Epigenetic reversion of post-implantation epiblast to pluripotent embryonic stem cells.
Epigenetic reversion of post-implantation epiblast to pluripotent embryonic stem cells.
复制标题
作者：
最初在囊胚的原始外胚层细胞（PE）中建立的多能性状态在随后的发育过程中逐渐且不可逆地丧失。例如，PE的植入后上胚层的发育涉及显著的转录和表观遗传变化，包括DNA甲基化和X失活，这产生了强大的表观遗传屏障，并防止它们恢复到PE样状态。上胚层细胞对白血病抑制因子（LIF）-STAT 3信号传导不敏感，但它们对激活素/bFGF应答以形成自我更新的上胚层干细胞（EpiSC），其表现出上胚层细胞的基本特性，不同于源自PE的胚胎干细胞（ESC）。在这里，我们展示了来自E5.5 - E7.5胚胎的晚期上胚层细胞的重编程，这些细胞具有均匀的N-钙粘蛋白表达和失活的X染色体，以响应于LIF-STAT 3信号传导而成为ES样细胞（rESC）。培养的上胚层细胞（cEpi）克服了表观遗传障碍，逐步进行擦除的关键属性的上胚层细胞，涉及DNA去甲基化，X重新激活和表达的E-钙粘蛋白。转录组的伴随变化导致上胚层细胞表型和表观遗传记忆的丧失。值得注意的是，使用这种新方法，我们报告了已建立的EpiSC向rESC的逆转。此外，与上胚层和EpiSC不同，rESC有助于嵌合体中的体细胞组织和生殖细胞。这是一个研究信号分子诱导的表观遗传重编程的易处理模型，可以促进基本多能状态的重新获得。
The pluripotent state, which is first established in the primitive ectoderm cells (PE) of blastocysts, is lost progressively and irreversibly during subsequent development. For example, development of postimplantation epiblast from PE involves significant transcriptional and epigenetic changes, including DNA methylation and X inactivation, which creates a robust epigenetic barrier and prevents their reversion to a PE-like state. Epiblast cells are refractory to leukaemia inhibitory factor (LIF)-STAT3 signaling, but they respond to Activin/bFGF to form self-renewing epiblast stem cells (EpiSC), which exhibit essential properties of epiblast cells, that differ from embryonic stem cells (ESC) derived from PE. Here we show reprogramming of advanced epiblast cells from E5.5 - E7.5 embryos with uniform expression of N-cadherin and inactive X chromosome, to ES-like cells (rESC) in response to LIF-STAT3 signaling. Cultured epiblast cells (cEpi) overcome the epigenetic barrier progressively as they proceed with the erasure of key properties of epiblast cells, involving DNA demethylation, X reactivation and expression of E-cadherin. The accompanying changes in the transcriptome result in a loss of phenotypic and epigenetic memory of epiblast cells. Notably, using this new approach, we report reversion of established EpiSC to rESC. Furthermore, unlike epiblast and EpiSC, rESC contribute to somatic tissues and germ cells in chimeras. This is a tractable model to investigate signaling molecule induced epigenetic reprogramming that can promote reacquisition of the fundamental pluripotent state.
登录
查看更多内容
影响因子：
64.8
作者：
Brons, I. Gabrielle M.;Smithers, Lucy E.;Vallier, Ludovic
通讯作者：
Vallier, Ludovic
影响因子：
23.9
作者：
Hayashi K;de Sousa Lopes SMC;Tang F;Lao K;Surani MA
通讯作者：
Surani MA
影响因子：
11.8
作者：
Silva, J;Mak, W;Brockdorff, N
通讯作者：
Brockdorff, N
影响因子：
4.6
作者：
Guo, Ge;Yang, Jian;Smith, Austin
通讯作者：
Smith, Austin
影响因子：
9.8
作者：
Silva, Jose;Barrandon, Ornella;Nichols, Jennifer;Kawaguchi, Jitsutaro;Theunissen, Thorold W.;Smith, Austin
通讯作者：
Smith, Austin