全球表观遗传状态网络控制细胞多能重编程和转分化
Global Epigenetic State Network Governs Cellular Pluripotent Reprogramming and Transdifferentiation
摘要：
共享相同基因组的哺乳动物细胞如何以显著不同的表型存在，表现出形态、基因表达模式和表观遗传染色质状态的差异？此外，不同表型的细胞是如何从单个受精卵中分化出来的？这些基本问题与发育生物学中根深蒂固的范式密切相关，即细胞分化是不可逆的。然而，最近越来越多的研究表明细胞重编程的可能性，这为我们提供了将一种细胞转化为另一种细胞的可能性。尽管细胞重编程的定量理解的重要性，理论上的努力往往受到大电路的复杂性，维持细胞表型耦合在许多不同的表观遗传和基因调控水平。为了捕获细胞表型的全局结构，我们提出了一种“表观遗传状态网络”方法，该方法将表观遗传景观的经典概念转化为简单但可预测的数学模型。作为一个测试案例，我们将该方法应用于成纤维细胞（FB）到心肌细胞（CM）的重编程。这种情况下的表观遗传状态网络预测了三种主要的重编程途径。一种途径通过诱导多能干细胞（iPSC）并继续进入心肌细胞分化的正常途径。另外两条途径涉及通过心脏祖细胞（CP）间接或直接从成纤维细胞向心肌细胞的转分化（TD）。大量的实验观察支持预测的状态和途径。
英文摘要：
How do mammalian cells that share the same genome exist in notably distinct phenotypes, exhibiting differences in morphology, gene expression patterns, and epigenetic chromatin statuses? Furthermore how do cells of different phenotypes differentiate reproducibly from a single fertilized egg? These fundamental questions are closely related to a deeply rooted paradigm in developmental biology that cell differentiation is irreversible. Yet, recently a growing body of research suggests the possibility of cell reprogramming, which offers the potential for us to convert one type of cell into another. Despite the significance of quantitative understandings of cell reprogramming, theoretical efforts often suffer from the complexity of large circuits maintaining cell phenotypes coupled at many different epigenetic and gene regulation levels. To capture the global architecture of cell phenotypes, we propose an "epigenetic state network" approach that translates the classical concept of an epigenetic landscape into a simple-yet-predictive mathematical model. As a testing case, we apply the approach to the reprogramming of fibroblasts (FB) to cardiomyocytes (CM). The epigenetic state network for this case predicts three major pathways of reprogramming. One pathway goes by way of induced pluripotent stem cells (iPSC) and continues on to the normal pathway of cardiomyocyte differentiation. The other two pathways involve transdifferentiation (TD) either indirectly through cardiac progenitor (CP) cells or directly from fibroblast to cardiomyocyte. Numerous experimental observations support the predicted states and pathways.
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