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Uncovering the role of 5-hydroxymethylcytosine in the epigenome

Nature Reviews Genetics volume 13, pages 7–13 (2012)Cite this article

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Abstract

Just over 2 years ago, TET1 was found to catalyse the oxidation of 5-methylcytosine, a well-known epigenetic mark, into 5-hydroxymethylcytosine in mammalian DNA. The exciting prospect of a novel epigenetic modification that may dynamically regulate DNA methylation has led to the rapid accumulation of publications from a wide array of fields, from biochemistry to stem cell biology. Although we have only started to scratch the surface, interesting clues on the role of 5-hydroxymethylcytosine are quickly emerging.

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Figure 1: Potential pathways for DNA demethylation.
Figure 2: Mechanisms of gene expression control by 5-hydroxymethylcytosine and TETs.

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Acknowledgements

We would like to thank all members of the Reik laboratory for stimulating discussions. Our work is supported by the Wellcome Trust, the Biotechnology and Biological Sciences Research Council (BBSRC), the Medical Research Council (MRC), the EU Network of Excellence (NoE) EpiGeneSys and EU SP BLUEPRINT.

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Authors and Affiliations

  1. Epigenetics Programme, The Babraham Institute, Cambridge, CB22 3AT, UK

    Miguel R. Branco, Gabriella Ficz & Wolf Reik

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  1. Miguel R. Branco
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Correspondence to Miguel R. Branco, Gabriella Ficz or Wolf Reik.

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Glossary

Blastocyst

A pre-implantation embryo that contains a fluid-filled cavity (the blastocoel), a focal cluster of cells from which the embryo develops (the inner cell mass (ICM)), an epithelial layer of cells on the surface of the ICM (the primitive endoderm) and peripheral trophectoderm cells, which form the extra-embryonic part of the placenta.

CCCTC binding factor

(CTCF). A zinc finger transcriptional repressor that recognizes and binds many sites in the genome and has insulator activity, as well as being important for higher-order chromatin organization.

Click chemistry

A general term for chemical reactions with very high chemical yields and a large thermodynamic driving force. Reactions of this type are wide in scope, are stereospecific, are simple to perform and create products that are stable at physiological conditions and by-products that are easily removable.

CpG islands

(CGIs). DNA sequences that have a considerably higher CG content than expected from the genome average. Most CGIs are depleted of DNA methylation and more than half of the CGIs in the genome are found in promoter regions of genes in mammals.

Embryoid bodies

Spherical structures formed by differentiating embryonic stem cells in culture, which resemble the early embryo.

Embryonic stem cells

(ESCs). Pluripotent cells that are established in culture from the inner cells mass of the blastocyst. These cells can self-renew indefinitely in culture and can differentiate into derivatives of all three embryonic cell lineages in vitro and in vivo.

Inner cell mass

(ICM). A cluster of undifferentiated cells in the blastocyst, which give rise to the entire fetus and to some of its extra-embryonic (placental) tissues.

Morula

A stage of pre-implantation development in which the embryo is a ball containing 8–32 cells inside the zona pellucida and precedes the formation of the blastocyst. The outer cells have a tendency to become the trophectoderm, and the inner cells have a tendency to become the inner cell mass, from which the epiblast and subsequently the fetal tissues form.

Primordial germ cells

(PGCs). These cells arise in the early embryo and give rise to the mature gametes (oocyte and sperm). They are set aside early in development and migrate to the gonads, where they eventually undergo meiosis and develop into mature gametes.

Pronucleus

Separate pronuclei form around the maternal and paternal genomes, respectively, shortly after fertilization in the mammalian embryo. Following DNA replication, the pronuclei dissolve and the zygote undergoes the first mitotic division.

Teratomas

Tumours that contain differentiated cells from all three germ layers (ectoderm, mesoderm and endoderm) and that arise from germ cells or pluripotent cells.

Trophectoderm

The outer layer of the blastocyst-stage embryo that gives rise to the trophoblast after implantation and will provide the bulk of the extra-embryonic lineages of the placenta.

Trophoblast

The cell lineage that first emerges as the outer trophectoderm layer of the blastocyst and after implantation becomes the predominant cell type in extra-embryonic tissues of the placenta.

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Branco, M., Ficz, G. & Reik, W. Uncovering the role of 5-hydroxymethylcytosine in the epigenome. Nat Rev Genet 13, 7–13 (2012). https://doi.org/10.1038/nrg3080

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