Modelling human zygotic genome activation in 8C-like cells in vitro
Modelling human zygotic genome activation in 8C-like cells in vitro
复制标题
体外模拟 8C 样细胞中的人类合子基因组激活
DOI：
10.1101/2021.10.28.466259
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Taubenschmid-Stowers J
中科院分区：
文献类型：
--
作者：
Taubenschmid-Stowers J
重塑受精卵的表观基因组和转录组以建立受精卵和发育中的胚胎的全能性是哺乳动物胚胎发生中最关键的过程之一。在小鼠2细胞胚胎和人类8细胞胚胎中，合子或胚胎基因组激活（ZGA， EGA）构成了转录的第一波主要浪潮。未能启动ZGA会导致发育缺陷，并导致人类植入前胚胎的高损耗率。由于细胞数量和实验可操作性的限制，调控人类胚胎基因组激活的机制在全能性胚胎中仍然知之甚少。在这里，我们报告了人类8细胞样细胞（8clc）的发现，特别是在naïve胚胎干细胞中，但不是引物多能细胞。8clc表达ZGA标记基因如zscan4、leutxandduxa，它们的转录组与8细胞人胚胎的转录组非常相似。8细胞样细胞重新激活8细胞阶段特异性转座元件，如hervlandmlt2a1，其特征是DNA甲基化调节因子dppa3上调。8clc显示SOX2蛋白减少，可以通过新的zga相关蛋白标记TPRX1和H3的表达来鉴定。阴体外。转录因子dux4过表达。剪接体抑制增加zga样转录，促进TPRX1+ 8clc的形成。令人兴奋的是，他们在体外鉴定出8CLC标记蛋白TPRX1和H3。Y在基因组激活时也在8细胞人类胚胎中表达，因此可能与体内相关。8clc的发现为在体外模拟和操纵人类zga样转录程序提供了一个独特的机会，并可能为人类胚胎发生的最早事件之一提供关键的功能见解。zga标记和转座因子在naïve人干细胞8clc中表达，转录因子dux4和剪接体抑制诱导zga样转录8clc标记蛋白TPRX1和H3。Y在8细胞人胚胎的细胞核中表达。8clc是人类ZGA的一种新的体外模型
The remodelling of the epigenome and transcriptome of the fertilised oocyte to establish totipotency in the zygote and developing embryo is one of the most critical processes in mammalian embryogenesis. Zygotic or embryonic genome activation (ZGA, EGA) in the 2-cell embryo in mouse, and the 8-cell embryo in humans, constitutes the first major wave of transcription. Failure to initiate ZGA leads to developmental defects, and contributes to the high attrition rates of human pre-implantation embryos. Due to limitations in cell numbers and experimental tractability, the mechanisms that regulate human embryonic genome activation in the totipotent embryo remain poorly understood. Here we report the discovery of human 8-cell like cells (8CLCs) specifically among naïve embryonic stem cells, but not primed pluripotent cells. 8CLCs express ZGA marker genes such asZSCAN4, LEUTXandDUXAand their transcriptome closely resembles that of the 8-cell human embryo. 8-cell like cells reactivate 8-cell stage specific transposable elements such asHERVLandMLT2A1and are characterized by upregulation of the DNA methylation regulatorDPPA3. 8CLCs show reduced SOX2 protein, and can be identified based on expression of the novel ZGA-associated protein markers TPRX1 and H3.Yin vitro. Overexpression of the transcription factorDUX4. as well as spliceosome inhibition increase ZGA-like transcription and enhance TPRX1+ 8CLCs formation. Excitingly, thein vitroidentified 8CLC marker proteins TPRX1 and H3.Y are also expressed in 8-cell human embryos at the time of genome activation and may thus be relevantin vivo. The discovery of 8CLCs provides a unique opportunity to model and manipulate human ZGA-like transcriptional programsin vitro, and might provide critical functional insights into one of the earliest events in human embryogenesisin vivo.HighlightsZGA markers and transposable elements are expressed in 8CLCs among naïve human stem cellsThe transcription factorDUX4and spliceosome inhibition induce ZGA-like transcription8CLC marker proteins TPRX1 and H3.Y are expressed in nuclei of 8-cell human embryos8CLCs serve as a novelin vitromodel for human ZGA
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影响因子：
8.8
作者：
Messmer, Tobias;von Meyenn, Ferdinand;Reik, Wolf
通讯作者：
Reik, Wolf
DOI：
10.1146/annurev-cellbio-100913-013027
发表时间：
2014
影响因子：
11.3
作者：
Lee MT;Bonneau AR;Giraldez AJ
通讯作者：
Giraldez AJ
Wnt 抑制促进 RNA 介导的人类体细胞重编程至原始多能性
DOI：
10.3929/ethz-b-000377412
发表时间：
2019
期刊：
--
影响因子：
--
作者：
Bredenkamp, Nicholas
通讯作者：
Bredenkamp, Nicholas
影响因子：
11.8
作者：
Peaston, AE;Evsikov, AV;Knowles, BB
通讯作者：
Knowles, BB
影响因子：
23.9
作者：
Huang K;Maruyama T;Fan G
通讯作者：
Fan G