title: Impaired imprinted X chromosome inactivation is responsible for the skewed sex ratio following in vitro fertilization.
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.
authors.affiliation: National Engineering Laboratory for Animal Breeding, Key Laboratory of Animal Genetics, Breeding and Reproduction of the Ministry of Agriculture, College of Animal Science and Technology, China Agricultural University, Beijing 100193, People's Republic of China;
authors.forename: Kun
authors.initials: K
authors.lastname: Tan
authors.affiliation: National Engineering Laboratory for Animal Breeding, Key Laboratory of Animal Genetics, Breeding and Reproduction of the Ministry of Agriculture, College of Animal Science and Technology, China Agricultural University, Beijing 100193, People's Republic of China;
authors.forename: Lei
authors.initials: L
authors.lastname: An
authors.affiliation: National Engineering Laboratory for Animal Breeding, Key Laboratory of Animal Genetics, Breeding and Reproduction of the Ministry of Agriculture, College of Animal Science and Technology, China Agricultural University, Beijing 100193, People's Republic of China;
authors.forename: Kai
authors.initials: K
authors.lastname: Miao
authors.affiliation: National Engineering Laboratory for Animal Breeding, Key Laboratory of Animal Genetics, Breeding and Reproduction of the Ministry of Agriculture, College of Animal Science and Technology, China Agricultural University, Beijing 100193, People's Republic of China;
authors.forename: Likun
authors.initials: L
authors.lastname: Ren
authors.affiliation: National Engineering Laboratory for Animal Breeding, Key Laboratory of Animal Genetics, Breeding and Reproduction of the Ministry of Agriculture, College of Animal Science and Technology, China Agricultural University, Beijing 100193, People's Republic of China;
authors.forename: Zhuocheng
authors.initials: Z
authors.lastname: Hou
authors.affiliation: National Engineering Laboratory for Animal Breeding, Key Laboratory of Animal Genetics, Breeding and Reproduction of the Ministry of Agriculture, College of Animal Science and Technology, China Agricultural University, Beijing 100193, People's Republic of China;
authors.forename: Li
authors.initials: L
authors.lastname: Tao
authors.affiliation: National Engineering Laboratory for Animal Breeding, Key Laboratory of Animal Genetics, Breeding and Reproduction of the Ministry of Agriculture, College of Animal Science and Technology, China Agricultural University, Beijing 100193, People's Republic of China;
authors.forename: Zhenni
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: National Engineering Laboratory for Animal Breeding, Key Laboratory of Animal Genetics, Breeding and Reproduction of the Ministry of Agriculture, College of Animal Science and Technology, China Agricultural University, Beijing 100193, People's Republic of China;
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Wang
authors.affiliation: National Engineering Laboratory for Animal Breeding, Key Laboratory of Animal Genetics, Breeding and Reproduction of the Ministry of Agriculture, College of Animal Science and Technology, China Agricultural University, Beijing 100193, People's Republic of China;
authors.forename: Wei
authors.initials: W
authors.lastname: Xia
authors.affiliation: Laboratory Animal Centre, Peking University, Beijing 100871, People's Republic of China;
authors.forename: Jinghao
authors.initials: J
authors.lastname: Liu
authors.affiliation: National Engineering Laboratory for Animal Breeding, Key Laboratory of Animal Genetics, Breeding and Reproduction of the Ministry of Agriculture, College of Animal Science and Technology, China Agricultural University, Beijing 100193, People's Republic of China;
authors.forename: Zhuqing
authors.initials: Z
authors.lastname: Wang
authors.affiliation: National Engineering Laboratory for Animal Breeding, Key Laboratory of Animal Genetics, Breeding and Reproduction of the Ministry of Agriculture, College of Animal Science and Technology, China Agricultural University, Beijing 100193, People's Republic of China;
authors.forename: Guangyin
authors.initials: G
authors.lastname: Xi
authors.affiliation: National Engineering Laboratory for Animal Breeding, Key Laboratory of Animal Genetics, Breeding and Reproduction of the Ministry of Agriculture, College of Animal Science and Technology, China Agricultural University, Beijing 100193, People's Republic of China;
authors.forename: Shuai
authors.initials: S
authors.lastname: Gao
authors.affiliation: National Engineering Laboratory for Animal Breeding, Key Laboratory of Animal Genetics, Breeding and Reproduction of the Ministry of Agriculture, College of Animal Science and Technology, China Agricultural University, Beijing 100193, People's Republic of China;
authors.forename: Linlin
authors.initials: L
authors.lastname: Sui
authors.affiliation: Laboratory Animal Centre, Peking University, Beijing 100871, People's Republic of China;
authors.forename: De-Sheng
authors.initials: DS
authors.lastname: Zhu
authors.affiliation: National Engineering Laboratory for Animal Breeding, Key Laboratory of Animal Genetics, Breeding and Reproduction of the Ministry of Agriculture, College of Animal Science and Technology, China Agricultural University, Beijing 100193, People's Republic of China;
authors.forename: Shumin
authors.initials: S
authors.lastname: Wang
authors.affiliation: National Engineering Laboratory for Animal Breeding, Key Laboratory of Animal Genetics, Breeding and Reproduction of the Ministry of Agriculture, College of Animal Science and Technology, China Agricultural University, Beijing 100193, People's Republic of China;
authors.forename: Zhonghong
authors.initials: Z
authors.lastname: Wu
authors.affiliation: Department of Molecular, Cell and Cancer Biology and Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605;
authors.forename: Ingolf
authors.initials: I
authors.lastname: Bach
authors.affiliation: Department of Obstetrics and Gynecology, University of California, Irvine, CA 92697.
authors.forename: Dong-Bao
authors.initials: DB
authors.lastname: Chen
authors.affiliation: National Engineering Laboratory for Animal Breeding, Key Laboratory of Animal Genetics, Breeding and Reproduction of the Ministry of Agriculture, College of Animal Science and Technology, China Agricultural University, Beijing 100193, People's Republic of China; tianjh@cau.edu.cn.
authors.forename: Jianhui
authors.initials: J
authors.lastname: Tian
mesh_terms: D041321:Chromosomes, Human, X; D005260:Female; D005307:Fertilization in Vitro; D018392:Genomic Imprinting; D006801:Humans; D012744:Sex Ratio; D049951:X Chromosome Inactivation
keywords: Rnf12; X chromosome inactivation; Xist; in vitro fertilization; sex ratio