H3K4 Methylation-Dependent Memory of Somatic Cell Identity Inhibits Reprogramming and Development of Nuclear Transfer Embryos.
H3K4 Methylation-Dependent Memory of Somatic Cell Identity Inhibits Reprogramming and Development of Nuclear Transfer Embryos.
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DOI：
10.1016/j.stem.2017.03.003
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发表时间：
2017-07-06
期刊：
影响因子：
23.9
通讯作者：
Jullien J
中科院分区：
文献类型：
--
作者：
Hörmanseder E;Simeone A;Allen GE;Bradshaw CR;Figlmüller M;Gurdon J;Jullien J
脊椎动物的卵子可以诱导体细胞的核重编程，从而能够产生克隆动物。核重编程相对低效，并且所得胚胎的发育经常受到损害，部分原因是先前在供体核中活跃的基因的不适当表达。在这里，我们确定H3 K4甲基化作为一个主要的表观遗传障碍，限制转录重编程和有效的核转移（NT）。在NT胚胎的不适当的细胞类型中观察到供体细胞特异性基因的广泛表达，限制了它们的发育能力。这些基因在重编程胚胎中的表达源于供体细胞中先前活跃转录状态的表观遗传记忆，其特征在于高H3 K4甲基化。减少H3 K4甲基化对供体细胞中的基因表达几乎没有影响，但它大大改善了NT胚胎的转录重编程和发育。这些结果表明，H3 K4甲基化对有效的核重编程施加了障碍，并提出了改进重编程策略的方法。核移植胚胎保留了过去活跃转录状态的记忆（ON-记忆）ON-记忆基因在体细胞供体核中富集H3 K4甲基化H3 K4去甲基化改善转录重编程去除H3 K4甲基化增强核移植胚胎的发育Hörmanseder et al.发现供体细胞身份基因中转录活性的持久记忆对核转移后的细胞命运重编程构成障碍。他们表明，减少供体细胞中的H3 K4甲基化会降低转录记忆，并改善核移植胚胎的发育。
Vertebrate eggs can induce the nuclear reprogramming of somatic cells to enable production of cloned animals. Nuclear reprogramming is relatively inefficient, and the development of the resultant embryos is frequently compromised, in part due to the inappropriate expression of genes previously active in the donor nucleus. Here, we identify H3K4 methylation as a major epigenetic roadblock that limits transcriptional reprogramming and efficient nuclear transfer (NT). Widespread expression of donor-cell-specific genes was observed in inappropriate cell types in NT embryos, limiting their developmental capacity. The expression of these genes in reprogrammed embryos arises from epigenetic memories of a previously active transcriptional state in donor cells that is characterized by high H3K4 methylation. Reducing H3K4 methylation had little effect on gene expression in donor cells, but it substantially improved transcriptional reprogramming and development of NT embryos. These results show that H3K4 methylation imposes a barrier to efficient nuclear reprogramming and suggest approaches for improving reprogramming strategies. Nuclear transfer embryos retain the memory of a past state of active transcription (ON-memory) ON-memory genes are enriched for H3K4 methylation in somatic donor nuclei H3K4 demethylation improves transcriptional reprogramming Removing H3K4 methylation enhances the development of nuclear transfer embryos Hörmanseder et al. find that persistent memories of transcriptional activity in donor cell identity genes present a barrier to cell-fate reprogramming following nuclear transfer. They show that reducing H3K4 methylation in donor cells reduces transcriptional memory and improves the development of embryos derived by nuclear transfer.
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影响因子：
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作者：
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通讯作者：
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