Small molecule-based regulation of gene expression in human astrocytes switching on and off the G-quadruplex control systems.

IF 4 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Journal of Biological Chemistry Pub Date : 2025-01-01 Epub Date: 2024-11-29 DOI:10.1016/j.jbc.2024.108040
Vijay Kumar M J, Jérémie Mitteaux, Zi Wang, Ellery Wheeler, Nitin Tandon, Sung Yun Jung, Robert H E Hudson, David Monchaud, Andrey S Tsvetkov
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引用次数: 0

Abstract

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.

基于小分子的人类星形胶质细胞基因表达调控开关g -四重体控制系统。
通过四链核酸结构g -四plex (G4)在具有G4特异性配体的细胞中的稳定,寻求揭示其生物学特性的策略受到了极大的关注。化学生物学的传统定义意味着,对G4生物学的完整评估只能通过实施一种互补的方法来实现,这种方法包括通过特殊的分子效应来破坏细胞G4的稳定性。我们在这里报道了一项前所未有的比较,在转录组和蛋白质组范围内,在患者来源的原发性人类星形胶质细胞中,pyridostatin (PDS)的G4化学稳定和苯基pyroro胞嘧啶(PhpC)的不稳定对细胞的影响。我们的研究结果表明,PDS对G4s的稳定引发了许多细胞回路的失调,最剧烈的影响源于354个转录本和158个主要参与RNA交易的蛋白质的下调。相比之下,PhpC对G4s的不稳定作用通过上调295种蛋白质(主要涉及RNA交易)以更集中的方式调节G4结构,从而反映了PDS的作用。我们的研究首次以直接和公正的方式系统地对比了G4稳定对不稳定的影响,从而报告了人类细胞中与G4相关的细胞回路的程度。
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来源期刊
Journal of Biological Chemistry
Journal of Biological Chemistry Biochemistry, Genetics and Molecular Biology-Biochemistry
自引率
4.20%
发文量
1233
期刊介绍: The Journal of Biological Chemistry welcomes high-quality science that seeks to elucidate the molecular and cellular basis of biological processes. Papers published in JBC can therefore fall under the umbrellas of not only biological chemistry, chemical biology, or biochemistry, but also allied disciplines such as biophysics, systems biology, RNA biology, immunology, microbiology, neurobiology, epigenetics, computational biology, ’omics, and many more. The outcome of our focus on papers that contribute novel and important mechanistic insights, rather than on a particular topic area, is that JBC is truly a melting pot for scientists across disciplines. In addition, JBC welcomes papers that describe methods that will help scientists push their biochemical inquiries forward and resources that will be of use to the research community.
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