Aberrant H3K4me3 modification of epiblast genes of extraembryonic tissue causes placental defects and implantation failure in mouse IVF embryos
Aberrant H3K4me3 modification of epiblast genes of extraembryonic tissue causes placental defects and implantation failure in mouse IVF embryos
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胚胎外组织外胚层基因的异常 H3K4me3 修饰导致小鼠 IVF 胚胎胎盘缺陷和植入失败
DOI：
10.1016/j.celrep.2022.110784
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发表时间：
2022-05-06
期刊：
影响因子：
8.8
通讯作者：
Chen, Miaoxin
中科院分区：
文献类型：
--
作者：
Bai, Dandan;Sun, Jin;Chen, Miaoxin
辅助生殖技术已广泛应用于人类不孕不育的治疗。然而，越来越多的证据表明，体外受精（IVF）与低妊娠率，胎盘缺陷和后代代谢性疾病有关。在这里，我们发现，IVF操作显着破坏胚外组织特异性基因的表达，和334外胚层（Epi）特异性基因和24 Epi特异性转录因子异常表达在胚胎7.5天的IVF胚胎的胚外外胚层（ExE）。组合的组蛋白修饰分析揭示，在Epi活性启动子处的异常H3K4me3修饰导致这些基因在ExE中的表达增加。重要的是，我们证明了在IVF胚胎中高度表达的H3K4me3募集调节因子Kmt2e的敲低，极大地改善了IVF胚胎的发育，并降低了ExE中的异常基因表达。因此，我们的研究确定，在胚胎外组织中的异常H3K4me3修饰是IVF胚胎着床失败和胎盘发育异常的主要原因。
Assisted reproductive technology has been widely applied in the treatment of human infertility. However, accumulating evidence indicates that in vitro fertilization (IVF) is associated with a low pregnancy rate, placental defects, and metabolic diseases in offspring. Here, we find that IVF manipulation notably disrupts extraembryonic tissue-specific gene expression, and 334 epiblast (Epi)-specific genes and 24 Epi-specific transcription factors are abnormally expressed in extraembryonic ectoderm (ExE) of IVF embryos at embryonic day 7.5. Combined histone modification analysis reveals that aberrant H3K4me3 modification at the Epi active promoters results in increased expression of these genes in ExE. Importantly, we demonstrate that knockdown of the H3K4me3-recruited regulator Kmt2e, which is highly expressed in IVF embryos, greatly improves the development of IVF embryos and reduces abnormal gene expression in ExE. Our study therefore identifies that abnormal H3K4me3 modification in extraembryonic tissue is a major cause of implantation failure and abnormal placental development of IVF embryos.