Collaboration of chromatin remodeling and signaling pathways in pluripotency

摘要 当细胞命运由特定基因决定时，多细胞生物的功能特化就产生了 表达模式在从全能细胞发育的过程中，这是通过合成空间 以及导致表观遗传修饰以引发单能基因表达的信号线索。一旦建立， 这种基因表达模式是稳定的，除非被疾病或损伤破坏。值得注意的是， 一些蛋白质的表达可以导致已建立的细胞命运的重编程，以产生诱导的细胞凋亡。 多能干细胞（iPSC）有潜力发育成胚胎的任何细胞，就像 胚胎干细胞（ESCs）。iPSC是再生治疗的理想起点，因为它们克服了 使用ESC的伦理和实际问题。因此，重编程提供了理想的模型系统， 机械地定义小区身份保护。然而，研究重编程的一个关键障碍是 获得iPSC的效率（~3%）和差异动力学（2-3周），使得异源转录 在基于人群的研究中，变化被掩盖。我们创造了一个高效率的系统， 表观遗传和信号调节器。使用该系统，在本提案中，我们将确定 重新编程为iPSC的简约途径，并阐明细胞中的染色质转变， 重新编程

ABSTRACT Functional specialization in a multicellular organism arises when cell fate is established by a specific gene expression pattern. During development from a totipotent cell this is accomplished by the synthesis of spatial and signaling cues that result in epigenetic modifications to elicit unipotent gene expression. Once established, such gene expression patterns are stable unless disrupted by disease or injury. Remarkably the over expression of a few proteins can result in reprogramming of an established cell fate to generate induced pluripotent stem cells (iPSCs) that have the potential to develop into any of the cells of an embryo just like embryonic stem cells (ESCs). iPSCs are the ideal starting point for regenerative therapy since they overcome the ethical and practical concerns of using ESCs. Thus reprogramming provides an ideal model system to mechanistically define cell identity safeguards. However a critical barrier to studying reprogramming is the low efficiency (~3%) and differential kinetics (2-3 weeks) of obtaining iPSCs, so that heterogeneous transcriptional changes are masked in population based studies. We have generated a high efficiency system that combines epigenetic and signaling regulators. Using this system, in this proposal we will determine the most parsimonious route of reprogramming to iPSCs and elucidate the chromatin transitions in cells that become reprogrammed.