DNA methylation: TET proteins-guardians of CpG islands?

Abstract

DNA methylation is involved in key cellular processes, including X-chromosome inactivation, imprinting and transcriptional silencing of specific genes and repetitive elements. DNA methylation patterns are frequently perturbed in human diseases such as imprinting disorders and cancer. The recent discovery that the three members of the TET protein family can convert 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC) has provided a potential mechanism leading to DNA demethylation. Moreover, the demonstration that TET2 is frequently mutated in haematopoietic tumours suggests that the TET proteins are important regulators of cellular identity. Here, we review the current knowledge regarding the function of the TET proteins, and discuss various mechanisms by which they contribute to transcriptional control. We propose that the TET proteins have an important role in regulating DNA methylation fidelity, and that their inactivation contributes to the DNA hypermethylation phenotype often observed in cancer.

Figure 1

Possible biological roles of TET proteins and 5hmC. (A) The domain structure of human TET proteins. TET1–3 contain a cysteine (Cys)-rich region followed by the double-stranded β-helix (DSBH) fold characteristic of the 2OG-Fe(II) oxygenases and required for catalytic activity. TET1 and TET3 also contain a CXXC domain. (B) Several biological consequences of the TET-mediated conversion of 5mC to 5hmC can be envisioned. 5hmC might facilitate a passive demethylation that is replication-dependent or could be converted to cytosine through an active demethylation pathway. Finally, 5hmC might also have direct effects by displacing or recruiting effector proteins. 5hmC, 5-hydroxymethylcytosine; 5mC, 5-methylcytosine.

Figure 2

Potential roles of Tet1 in transcriptional regulation. (A,B) Tet1 could be involved in transcriptional repression in ESCs through the recruitment of repressive complexes. Tet1 has been proposed to facilitate PRC2 binding indirectly by reducing DNA methylation at PRC2 target genes (A). Moreover, Tet1 could mediate transcriptional repression by directly recruiting the Sin3A co-repressor complex to a subset of its target genes (B). During differentiation, Tet1 is downregulated, which would allow for the repressed genes to be activated. (C,D) Tet1 might also contribute to transcriptional activation by preventing DNA methylation. At strong CpG islands that rarely undergo DNA methylation, Tet1 binding might act as a failsafe mechanism to remove aberrant DNA methylation (C). However, Tet1 also binds to weak CpG islands that have been reported to become de novo DNA-methylated during differentiation. They often also display high levels of 5hmC, indicating that Tet1, by converting 5mC into 5hmC, ensures the timely methylation and silencing of these target genes during differentiation (D). 5hmC, 5-hydroxymethylcytosine; ESC, embryonic stem cell; PRC, Polycomb repressive complex; Tet1, ten-eleven translocation 1.

Figure 3

The function of Tet1 in DNA methylation fidelity. Tet1 associates with the CpG islands of a large number of genes. If aberrant DNA methylation occurs at these promoters, conversion into hydroxymethylation by Tet1 could facilitate passive or active DNA demethylation. In this way, Tet1 regulates DNA methylation fidelity by preventing the accumulation of aberrant DNA methylation at CpG islands.

Jesper Christensen, Kristine Williams & Kristian Helin