Author:
Tan Kun,An Lei,Miao Kai,Ren Likun,Hou Zhuocheng,Tao Li,Zhang Zhenni,Wang Xiaodong,Xia Wei,Liu Jinghao,Wang Zhuqing,Xi Guangyin,Gao Shuai,Sui Linlin,Zhu De-Sheng,Wang Shumin,Wu Zhonghong,Bach Ingolf,Chen Dong-bao,Tian Jianhui
Abstract
Dynamic epigenetic reprogramming occurs during normal embryonic development at the preimplantation stage. Erroneous epigenetic modifications due to environmental perturbations such as manipulation and culture of embryos during in vitro fertilization (IVF) are linked to various short- or long-term consequences. Among these, the skewed sex ratio, an indicator of reproductive hazards, was reported in bovine and porcine embryos and even human IVF newborns. However, since the first case of sex skewing reported in 1991, the underlying mechanisms remain unclear. We reported herein that sex ratio is skewed in mouse IVF offspring, and this was a result of female-biased peri-implantation developmental defects that were originated from impaired imprinted X chromosome inactivation (iXCI) through reduced ring finger protein 12 (Rnf12)/X-inactive specific transcript (Xist) expression. Compensation of impaired iXCI by overexpression of Rnf12 to up-regulate Xist significantly rescued female-biased developmental defects and corrected sex ratio in IVF offspring. Moreover, supplementation of an epigenetic modulator retinoic acid in embryo culture medium up-regulated Rnf12/Xist expression, improved iXCI, and successfully redeemed the skewed sex ratio to nearly 50% in mouse IVF offspring. Thus, our data show that iXCI is one of the major epigenetic barriers for the developmental competence of female embryos during preimplantation stage, and targeting erroneous epigenetic modifications may provide a potential approach for preventing IVF-associated complications.
Funder
the National Natural Science Foundation of China
the National High-Tech R&D Program
Publisher
Proceedings of the National Academy of Sciences
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