Histone variant macroH2A confers resistance to nuclear reprogramming.
Histone variant macroH2A confers resistance to nuclear reprogramming.
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DOI：
10.1038/emboj.2011.144
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发表时间：
2011-05-06
期刊：
影响因子：
11.4
通讯作者：
Gurdon, John B.
中科院分区：
文献类型：
--
作者：
Pasque, Vincent;Gillich, Astrid;Garrett, Nigel;Gurdon, John B.
不同层次的表观遗传抑制如何限制体细胞核重编程还知之甚少。哺乳动物体细胞核转移到非洲爪蟾卵母细胞诱导转录重编程以前抑制的基因。在这里，我们通过评估失活X染色体（Xi）在不同失活阶段的稳定性来解决核转移后限制重编程的机制。我们发现小鼠植入后衍生的外胚层干细胞（EpiSC）的Xi可以通过核移植逆转，而分化或胚外细胞的Xi通过核移植到卵母细胞是不可逆的。核转移后，Xist RNA从Xi的染色质中丢失。大多数表观遗传标记，如DNA甲基化和Polycomb沉积的H3K27me3不能解释可逆和不可逆Xi之间的差异。对重编程的抗性与组蛋白变体macroH2A的掺入有关，macroH2A保留在分化细胞的Xi上，但不存在于EpiSC的Xi中。我们的研究结果揭示了EpiSC中Xi的稳定性降低，并强调了涉及macroH2A的组合表观遗传抑制在限制卵母细胞转录重编程中的重要性。
How various layers of epigenetic repression restrict somatic cell nuclear reprogramming is poorly understood. The transfer of mammalian somatic cell nuclei into Xenopus oocytes induces transcriptional reprogramming of previously repressed genes. Here, we address the mechanisms that restrict reprogramming following nuclear transfer by assessing the stability of the inactive X chromosome (Xi) in different stages of inactivation. We find that the Xi of mouse post-implantation-derived epiblast stem cells (EpiSCs) can be reversed by nuclear transfer, while the Xi of differentiated or extraembryonic cells is irreversible by nuclear transfer to oocytes. After nuclear transfer, Xist RNA is lost from chromatin of the Xi. Most epigenetic marks such as DNA methylation and Polycomb-deposited H3K27me3 do not explain the differences between reversible and irreversible Xi. Resistance to reprogramming is associated with incorporation of the histone variant macroH2A, which is retained on the Xi of differentiated cells, but absent from the Xi of EpiSCs. Our results uncover the decreased stability of the Xi in EpiSCs, and highlight the importance of combinatorial epigenetic repression involving macroH2A in restricting transcriptional reprogramming by oocytes.
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