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Tet1 controls meiosis by regulating meiotic gene expression


Meiosis is a germ-cell-specific cell division process through which haploid gametes are produced for sexual reproduction1. Before the initiation of meiosis, mouse primordial germ cells undergo a series of epigenetic reprogramming steps2,3, including the global erasure of DNA methylation at the 5-position of cytosine (5mC) in CpG-rich DNA4,5. Although several epigenetic regulators, such as Dnmt3l and the histone methyltransferases G9a and Prdm9, have been reported to be crucial for meiosis6, 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.

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Figure 1: The subfertility of Tet1 Gt/Gt mice is associated with oocyte loss in the late embryonic stage.
Figure 2: Meiotic defects in Tet1 Gt/Gt oocytes.
Figure 3: Tet1 activates meiotic genes through DNA demethylation.
Figure 4: WGBS analysis of the effect of Tet1 knockout on DNA methylation in PGCs.

Accession codes

Primary accessions

Gene Expression Omnibus

Data deposits

RNA-seq and WGBS data have been deposited in the Gene Expression Omnibus under accession numbers GSE41908 and GSE41912, respectively.


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We thank J. Wang and W. Jiang for FACS sorting, A. Adey and J. Shendure for sharing reagents and protocols for Tn5mC-seq, and H.-L. Fung for Illumina sequencing. This work was partially supported by U01DK089565 (National Institutes of Health) (to Y.Z.), R01GM097253 and CIRM BRB3-05083 (to K.Z.). Y.Z. is an Investigator of the Howard Hughes Medical Institute. D.D. is a CIRM-UCSD pre-doctoral fellow.

Author information

Authors and Affiliations



Y.Z. conceived the project; S.Y., K.H. and Y.Z. designed the experiments; S.Y., K.H., R.L., L.S. and A.I. performed the experiments; S.Y., K.H., R.L., D.D., K.Z. and Y.Z. analysed and interpreted the data; S.Y., K.H., R.L., K.Z. and Y.Z. wrote the manuscript.

Corresponding authors

Correspondence to Kun Zhang or Yi Zhang.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Figures 1-20 and Supplementary Tables 1, 2, 4 and 7 (see separate files for Supplementary Tables 3, 5 and 6). (PDF 13096 kb)

Supplementary Table 3

This file contains a list of differentially expressed genes (DEG) based on RNAseq. (XLSX 115 kb)

Supplementary Table 5

This table contains a List of differentially methylated regions (DMR) in female Tet1Gt/Gt PGC. (XLSX 296 kb)

Supplementary Table 6

This table contains a List of differentially expressed genes (DEG) associated with DMR. (XLSX 46 kb)

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Yamaguchi, S., Hong, K., Liu, R. et al. Tet1 controls meiosis by regulating meiotic gene expression. Nature 492, 443–447 (2012).

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