CSIR-Indian Institute of Chemical Biology, Kolkata, 700 032, West Bengal, India.
IUBMB Life. 2014 Feb;66(2):100-9. doi: 10.1002/iub.1249. Epub 2014 Feb 27.
It is becoming increasingly clear that the functionalities of an organism are mostly derived from regulation of its gene repertoire. Specialized cell types are created from pluripotent stem cells by regulating expression of genes. In eukaryotes, genes are primarily regulated by gene regulatory networks consisting of highly sequence-specific transcription factors and epigenetic modifications. The former mode of regulation is more readily reversible and non-heritable across cell generations, whereas the latter mode is less reversible and heritable. In this article, we explore the relationship between cell differentiation and the two modes of regulation of gene expression, focusing primarily on pluripotent and multipotent stem cells. Recent studies suggest that stem cells execute different gene expression programs, probably driven by one or more gene regulatory network(s). It is now also evident that as stem cells differentiate to more specialized progeny cells, rewriting of epigenetic marks occurs in parallel with the change in the pattern of gene expression. A conceptual framework is put forward in which it is proposed that the cell fate determining gene regulatory network in a pluripotent or multipotent cell has the capability to exist in multiple stationary states with each stationary state dictating a particular pattern of gene expression. We also propose that the broad pattern of gene expression in each stationary state, termed the lineage biased state or LIBS, resembles that of a more differentiated progeny cell. The differentiation process leading to a particular progeny cell involves rewriting of epigenetic marks that result in upregulation of genes in a LIBS and silencing of genes involved in alternative LIBS; thus selecting a particular pattern of gene expression and making a lineage commitment.
越来越明显的是，生物体的功能主要来自于其基因库的调节。特化细胞类型是通过调节基因的表达从多能干细胞中产生的。在真核生物中，基因主要通过由高度序列特异性转录因子和表观遗传修饰组成的基因调控网络进行调控。前者的调控模式更容易逆转，并且在细胞代际之间是非遗传性的，而后者的调控模式则不太容易逆转且具有遗传性。在本文中，我们探讨了细胞分化与基因表达的两种调控模式之间的关系，主要集中在多能和多能干细胞上。最近的研究表明，干细胞执行不同的基因表达程序，可能由一个或多个基因调控网络驱动。现在也很明显，随着干细胞分化为更特化的祖细胞，表观遗传标记的重写与基因表达模式的变化同时发生。提出了一个概念框架，其中提出多能或多能细胞中的细胞命运决定基因调控网络具有存在于多个静止状态的能力，每个静止状态决定特定的基因表达模式。我们还提出，每个静止状态中的广泛基因表达模式，称为谱系偏向状态或 LIBS，类似于更分化的祖细胞。导致特定祖细胞的分化过程涉及对 LIBS 中基因的表观遗传标记的重写，导致 LIBS 中的基因上调和参与替代 LIBS 的基因沉默；从而选择特定的基因表达模式并做出谱系承诺。
