mark, however, remains elusive. Here, we show that 5-methylcytosine (5mC) hydroxylase TET1, by converting 5mCs to 5-hydroxymethylcytosines (5hmCs), promotes DNA demethylation in mammalian cells through a process that requires the base excision repair pathway. Though expression of the 12 known human DNA glycosylases individually did not enhance removal of 5hmCs in mammalian cells, demethylation of both exogenously introduced and endogenous 5hmCs is promoted by the AID (activation-induced deaminase)/APOBEC (apolipoprotein B mRNA-editing enzyme complex) family of cytidine deaminases. Furthermore, Tet1 and Apobec1 are involved in neuronal activity-induced, region-specific, active DNA demethylation and subsequent gene expression in the dentate gyrus of the adult mouse brain in vivo. Our study suggests a TET1-induced oxidation-deamination mechanism for active DNA demethylation in mammals. Copyright © 2011 Elsevier Inc. All rights reserved.
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              Role of TET enzymes in DNA methylation, development, and cancer

              Kasper Rasmussen, Kristian Helin (2016)
              Ten eleven translocation (TET) genes, and especially TET2, are frequently mutated in various cancers, but how the TET proteins contribute to the onset and maintenance of these malignancies is largely unknown. In this review, Rasmussen and Helin highlight recent advances in understanding the physiological function of the TET proteins and their role in regulating DNA methylation and transcription. The pattern of DNA methylation at cytosine bases in the genome is tightly linked to gene expression, and DNA methylation abnormalities are often observed in diseases. The ten eleven translocation (TET) enzymes oxidize 5-methylcytosines (5mCs) and promote locus-specific reversal of DNA methylation. TET genes, and especially TET2 , are frequently mutated in various cancers, but how the TET proteins contribute to prevent the onset and maintenance of these malignancies is largely unknown. Here, we highlight recent advances in understanding the physiological function of the TET proteins and their role in regulating DNA methylation and transcription. In addition, we discuss some of the key outstanding questions in the field.
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                Author and article information

                Journal
                Title: Nature Reviews Genetics
                Abbreviated Title: Nat Rev Genet
                Publisher: Springer Nature
                ISSN (Print): 1471-0056
                ISSN (Electronic): 1471-0064
                Publication date Created: May 30 2017
                Publication date (Print): May 30 2017
                Volume:
                Issue:
                Article
                DOI: 10.1038/nrg.2017.33
                PubMed ID: 28555658
                SO-VID: 6bd736b7-321d-4c11-8f31-a2f50a8e935e
                Copyright © © 2017
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