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首页> 外文期刊>Cell cycle >Understanding impediments to cellular conversion to pluripotency by assessing the earliest events in ectopic transcription factor binding to the genome
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Understanding impediments to cellular conversion to pluripotency by assessing the earliest events in ectopic transcription factor binding to the genome

机译：通过评估异位转录因子与基因组结合的最早事件，了解细胞转化为多能性的障碍

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In all known cases of transcription factor (TF)-based reprogramming, the process is relatively slow and inefficient. For example, it takes about a month for the ectopic expression of the transcription factors Oct4, Sox2, Klf4 and c-Myc (OSKM) to fully reprogram human somatic cells to pluripotency. Furthermore, recent studies indicate that there is an initial stochastic phase, whereby random cells in the converting population begin to express a few genes of the new fate, followed by a so-called deterministic phase, whereby activation of a network for the new fate leads to homogeneous changes in gene expression patterns within a subset of the cell population. We recently mapped the initial interactions between OSKM factors and the human genome during the first 48 h of human fibroblast conversion to pluripotency. Unlike that reported in ES and iPS cells, distal enhancer sites in closed chromatin dominate the initial O, S, K and M binding distribution, showing that promoter occupancy is a later event in reprogramming. O, S and K act as pioneer factors for c-Myc, and c-Myc enhances the engagement of O, S and K. Despite the ability of OSKM to access closed chromatin, megabase-scale chromatin regions in somatic cells, referred to as "differentially bound regions" (DBRs), are remarkably refractory to OSKM binding at 48 h, though they become bound in pluripotent cells. These DBRs are highly enriched for the repressive H3K9me3 mark and span genes at the top of the deterministic hierarchy. Transient knockdown of the relevant chromatin modifiers allows access of OSKM to DBRs and a more rapid and efficient conversion to pluripotency. Thus, overcoming DBR barriers helps explain the conversion from a stochastic to a deterministic phase of transcription factor-mediated cell type conversion.
机译：在所有已知的基于转录因子（TF）的重编程情况下，该过程都相对缓慢且效率低下。例如，异位表达转录因子Oct4，Sox2，Klf4和c-Myc（OSKM）大约需要一个月，才能将人体细胞完全重编程为多能性。此外，最近的研究表明，存在一个初始的随机阶段，即转化种群中的随机细胞开始表达新命运的一些基因，随后是所谓的确定性阶段，从而激活新命运的网络导致在细胞群的一个子集内基因表达模式的均匀变化。我们最近在人类成纤维细胞转化为多能性的前48小时内绘制了OSKM因子与人类基因组之间的初始相互作用图。与在ES和iPS细胞中报道的不同，封闭染色质中的远端增强子位点占据了最初的O，S，K和M结合分布，这表明启动子占据是重编程中的后来事件。 O，S和K充当c-Myc的先驱因子，而c-Myc增强了O，S和K的参与。尽管OSKM具有访问封闭染色质的能力，但体细胞中的百万碱基级染色质区域称为尽管在多能细胞中结合，但“差异结合区”（DBR）在48 h时对OSKM的结合却非常困难。这些DBR高度富集抑制性H3K9me3标记，并跨越确定性层次结构顶部的基因。相关染色质修饰剂的瞬时敲低允许OSKM访问DBR，并更快，更有效地转换为多能性。因此，克服DBR障碍有助于解释转录因子介导的细胞类型转化从随机阶段到确定阶段的转变。

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