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Early Expression of Tet1 and Tet2 in Mouse Zygotes Altered DNA Methylation Status and Affected Embryonic Development
Qi Qi1, Qianqian Wang1, Kailing Liu1
1State Key Laboratory of Agrobiotechnology and College of Biological Science, China Agricultural University, Beijing 100193, China.
Abstract:
Ten-eleven translocation (Tet) dioxygenases can induce DNA demethylation by catalyzing 5-methylcytosine(5mC) to 5-hydroxymethylcytosine(5hmC), and play important roles during mammalian development. In mouse, Tet1 and Tet2 are not expressed in pronucleus-staged embryos and are not involved in the genomic demethylation of early zygotes. Here, we investigated the influence of Tet1 and Tet2 on methylation of parental genomes by ectopically expressing Tet1 and Tet2 in zygotes. Immunofluorescence staining showed a marked 5hmC increase in the maternal pronucleus after injection of Tet1 or Tet2 mRNA into zygotes. Whole-genome bisulfite sequencing further revealed that Tet2 greatly enhanced the global demethylation of both parental genomes, while Tet1 only promoted the paternal demethylation. Tet1 and Tet2 overexpression altered the DNA methylation across genomes, including various genic elements and germline-specific differently methylated regions. Tet2 exhibited overall stronger demethylation activity than Tet1. Either Tet1 or Tet2 overexpression impaired preimplantation embryonic development. These results demonstrated that early expression of Tet1 and Tet2 could substantially alter the zygotic methylation landscape and damage embryonic development. These findings provide new insights into understanding the function of Tet dioxygenases and the mechanism of DNA methylation in relation to embryogenesis.
Insights
Early expression of Ten-eleven translocation (Tet) dioxygenases 1 and 2 in mouse zygotes significantly altered DNA methylation patterns. This ectopic expression impaired embryonic development, highlighting Tet enzymes
Area of Science:
- Epigenetics and Developmental Biology
- Mammalian Embryogenesis
- DNA Methylation Dynamics
Background:
- Ten-eleven translocation (Tet) dioxygenases catalyze the conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), playing crucial roles in DNA demethylation and mammalian development.
- Tet1 and Tet2 are typically not expressed in early mouse zygotes, suggesting they are not involved in the initial genomic demethylation processes of zygotes.
Purpose of the Study:
- To investigate the influence of ectopically expressed Tet1 and Tet2 on the methylation status of parental genomes in mouse zygotes.
- To understand the impact of early Tet dioxygenase activity on zygotic DNA methylation and subsequent preimplantation embryonic development.
Main Methods:
- Ectopic expression of Tet1 and Tet2 mRNA in mouse zygotes.
- Immunofluorescence staining to detect 5hmC levels.
- Whole-genome bisulfite sequencing (WGBS) to analyze global and regional DNA methylation changes.
Main Results:
- Ectopic Tet1 or Tet2 expression led to a significant increase in 5hmC in the maternal pronucleus.
- Tet2 overexpression strongly promoted global demethylation of both parental genomes, while Tet1 primarily demethylated the paternal genome.
- Both Tet1 and Tet2 overexpression altered DNA methylation across genic elements and germline-specific differentially methylated regions, with Tet2 showing greater demethylation activity.
- Impairment of preimplantation embryonic development was observed in zygotes overexpressing either Tet1 or Tet2.
Conclusions:
- Early, ectopic expression of Tet1 and Tet2 profoundly reshapes the zygotic methylation landscape.
- The altered methylation patterns induced by early Tet dioxygenase activity negatively impact embryonic development.
- These findings provide novel insights into the functional roles of Tet dioxygenases and DNA methylation mechanisms during early embryogenesis.
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