Loss of H3K27me3 imprinting in the Sfmbt2 miRNA cluster causes enlargement of cloned mouse placentas
Loss of H3K27me3 imprinting in the Sfmbt2 miRNA cluster causes enlargement of cloned mouse placentas
复制标题
DOI：
10.1038/s41467-020-16044-8
复制
发表时间：
2020-05-01
影响因子：
16.6
通讯作者：
Ogura, Atsuo
中科院分区：
文献类型：
--
作者：
Inoue, Kimiko;Ogonuki, Narumi;Ogura, Atsuo
哺乳动物的体细胞核移植（SCNT）是一个低效的过程，通常与异常表型相关，尤其是在胎盘中。最近的研究表明，小鼠SCNT胎盘完全缺乏组蛋白甲基化（H3K27me3）依赖性印记，但其如何影响胎盘发育仍不清楚。在这里，我们提供的证据表明，H3K27me3 印记的缺失通过印记 miRNA 的上调而导致 SCNT 后异常胎盘增大和低出生率。当我们通过母体敲除恢复 SCNT 胎盘中 H3K27me3 依赖性印记基因（Sfmbt2、Gab1 和 Slc38a4）的正常父系表达时，胎盘仍然增大。有趣的是，纠正 Sfmbt2 基因内簇状 miRNA 的表达可以改善胎盘表型。重要的是，它们的靶基因被证实能引起类似 SCNT 的胎盘组织学，恢复了表达水平。出生率增加了大约两倍。因此，我们将 H3K27me3 印记的丢失确定为一种表观遗传错误，会损害 SCNT 后的胚胎发育。体细胞核移植（SCNT）经常导致克隆小鼠胎盘发育异常。在这里，作者表明，聚集的 Sfmbt2 miRNA 中组蛋白甲基化 (H3K27me3) 印记的丢失会导致 SCNT 胎盘缺陷。
Somatic cell nuclear transfer (SCNT) in mammals is an inefficient process that is frequently associated with abnormal phenotypes, especially in placentas. Recent studies demonstrated that mouse SCNT placentas completely lack histone methylation (H3K27me3)-dependent imprinting, but how it affects placental development remains unclear. Here, we provide evidence that the loss of H3K27me3 imprinting is responsible for abnormal placental enlargement and low birth rates following SCNT, through upregulation of imprinted miRNAs. When we restore the normal paternal expression of H3K27me3-dependent imprinted genes (Sfmbt2, Gab1, and Slc38a4) in SCNT placentas by maternal knockout, the placentas remain enlarged. Intriguingly, correcting the expression of clustered miRNAs within the Sfmbt2 gene ameliorates the placental phenotype. Importantly, their target genes, which are confirmed to cause SCNT-like placental histology, recover their expression level. The birth rates increase about twofold. Thus, we identify loss of H3K27me3 imprinting as an epigenetic error that compromises embryo development following SCNT. Somatic cell nuclear transfer (SCNT) frequently results in abnormal placenta development in cloned mice. Here the authors show that loss of histone methylation (H3K27me3) imprinting in clustered Sfmbt2 miRNAs contributes to SCNT placenta defect.