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TETonic shift: biological roles of TET proteins in DNA demethylation and transcription

Key Points

  • Ten-eleven translocation (TET) proteins oxidize the methyl group of 5-methylcytosine (5mC) in DNA to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC). They constitute a subset of TET–J-binding protein (JBP)-family proteins, which are Fe2+- and 2-oxoglutarate-dependent dioxygenases that oxidize methylpyrimidines.

  • Mammalian TET proteins contain two distinguishable domains, a CXXC domain that targets them to DNA, and a carboxy-terminal catalytic domain. The catalytic activity of TET proteins seems to be dispensable for some of their effects on gene transcription, probably because of their interaction with chromatin modifiers such as O-linked β-D-N-acetylglucosamine (O-GlcNAc) transferase and the switch-independent 3A (SIN3A) complex.

  • TET proteins and oxidized methylcytosines are implicated in several pathways of DNA demethylation. So far the two most well-established mechanisms are removal of 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC) by thymine DNA glycosylase (TDG), and inhibition of DNA methyltransferase (DNMT)1-mediated maintenance DNA methylation.

  • Several methods have been developed to map the genomic distribution of 5hmC, including new technologies that allow mapping at single-base resolution. Recent studies have identified proteins that bind 5hmC and other oxidized methylcytosines.

  • Mice doubly-deficient in TET1 and TET2 survive until birth, indicating that these two proteins are dispensable for pluripotency. However recent evidence suggests a role for TET proteins in the reprogramming of fibroblasts to induced pluripotent stem (iPS) cells.

  • TET3 has an established role in methylcytosine oxidation in the male pronucleus in the zygote, whereas PGC7 prevents this process from occurring in the female pronucleus. Whether this process of mass oxidation is involved in DNA demethylation in the zygote is still unclear.

  • TET1 and TET2 mediate mass methylcytosine oxidation in primordial germ cells (PGCs). Although DNA demethylation in PGCs is a passive process for which TET1 and TET2 are largely dispensable, methylcytosine oxidation seems to be important for removing imprints during germ cell development.

Abstract

In many organisms, the methylation of cytosine in DNA has a key role in silencing 'parasitic' DNA elements, regulating transcription and establishing cellular identity. The recent discovery that ten-eleven translocation (TET) proteins are 5-methylcytosine oxidases has provided several chemically plausible pathways for the reversal of DNA methylation, thus triggering a paradigm shift in our understanding of how changes in DNA methylation are coupled to cell differentiation, embryonic development and cancer.

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Figure 1: Mechanisms of TET-mediated demethylation.
Figure 2: Known protein domains of TET family members.
Figure 3: Methylation dynamics in mammalian development.

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Acknowledgements

The authors thank S. Evans and A. Clark for comments on the manuscript. This work was supported by US National Institutes of health (NIH) R01 grants AI44432, HD065812 and CA151535, grant RM-01729 from the California Institute of Regenerative Medicine, and Translational Research grant TRP 6187–12 from the Leukemia and Lymphoma Society (to A.R). Work in the laboratory of L.A. is supported by intramural funds of the National Library of Medicine, NIH. W.A.P. was supported by a predoctoral graduate research fellowship from the National Science Foundation and is currently supported by a postdoctoral fellowship from the Jane Coffin Childs Memorial Fund for Medical Research.

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The CXXC domain of TET family members. (PDF 212 kb)

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Protein Data Bank

Glossary

Dioxygenases

Enzymes that catalyse the addition of both oxygen atoms from molecular oxygen to one or two organic substrates.

DNA demethylation

Here, defined as replacement of 5-methylcytosine, the major methylated base in mammalian DNA, with unmodified cytosine, either directly or through intermediates.

CXXC domain

A Zn2+-chelating domain typified by the signature amino acid sequence CGXCXXC(X)NC, in which X represents any amino acid. CXXC domains in metazoans always contain two such sequences.

CpG sequences

Any instance of a cytosine followed immediately by a guanine on the same strand of DNA. Most DNA methylation in mammals occurs at CpG sites.

Base excision repair

(BER). A DNA repair pathway in which a DNA base is removed by a glycosylase enzyme and ultimately replaced by a new base.

Primordial germ cells

(PGCs). Precursors of mature germ cells (egg in female and sperm in male).

Click chemistry

Chemistry involving high-yield, highly specific reactions that are compatible with physiological conditions and maintain the integrity of biological molecules.

Sequencing coverage

Average number of times that a genome or a DNA region is sequenced using a next-generation sequencing instrument.

Zygote

Cell formed by fertilization of the oocyte (egg) with a sperm cell.

Imprinted locus

In epigenetics this describes a genomic region with a methylation mark that is present only on the maternally or paternally derived copy of an allele.

Trophectoderm

Cells that give rise to the placenta and other extra-embryonic tissue.

Embryoid bodies

Aggregates of cells formed by allowing embryonic stem cells to differentiate without contact with a solid surface.

Inbred mouse strain

Experiments are typically conducted using inbred mouse strains, in which all mice are genetically extremely similar. C57BL/6 is one of the most frequently used strains. 129P2/OlaHsd is another inbred mouse strain. The same mutation can have different effects in different backgrounds

Gene-trap

A mutant in which a gene is disrupted by the random insertion of transgenic DNA that contains a splice acceptor site followed by stop codons.

Meiotic synapsis

The event in meiosis prophase I in which homologous chromosomes align to allow recombination of genetic material (known as 'crossing over').

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Pastor, W., Aravind, L. & Rao, A. TETonic shift: biological roles of TET proteins in DNA demethylation and transcription. Nat Rev Mol Cell Biol 14, 341–356 (2013). https://doi.org/10.1038/nrm3589

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