Role of TET enzymes in DNA methylation, development, and cancer - PubMed (original) (raw)

Review

Role of TET enzymes in DNA methylation, development, and cancer

Kasper Dindler Rasmussen et al. Genes Dev. 2016.

Abstract

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.

Keywords: DNA demethylation; DNA methylation; TET; hydroxymethyl cytosine; hematopoiesis; leukemia.

© 2016 Rasmussen and Helin; Published by Cold Spring Harbor Laboratory Press.

PubMed Disclaimer

Figures

Figure 1.

Figure 1.

Domain structure of TET proteins. The C-terminal core catalytic domain shared by all TET enzymes consists of the DSBH domain, a cysteine-rich (Cys) domain, and binding sites for the Fe(II) and 2-OG cofactors. The DSBH domain contains a large low-complexity region of unknown function. TET1 and TET3 have an N-terminal CXXC domain that can bind directly to DNA and facilitate recruitment to genomic target sites.

Figure 2.

Figure 2.

Pathways of DNA demethylation mediated by TET enzymes. (A) Model of passive replication-dependent DNA demethylation. The diagrams illustrate the two opposite fates of a hemihydroxymethylated CpG dinucleotide through two rounds of DNA replication. The left panel shows the replication-dependent DNA demethylation, in which DNA methylation is lost on the DNA strand opposite to 5hmC. The right panel shows the reverse outcome, in which maintenance of DNA methylation is achieved by DNMT1 in complex with UHRF1/2 or DNMT3A/B. The relative extent of these two opposing outcomes of 5hmC deposition in vivo remains to be determined and is likely influenced by global as well as locus-specific factors. In both cases, newly replicated DNA dilutes 5hmC during cell division. (B) Model of active DNA demethylation by a TET/TDG (thymine–DNA–glycosylase)/BER (base excision repair)-dependent pathway. A cytosine base can be methylated by the DNA methylation machinery (DNMT1 or DNMT3A/B) to form 5mC, which in turn can be iteratively oxidized by TET enzymes to produce 5hmC, 5fC, and 5caC. TDG then recognizes 5fC and 5caC, and the oxidized cytosine base is excised. This yields an abasic site that is repaired by BER and results in restoration of the unmodified cytosine state. Additional pathways of active DNA demethylation have been suggested (for review, see Wu and Zhang 2014). (SAH) _S_-adenosyl-homocysteine; (SAM) _S_-adenosyl-methionine.

Figure 3.

Figure 3.

The dynamics of TET-mediated cytosine oxidation and its impact on DNA methylation patterns on regulatory elements in vivo. (A) Diagram illustrating the relative abundance of cytosines in the genome with “stable” levels of modifications as well as the small “transient” fractions that undergo rapid turnover and removal by active DNA demethylation processes. The stable levels of genomic 5caC have not been experimentally determined, as they are often under the detection limit. (B) Model illustrating the dual role of TET enzymes. The rate constant of TET enzymes to produce 5hmC from 5mC is fast, whereas the rate constants for further oxidation to 5fC and 5caC are considerably slower. On a majority of TET target sites, 5mC is oxidized and persists as “stable” 5hmC, likely due to low TET residence time (“stalling TET modification”). On a minority of sites, preferably located in open chromatin associated with regulatory elements, 5mC is oxidized iteratively to 5fC and 5caC and results in net DNA demethylation by the TET/TDG/BER pathway (“processive TET modification”). (C) Model illustrating the impact of loss of TET protein function on different regulatory elements. The protection of active and inactive CpG island promoters by the TET proteins is only one of several mechanisms by which they are protected against ectopic DNA methylation. In contrast, distal regulatory elements such as active enhancers are vulnerable to aberrant DNMT activity and become DNA hypermethylated upon loss of TET activity. (PcG) Polycomb group.

Figure 4.

Figure 4.

Illustration of the mutational landscape of TET2 in hematological diseases. A somatic mutation in TET2 results in premalignant hematopoiesis and clonal expansion. Additional oncogenic events cooperate with the initial TET2 mutation to drive the onset of a wide variety of hematopoietic malignancies. The frequencies of TET2 mutations in the different patient groups are indicated (for review, see Scourzic et al. 2015).

Similar articles

Cited by

References

    1. Abdel-Wahab O, Gao J, Adli M, Dey A, Trimarchi T, Chung YR, Kuscu C, Hricik T, Ndiaye-Lobry D, LaFave LM, et al. 2013. Deletion of Asxl1 results in myelodysplasia and severe developmental defects in vivo. J Exp Med 210: 2641–2659. - PMC - PubMed
    1. An J, González-Avalos E, Chawla A, Jeong M, López-Moyado IF, Li W, Goodell MA, Chavez L, Ko M, Rao A. 2015. Acute loss of TET function results in aggressive myeloid cancer in mice. Nat Commun 6: 10071. - PMC - PubMed
    1. Bachman M, Uribe-Lewis S, Yang X, Williams M, Murrell A, Balasubramanian S. 2014. 5-hydroxymethylcytosine is a predominantly stable DNA modification. Nat Chem 6: 1049–1055. - PMC - PubMed
    1. Bachman M, Uribe-Lewis S, Yang X, Burgess HE, Iurlaro M, Reik W, Murrell A, Balasubramanian S. 2015. 5-formylcytosine can be a stable DNA modification in mammals. Nat Chem Biol 11: 555–557. - PMC - PubMed
    1. Baylin SB, Jones PA. 2011. A decade of exploring the cancer epigenome—biological and translational implications. Nat Rev Cancer 11: 726–734. - PMC - PubMed

Publication types

MeSH terms

Substances

LinkOut - more resources