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Review
. 2013 Jun;25(3):289-96.
doi: 10.1016/j.ceb.2013.02.017. Epub 2013 Mar 13.

5-Hydroxymethylcytosine: generation, fate, and genomic distribution

Li Shen  1 , Yi Zhang
Affiliations
Review

5-Hydroxymethylcytosine: generation, fate, and genomic distribution

Li Shen et al. Curr Opin Cell Biol. 2013 Jun.

Abstract

5-Methylcytosine (5mC) can be converted to 5-hydroxymethylcytosine (5hmC) in mammalian cells by the ten-eleven translocation (Tet) family of dioxygenases. While 5mC has been extensively studied, we have just started to understand the distribution and function of 5hmC in mammalian genomes. Despite the fact that this new epigenetic mark has only been discovered three years ago, exciting progress has been made in understanding its generation, fate, and genomic distribution. In this review we discuss these progresses as well as the recent advance in the single-base resolution mapping of 5hmC.

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Figures

Figure 1
Figure 1
Schematic diagrams of the Tet proteins. Three conserved domains are indicated in mouse Tet proteins, including CXXC zinc finger, cysteine-rich region (Cys-rich), and the double-stranded β-helix (DSBH) fold of the 2OG-dependent and Fe(II)-dependent dioxygenase domain (2OGFeDO). Note that Tet3 has a shorter form, which starts at amino acid 136, that does not contain the CXXC domain. For the 2OGFeDO domain, a multiple sequence alignment of selected JBP/Tet family proteins is shown. Sequences used in the alignment include the Trypanosoma brucei JBP1 (Q9U6M3) and JBP2 (Q57X81); human TET1 (NP_085128), TET2 (NP_001120680), and TET3 (ADU77107); and mouse Tet1 (NP_001240786), Tet2 (ACY38292), and Tet3 (ADR57137). Predicted Fe(II) and 2OG-binding sites are indicated, and the conserved strands that constitute the DSBH fold are shown above the multiple sequence alignment. Numbers represent the amino acid numbers.
Figure 2
Figure 2
Proposed DNA demethylation pathways that involve 5hmC. DNA methylation (5mC) is established and maintained by DNA methyltransferases (DNMTs). In mammals, 5mC can be oxidized by the Tet proteins to generate 5hmC. 5hmC is recognized poorly by Dnmt1 and can be diluted during DNA replication. 5hmC can also be further oxidized by Tet proteins to produce 5fC and 5caC. Alternatively, 5hmC may be deaminated by AID/APOBECs to become 5hmU. 5fC, 5caC, and 5hmU can be excised from DNA by glycosylases. In addition, DNMT3A and DNMT3B may directly dehydroxymethylate 5hmC to generate unmodified C. Note that solid lines represent processes with strong evidence, while the dashed lines indicate processes which need to be further confirmed controversial process.
Figure 3
Figure 3
Genomic distribution of 5hmC. 1. Schematic diagram illustrating the 5hmC distribution in the genome of mouse ESCs. 5hmC is preferentially enriched at gene bodies of actively transcribed genes, bivalent and silent promoters, as well as active enhancers and a cohort of pluripotency transcription factor binding sites. 2. Comparison between the antibody-based 5hmC profiling methods and the single-base resolution methods. Antibody-based methods are not sensitive enough to detect all orphan 5hmCs, and thus may not be able to detect low 5hmC-density regions. In contrast, the single-base resolution methods can quantitatively determine the levels of orphan 5hmCs. However, the single-base resolution methods still cannot achieve low detection limitation (red dashed line) with normal sequencing depth. Thus, 5hmCs with low abundance in a population of cells may not be confidently identified.
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