Profiling and quantification of pluripotency reprogramming reveal that WNT pathways and cell morphology have to be reprogramed extensively
Profiling and quantification of pluripotency reprogramming reveal that WNT pathways and cell morphology have to be reprogramed extensively
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DOI：
10.1016/j.heliyon.2020.e04035
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发表时间：
2020-05-01
期刊：
影响因子：
4
通讯作者：
Crossman, David
中科院分区：
文献类型：
--
作者：
Hu, Kejin;Ianov, Lara;Crossman, David
多能状态可以通过卵母细胞内的因子对体细胞核进行重新编程或通过少数转基因的异位表达来建立。被认为是广泛和密集的，然而，要重新编程的全部基因从未被定义，也没有定量地确定重新编程的程度。在这里，我们提出了一个新的重新编程的概念，它被定义为要重新编程到多潜能干细胞(PSCs)中的表达水平的全部基因。这一概念与RNA-SEQ相结合，使我们能够准确地描绘重编程组和子重编程组，并借助其他可用的工具，如GO分析，研究重编程过程。以人成纤维细胞重编程为PSC为例，我们已经定义了人成纤维细胞到PSC重编程的完整补充。此外，我们对重编程序组的分析表明，WNT途径和在细胞形态发生中起作用的基因应该被广泛和强烈地重新编程，以建立多能性。我们进一步开发了一个新的数学模型来量化整体的重编程，以及特定细胞功能的重编程，如WNT信号通路和调节细胞形态发生的基因。我们预计，我们的概念和数学模型可以应用于研究和量化其他重编程(来自其他体细胞的多能性重编程，以及谱系重编程)，以及任何两种类型的细胞之间的转录和表观遗传差异，包括癌细胞和它们的正常对应物。
Pluripotent state can be established via reprogramming of somatic nuclei by factors within an oocyte or by ectopic expression of a few transgenes. Considered as being extensive and intensive, the full complement of genes to be reprogrammed, however, has never been defined, nor has the degree of reprogramming been determined quantitatively. Here, we propose a new concept of reprogramome, which is defined as the full complement of genes to be reprogrammed to the expression levels found in pluripotent stem cells (PSCs). This concept in combination with RNA-seq enables us to precisely profile reprogramome and sub-reprogramomes, and study the reprogramming process with the help of other available tools such as GO analyses. With reprogramming of human fibroblasts into PSCs as an example, we have defined the full complement of the human fibroblast-to-PSC reprogramome. Furthermore, our analyses of the reprogramome revealed that WNT pathways and genes with roles in cellular morphogenesis should be extensively and intensely reprogrammed for the establishment of pluripotency. We further developed a new mathematical model to quantitate the overall reprogramming, as well as reprogramming in a specific cellular feature such as WNT signaling pathways and genes regulating cellular morphogenesis. We anticipate that our concept and mathematical model may be applied to study and quantitate other reprogramming (pluripotency reprogramming from other somatic cells, and lineage reprogramming), as well as transcriptional and epigenetic differences between any two types of cells including cancer cells and their normal counterparts.