Tet1 controls meiosis by regulating meiotic gene expression

• Published in: Nature (London) Vol. 492; no. 7429; pp. 443 - 447
• Main Authors: Yamaguchi, Shinpei, Hong, Kwonho, Liu, Rui, Shen, Li, Inoue, Azusa, Diep, Dinh, Zhang, Kun, Zhang, Yi
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 20.12.2012; Nature Publishing Group
• Subjects: 631/136/2434; 631/208/176/1988; 631/208/200; 631/80/641/1633; Alleles; Amino acids; Animal experimentation; Animals; Apoptosis; Cell Count; Chromosomes; Defects; Deoxyribonucleic acid; DNA; DNA Breaks, Double-Stranded; DNA methylation; DNA Methylation - genetics; DNA-Binding Proteins - deficiency; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Embryo, Mammalian - cytology; Embryo, Mammalian - pathology; Female; Females; Fertility; Gene expression; Gene Expression Regulation - genetics; Genetics; Germ cells; Humanities and Social Sciences; Infertility, Female - pathology; letter; Male; Mass spectrometry; Meiosis; Meiosis - genetics; Methylation; Mice; Mice, Knockout; multidisciplinary; Oocytes - cytology; Oocytes - metabolism; Oocytes - pathology; Physiological aspects; Proteins; Proto-Oncogene Proteins - deficiency; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Science; Studies; Transcriptome
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature11709

A loss-of-function approach in mice is used to show that the methylcytosine dioxygenase Tet1 has a role in regulating meiosis and meiotic gene activation in female germ cells; Tet1 deficiency does not greatly affect genome-wide demethylation but has a more specific effect on the expression of a subset of meiotic genes. Tet enzyme role in female germ cells DNA methylation on cytosine is an important epigenetic modification, and the mechanisms controlling 5-methylcytosine (5mC) dynamics constitute an active area of research. The Tet family of dioxygenases can catalyse oxidation of 5mC to produce derivatives such as 5-hydroxymethylcytosine (5hmC), but little is known about the biological function of Tet proteins. Here, a loss-of-function approach in mice is used to show that Tet1 has a role in meiosis and meiotic gene activation in female germ cells. Tet1 deficiency does not greatly impact genome-wide demethylation, but has a more specific effect on the expression of a subset of meiotic genes. Meiosis is a germ-cell-specific cell division process through which haploid gametes are produced for sexual reproduction 1 . Before the initiation of meiosis, mouse primordial germ cells undergo a series of epigenetic reprogramming steps 2 , 3 , including the global erasure of DNA methylation at the 5-position of cytosine (5mC) in CpG-rich DNA 4 , 5 . Although several epigenetic regulators, such as Dnmt3l and the histone methyltransferases G9a and Prdm9, have been reported to be crucial for meiosis 6 , little is known about how the expression of meiotic genes is regulated and how their expression contributes to normal meiosis. Using a loss-of-function approach in mice, here we show that the 5mC-specific dioxygenase Tet1 has an important role in regulating meiosis in mouse oocytes. Tet1 deficiency significantly reduces female germ-cell numbers and fertility. Univalent chromosomes and unresolved DNA double-strand breaks are also observed in Tet1-deficient oocytes. Tet1 deficiency does not greatly affect the genome-wide demethylation that takes place in primordial germ cells, but leads to defective DNA demethylation and decreased expression of a subset of meiotic genes. Our study thus establishes a function for Tet1 in meiosis and meiotic gene activation in female germ cells.