Tet proteins regulate gene expression by removing methyl groups from DNA bases. This activity may be a facilitating step in turning on the cell-division pathway that produces sperm and egg cells. See Letter p.443
Meiosis is a type of cell division that is a key feature of sexual reproduction. Meiotic division of germ cells produces sperm and egg cells, which have only one copy of each chromosome and which fuse during fertilization to create a new organism with two copies of the genetic material. This highly orchestrated process requires the activation of a specific set of meiotic genes, but how these genes are activated at the right time and in the right place is poorly understood. On page 443 of this issue, Yamaguchi et al.1 report that Tet1, a member of the recently discovered Tet protein family, is required for the activation of meiotic genes in mouse egg cells. This is exciting because Tet proteins are involved in erasing DNA epigenetic marks, suggesting that this is a crucial mechanism in meiosis.
Epigenetic modifications are chemical or structural changes to DNA or DNA-bound proteins that modulate gene expression without changing the DNA sequence. One common epigenetic mark is the addition of a methyl group to cytosine, one of the four main DNA bases, thereby creating 5-methylcytosine. In mammals, this methylation modifies the accessibility of the DNA molecule and mediates long-lasting silencing of gene expression and of parasitic mobile elements (regions of DNA that can move within the genome)2. DNA methylation is essential for the survival of the embryo, and its occurrence is dynamically regulated during development3.
Members of the Tet (ten–eleven translocation) protein family have been implicated in removing this methylation mark from DNA — the proteins can oxidize 5-methylcytosine to form 5-hydroxymethylcytosine, 5-formylcytosine and 5-carboxylcytosine, which are potential intermediates of demethylation4,5,6. This discovery was groundbreaking, because the mechanisms of DNA demethylation in mammals were a mystery for decades, and it prompted intensive research on the three mammalian Tet proteins (Tet1–3). We now know that Tet3 is expressed in oocytes (egg cells) and is required for the reprogramming of epigenetic marks that occurs during the first cell divisions of the embryo7, and that Tet2 has a key role in blood-cell maintenance and is frequently mutated in human leukaemia8. But the biological function of Tet1 has been less clear, because no major developmental defects have been found in Tet1-deficient mice9.
Yamaguchi et al. studied the physiological function of Tet1 by generating genetically modified mice that do not produce a functional full-length Tet1 protein. They show that the absence of Tet1 leads to decreased fertility and fewer pups in the litters than in normal mice. This finding is consistent with the high expression of Tet1 seen in the precursor cells of eggs and sperm, and was also observed recently in another model of Tet1-deficient mice9.
Focusing on females, the authors report that Tet1 deficiency leads to a decrease in the size of the ovaries, an increased incidence of cell death in the ovaries and a reduced number of fully developed oocytes. They also show that the oocytes display meiotic defects, such as a failure to align and segregate chromosome pairs efficiently, together with defective genetic recombination (the 'shuffling' of DNA sequences that occurs during meiotic cell division). This failure to complete meiosis probably explains why a high proportion of developing oocytes in the Tet1-deficient mice are eliminated by apoptotic cell death.
To further study how Tet1 promotes meiosis, the authors examined gene-expression profiles of oocyte-precursor cells from wild-type and Tet1-deficient female mice. Strikingly, they observed that the mutant cells express reduced levels of several meiotic genes, such as those encoding components of the synaptonemal complex, which promotes chromosome alignment and recombination.
The obvious next question was, what is the role of Tet1 in activating these meiotic genes? Germ-cell precursors are known to undergo a genome-wide erasure of DNA methylation during their specification for becoming germ cells3. This affects all types of sequences, including the promoter regions of many meiotic genes that are repressed by DNA methylation in somatic (non-germ) cells and that need to be demethylated in germ cells10,11. (Promoter regions are the DNA sequences at which transcription of a gene is initiated.) Given the potential role of Tet proteins in DNA demethylation, it was tempting to speculate that Tet1 is involved in the demethylation of meiotic genes. To address this, the authors measured DNA methylation in the promoters of three meiotic genes and observed various degrees of residual DNA methylation in Tet1-deficient female germ cells, which could explain the genes' reduced expression.
The authors then investigated whether Tet1 is required for the broader erasure of DNA methylation in germ-cell precursors. They generated genome-scale maps of DNA methylation and, surprisingly, observed that the absence of Tet1 only marginally impairs genome-wide demethylation. This suggests that Tet1 is required only for demethylation of specific sequences, such as meiotic genes. Unfortunately, the authors' methylation data were at low coverage (meaning that each genomic position was measured only a small number of times), and this prevented detailed analysis of which sequences require Tet1 for demethylation in germ cells. Other aspects that need to be investigated include whether the role of Tet1 in meiotic-gene activation depends solely on its effect on 5-methylcytosine, and whether Tet1 has similar functions in males.
Since the discovery of Tet proteins, their role in epigenetic reprogramming in germ cells has been a matter of speculation. Yamaguchi and colleagues' study provides the first genetic clues about the specifics of this activity, by showing that Tet1 is not essential for general demethylation in germ cells but is required only at certain sequences. The finding raises many questions. Do other Tet proteins compensate for the absence of Tet1? What sequences are demethylated by Tet1, and how is the protein recruited to these DNA sites? What other mechanisms promote DNA demethylation in germ cells, and how do these processes interact? Could Tet1 be involved in human infertility? We are only beginning to understand the physiological and molecular roles of Tet proteins, and this work adds a new chapter to an exciting story.
Yamaguchi, S. et al. Nature 492, 443–447 (2012).
Feng, S., Jacobsen, S. E. & Reik, W. Science 330, 622–627 (2010).
Saitou, M., Kagiwada, S. & Kurimoto, K. Development 139, 15–31 (2012).
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