A great deal of attention is being paid to strategies seeking to uncover the biology of the four-stranded nucleic acid structure G-quadruplex (G4) via their stabilization in cells with G4-specific ligands. The conventional definition of chemical biology implies that a complete assessment of G4 biology can only be achieved by implementing a complementary approach involving the destabilization of cellular G4s by ad hoc molecular effectors. We report here on an unprecedented comparison of the cellular consequences of G4 chemical stabilization by pyridostatin (PDS) and destabilization by phenylpyrrolocytosine (PhpC) at both transcriptome- and proteome-wide scales in patient-derived primary human astrocytes. Our results show that the stabilization of G4s by PDS triggers the dysregulation of many cellular circuitries, the most drastic effects originating in the downregulation of 354 transcripts and 158 proteins primarily involved in RNA transactions. In contrast, destabilization of G4s by PhpC modulates the G4 landscapes in a far more focused manner with upregulation of 295 proteins, mostly involved in RNA transactions as well, thus mirroring the effects of PDS. Our study is the first of its kind to report the extent of G4-associated cellular circuitries in human cells by systematically pitting the effect of G4 stabilization against destabilization in a direct and unbiased manner.

中文翻译：

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基于小分子的人星形胶质细胞基因表达调节打开和关闭 G-四链体控制系统


人们非常关注寻求通过四链核酸结构 G-四链体 （G4） 在具有 G4 特异性配体的细胞中的稳定性来揭示其生物学的策略。化学生物学的常规定义意味着，只有通过实施一种涉及临时分子效应器破坏细胞 G4 的互补方法，才能实现对 G4 生物学的完整评估。我们在这里报告了在患者来源的原代人星形胶质细胞中，在转录组和蛋白质组范围的转录组范围内，吡啶抑素 （PDS） 的 G4 化学稳定和苯吡咯胞嘧啶 （PhpC） 不稳定的细胞后果的前所未有的比较。我们的结果表明，PDS 对 G4s 的稳定触发了许多细胞回路的失调，最剧烈的影响起源于主要参与 RNA 交易的 354 个转录本和 158 个蛋白质的下调。相比之下，PhpC 对 G4s 的不稳定以更集中的方式调节 G4 景观，上调 295 种蛋白质，主要也参与 RNA 交易，从而反映了 PDS 的效果。我们的研究是同类研究中第一个通过直接和公正的方式系统地将 G4 稳定与不稳定的影响对立起来，报告了人类细胞中 G4 相关细胞回路的范围。