论文标题
通过随机电路扰动来解码干细胞分化过程中细胞命令决策的基础机制
Decoding the mechanisms underlying cell-fate decision-making during stem cell differentiation by Random Circuit Perturbation
论文作者
论文摘要
干细胞可以精确,坚固地经历细胞分化和谱系承诺,称为茎。但是,尚不清楚如何可靠地指定细胞命运的基因网络如何可靠地指定细胞的命运。为了解决这个问题,我们将最近开发的计算方法(随机电路扰动(Racipe))应用于九组分基因调节网络(GRN)的控制茎,我们从中确定了15个健壮的基因状态。其中,在五个最可能的基因中,有四个在32细胞和64细胞阶段显示在单小鼠胚胎细胞中观察到的基因表达模式。这些基因态可以通过茎grn进行稳健预测,而不能通过茎grn的随机版本进行预测。令人惊讶的是,我们发现了GRN的分层结构,其OCT4/CDX2基序是第一个决策模块,其次是GATA6/Nanog。我们认为,干细胞群体,而不是被视为具有特定细胞状态的所有人,而是被视为一种异质混合物,包括各种状态的细胞。在受外部信号扰动时,干细胞失去了进入某些细胞状态的能力,从而变得区分了。研究结果表明,Stemness GRN的功能主要取决于其良好发展的网络拓扑,而不是由详细的动力学参数决定。
Stem cells can precisely and robustly undergo cellular differentiation and lineage commitment, referred to as stemness. However, how the gene network underlying stemness regulation reliably specifies cell fates is not well understood. To address this question, we applied a recently developed computational method, Random Circuit Perturbation (RACIPE), to a nine-component gene regulatory network (GRN) governing stemness, from which we identified fifteen robust gene states. Among them, four out of the five most probable gene states exhibit gene expression patterns observed in single mouse embryonic cells at 32-cell and 64-cell stages. These gene states can be robustly predicted by the stemness GRN but not by randomized versions of the stemness GRN. Strikingly, we found a hierarchical structure of the GRN with the Oct4/Cdx2 motif functioning as the first decision-making module followed by Gata6/Nanog. We propose that stem cell populations, instead of being viewed as all having a specific cellular state, can be regarded as a heterogeneous mixture including cells in various states. Upon perturbations by external signals, stem cells lose the capacity to access certain cellular states, thereby becoming differentiated. The findings demonstrate that the functions of the stemness GRN is mainly determined by its well-evolved network topology rather than by detailed kinetic parameters.