Collaboration of chromatin remodeling and signaling pathways in pluripotency

摘要 当细胞命运由特定的基因决定时，多细胞生物体的功能特化就出现了。 表达模式。在全能细胞的发育过程中，这是通过空间合成来完成的 以及导致表观遗传修饰以诱导单能性基因表达的信号线索。一旦建立起来， 这样的基因表达模式是稳定的，除非受到疾病或伤害的干扰。值得注意的是，过去 少数蛋白质的表达可以导致对既定细胞命运的重新编程，以产生诱导的 多能干细胞(IPSCs)有可能发育成胚胎的任何细胞，就像 胚胎干细胞(ESCs)。IPSCs是再生治疗的理想起点，因为它们克服了 使用ESCs的伦理和实践问题。因此，重新编程提供了一个理想的模型系统 机械地定义小区身份保护措施。然而，研究重新编程的一个关键障碍是低 获得IPSCs的效率(~3%)和差异动力学(2-3周)，因此异质转录 在基于人口的研究中，变化被掩盖了。我们已经产生了一个高效的系统，它结合了 表观遗传和信号调节。使用这个系统，在这个提案中，我们将确定最多 对IPSCs重新编程的简约途径，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.