Cohesin's role in pluripotency and reprogramming
Cohesin's role in pluripotency and reprogramming
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DOI：
10.1080/15384101.2015.1128593
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发表时间：
2016-02-01
期刊：
影响因子：
4.3
通讯作者：
Merkenschlager, Matthias
中科院分区：
文献类型：
--
作者：
Gupta, Preksha;Lavagnolli, Thais;Merkenschlager, Matthias
粘附素是ES细胞自我更新和iPS介导的体细胞重编程所必需的。这可能表明粘附素在多能性基因的调控中发挥了特殊的作用，可能是通过调节基因调控元件之间的长距离染色体相互作用。然而，粘附素对基因组的完整性也是必不可少的，它从循环细胞中耗尽会引发DNA损伤反应。因此，粘附素耗竭细胞未能建立或维持多能性基因表达可能是由于失去了长距离的相互作用，或者是DNA损伤反应破坏了多能性基因的表达。在最近的工作中，我们开始通过分析在没有细胞分裂的情况下重新编程来解开这些可能性。这些实验表明，重新编程并不特别需要粘附素，而且当ES细胞急剧耗尽粘附素时，大多数多能基因的表达都保持不变。在这里，我们通过证明故意造成的DNA损伤--以及在没有凝集素的情况下增殖导致的DNA损伤--可以直接干扰多能性和重新编程，从而得出这一分析的合乎逻辑的结论。因此，粘附素在多能性和重编程中的作用可以通过细胞周期中的基本粘附素功能得到最好的解释。
Cohesin is required for ES cell self-renewal and iPS-mediated reprogramming of somatic cells. This may indicate a special role for cohesin in the regulation of pluripotency genes, perhaps by mediating long-range chromosomal interactions between gene regulatory elements. However, cohesin is also essential for genome integrity, and its depletion from cycling cells induces DNA damage responses. Hence, the failure of cohesin-depleted cells to establish or maintain pluripotency gene expression could be explained by a loss of long-range interactions or by DNA damage responses that undermine pluripotency gene expression. In recent work we began to disentangle these possibilities by analyzing reprogramming in the absence of cell division. These experiments showed that cohesin was not specifically required for reprogramming, and that the expression of most pluripotency genes was maintained when ES cells were acutely depleted of cohesin. Here we take this analysis to its logical conclusion by demonstrating that deliberately inflicted DNA damage - and the DNA damage that results from proliferation in the absence of cohesin - can directly interfere with pluripotency and reprogramming. The role of cohesin in pluripotency and reprogramming may therefore be best explained by essential cohesin functions in the cell cycle.