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An Alternative Culture Method to Maintain Genomic Hypomethylation of Mouse Embryonic Stem Cells Using MEK Inhibitor PD0325901 and Vitamin C
Published on: June 1, 2018
Vitamin C rescues embryonic developmental arrest caused by maternal Kdm2a deficiency via regulating PTEN/PI3K/AKT
Qinhui Yang1, Yumian Xie1, Ying Cen2
1Key Laboratory for Animal Science of National Ethnic Affairs Commission, Southwest Minzu University, Chengdu, 610041, PR China; Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Reservation and Utilization, Ministry of Education and Sichuan Province, Southwest Minzu University, Chengdu, 610041, PR China.
Abstract:
The development of preimplantation embryos entails highly intricate molecular processes involving epigenetic regulation, particularly histone modification and DNA methylation. These two fundamental epigenetic mechanisms dynamically interact to maintain epigenetic homeostasis during early development. KDM2A, a key regulatory enzyme in the Jumonji C (JMJC) domain-containing histone demethylase family, plays a transcriptional program through its catalytic activity in histone modification, associated with oocyte meiotic maturation and embryo development. However, the specific regulatory mechanisms and strategies for correcting maternal Kdm2a deficiency-induced reproductive issues remain unclear. This study revealed that Vitamin C (VC) improved the reproductive ability of Kdm2a cKO (conditional knockout) mice as the number of uterine implantations and litters was increased after VC injection and mated with wild-type male mice (P < 0.05). RT-qPCR and TUNEL assays showed that VC suppressed early embryonic apoptosis and enhanced the expression of embryonic stemness genes in the embryo of Kdm2a cKO mice (P < 0.05). Additionally, the embryo transfer rate also indicated that VC significantly increased the developmental potential of early embryos in Kdm2a cKO mice (P < 0.05). Immunofluorescence and RT-qPCR results demonstrated that VC inhibited H3K36me1/2 and promoted DNA demethylation in early embryos of Kdm2a cKO mice (P < 0.05). Furthermore, Smart-seq revealed that VC regulates early embryonic development in Kdm2a cKO mice primarily through the PTEN/PI3K/AKT signaling axis. Collectively, VC supplementation promotes early embryonic histone and DNA demethylation in Kdm2a cKO embryo, thereby ameliorating the reproductive decline caused by maternal Kdm2a deficiency. This finding provides a potential therapeutic target for treating reproductive issues caused by KDM2A abnormalities.
Insights
Vitamin C (VC) supplementation improved reproductive outcomes in mice with Kdm2a deficiency by enhancing embryo development and reducing apoptosis. VC promotes epigenetic reprogramming, offering a potential therapy for KDM2A-related reproductive issues.
Area of Science:
- Reproductive Biology
- Epigenetics
- Developmental Biology
Background:
- Preimplantation embryo development relies on precise epigenetic regulation, including histone modification and DNA methylation.
- KDM2A, a histone demethylase, is crucial for oocyte maturation and embryo development, but its deficiency causes reproductive problems.
- The mechanisms to correct KDM2A deficiency-induced reproductive issues are not well understood.
Purpose of the Study:
- To investigate the efficacy of Vitamin C (VC) in ameliorating reproductive decline caused by maternal Kdm2a deficiency.
- To elucidate the molecular mechanisms by which VC impacts early embryonic development in Kdm2a-deficient embryos.
Main Methods:
- Kdm2a conditional knockout (cKO) mice were treated with VC.
- Reproductive parameters, including implantation and litter size, were assessed.
- RT-qPCR, TUNEL assays, immunofluorescence, and Smart-seq were used to analyze gene expression, apoptosis, histone modifications, DNA methylation, and signaling pathways.
Main Results:
- VC treatment significantly improved reproductive ability in Kdm2a cKO mice, increasing implantation and litter numbers.
- VC suppressed embryonic apoptosis and enhanced stemness gene expression.
- VC promoted DNA demethylation and modulated histone modifications (H3K36me1/2) in Kdm2a cKO embryos.
- VC regulated early embryonic development via the PTEN/PI3K/AKT signaling pathway.
Conclusions:
- Vitamin C supplementation effectively rescues reproductive deficits associated with maternal Kdm2a deficiency.
- VC acts by promoting embryonic histone and DNA demethylation and modulating key developmental signaling pathways.
- VC represents a potential therapeutic strategy for reproductive disorders linked to KDM2A abnormalities.
