ADP-ribosyltransferases Parp1 and Parp7 safeguard pluripotency of ES cells.
ADP-ribosyltransferases Parp1 and Parp7 safeguard pluripotency of ES cells.
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DOI：
10.1093/nar/gku591
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发表时间：
2014-08
影响因子：
14.9
通讯作者：
Hemberger M
中科院分区：
文献类型：
--
作者：
Roper SJ;Chrysanthou S;Senner CE;Sienerth A;Gnan S;Murray A;Masutani M;Latos P;Hemberger M
胚胎干细胞处于不同功能状态的动态平衡状态，其特征是关键多能因子的异质表达，并受到一系列可逆组蛋白修饰的调节。维持这种平衡是多能性的标志。在这里，我们发现adp -核糖基转移酶Parp1和Parp7通过占据关键的多能性基因，特别是Nanog， Pou5f1, Sox2, Stella， Tet1和Zfp42，在保护这种状态中发挥关键作用，从而保护它们免受渐进的表观遗传抑制。在缺乏Parp1或Parp7或抑制adp核糖基化活性的情况下，ES细胞表现出基态多能性的降低，因为它们不能维持亚稳态的典型异质性特征。因此，他们表现出更高的分化倾向。这些发现将Parp1和Parp7置于多能性网络的遗传-表观遗传界面，微调转录异质性，从而决定胚胎干细胞的发育可塑性。
Embryonic stem (ES) cells are in a dynamic equilibrium of distinct functional states, characterized by the heterogeneous expression of critical pluripotency factors and regulated by a spectrum of reversible histone modifications. Maintenance of this equilibrium is a hallmark of pluripotency. Here we find that the ADP-ribosyltransferases Parp1 and Parp7 play a critical role in safeguarding this state by occupying key pluripotency genes, notably Nanog, Pou5f1, Sox2, Stella, Tet1 and Zfp42, thereby protecting them from progressive epigenetic repression. In the absence of either Parp1 or Parp7, or upon inhibition of the ADP-ribosylating activity, ES cells exhibit a decrease in ground state pluripotency as they cannot maintain the typical heterogeneity characteristic of the metastable state. As a consequence, they display a higher propensity to differentiate. These findings place Parp1 and Parp7 at the genetic-epigenetic interface of pluripotency networks, fine-tuning the transcriptional heterogeneity and thereby determining the developmental plasticity of ES cells.
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