Impaired imprinted X chromosome inactivation is responsible for the skewed sex ratio following in vitro fertilization
Impaired imprinted X chromosome inactivation is responsible for the skewed sex ratio following in vitro fertilization
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印记 X 染色体失活受损是导致体外受精后性别比例失衡的原因
DOI：
10.1073/pnas.1523538113
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发表时间：
2016-03-22
影响因子：
11.1
通讯作者：
Tian, Jianhui
中科院分区：
文献类型：
--
作者：
Tan, Kun;An, Lei;Tian, Jianhui
性别比是生殖健康的重要指标，其倾斜反映了胚胎发育的紊乱。这项研究的重点是性别倾斜，这是最近在人类体外受精（IVF）婴儿中发现的。我们在此报道了小鼠体外受精后代的性别比例偏斜是由于通过抑制环指蛋白12 (Rnf12)/X非活性特异性转录物（Xist）途径导致印迹X染色体失活受损；通过过表达Rnf12或在胚胎培养基中添加视黄酸，可以纠正性别偏斜。因此，我们的研究不仅确定了导致试管婴儿后代性别倾斜的主要表观遗传错误，而且还暗示了通过靶向试管婴儿诱导的错误表观遗传修饰来预防性别倾斜和试管婴儿相关并发症的潜在策略。动态表观遗传重编程发生在正常胚胎发育的着床前阶段。在体外受精（IVF）过程中，由于环境扰动（如胚胎的操作和培养）引起的错误表观遗传修饰与各种短期或长期后果有关。其中，据报道，在牛和猪胚胎甚至人类试管婴儿新生儿中，性别比例失调是生殖危险的一个指标。然而，自从1991年报道了第一例性别失衡病例以来，其潜在机制仍不清楚。我们在此报道了小鼠体外受精后代的性别比例偏斜，这是雌性偏倚的植入期发育缺陷的结果，这种发育缺陷源于印迹X染色体失活（iXCI）通过减少无名指蛋白12 (Rnf12)/X失活特异性转录物（Xist）表达而受损。通过过表达Rnf12上调Xist来补偿iXCI受损，显著挽救了女性偏倚的发育缺陷，并纠正了IVF后代的性别比例。此外，在胚胎培养基中添加表观遗传调节剂维甲酸可上调Rnf12/Xist的表达，改善iXCI，并成功地将小鼠体外受精后代的性别比例扭转到近50%。因此，我们的数据表明，iXCI是植入前阶段女性胚胎发育能力的主要表观遗传障碍之一，针对错误的表观遗传修饰可能为预防ivf相关并发症提供了一种潜在的方法。
Significance Sex ratio is an important indicator of reproductive health, and its skewing reflects disturbed embryonic development. This study focused on sex skewing, which has recently identified in human in vitro fertilization (IVF) babies. We reported herein that the skewed sex ratio in mouse IVF offspring was due to the impaired imprinted X chromosome inactivation via suppressing the ring finger protein 12 (Rnf12)/X-inactive specific transcript (Xist) pathway; the sex skewing can be corrected by overexpressing Rnf12 or by supplementation of retinoic acid in embryo culture medium. Hence, our study not only identified a major epigenetic error responsible for sex skewing in IVF offspring, but also implicated a potential strategy for preventing sex skewing and IVF-associated complications by targeting erroneous epigenetic modifications induced by IVF. 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.