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Here, we developed a framework for mapping context-specific genetic interactions, enabling us to measure the plasticity of human genetic architecture upon environmental challenge for ∼250,000 interactions, using cell cycle interruption, genotoxic perturbation, and nutrient deprivation as archetypes. We discover large-scale rewiring of human gene relationships across conditions, highlighted by dramatic shifts in the functional connections of epigenetic regulators (TIP60), cell cycle regulators (PP2A), and glycolysis metabolism. Our study demonstrates that upon environmental perturbation, intra-complex genetic rewiring is rare while inter-complex rewiring is common, suggesting a modular and flexible evolutionary genetic strategy that allows a limited number of human genes to enable adaptation to a large number of environmental conditions.\n Citation Format: Luke Gilbert, Ben Herken. Environmental challenge rewires functional connections among human genes [abstract]. 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引用次数: 0
摘要
生物学中的一个基本问题是,数量有限的基因如何组合管理细胞对环境变化的反应。虽然普遍的假设是基因、过程和本体之间的关系可以通过塑性来实现这种适应性,但定量比较人类基因在特定环境条件下的功能连接是非常具有挑战性的。因此,目前仍不清楚人类基因相互作用网络是否以及如何随着环境条件的变化而重新布线。在这里,我们开发了一个绘制特定环境基因相互作用图谱的框架,使我们能够以细胞周期中断、基因毒性扰乱和营养剥夺为原型,测量人类基因结构在环境挑战下的∼250,000 种相互作用的可塑性。我们发现人类基因关系在不同条件下发生了大规模的重新布线,突出表现在表观遗传调控因子(TIP60)、细胞周期调控因子(PP2A)和糖酵解代谢的功能连接发生了巨大变化。我们的研究表明,在环境扰动下,复合物内的基因重配很少见,而复合物间的基因重配却很常见,这表明一种模块化和灵活的进化遗传策略使数量有限的人类基因能够适应大量的环境条件。引用格式:卢克-吉尔伯特、本-赫肯环境挑战重塑人类基因之间的功能连接[摘要].In:AACR 癌症研究特别会议论文集:扩展和转化癌症合成漏洞;2024 年 6 月 10-13 日;加拿大魁北克省蒙特利尔。费城(宾夕法尼亚州):AACR; Mol Cancer Ther 2024;23(6 Suppl):Abstract nr IA021.
Abstract IA021: Environmental challenge rewires functional connections among human genes
A fundamental question in biology is how a limited number of genes combinatorially govern cellular responses to environmental changes. While the prevailing hypothesis is that relationships between genes, processes, and ontologies could be plastic to achieve this adaptability, quantitatively comparing human gene functional connections between specific environmental conditions at scale is very challenging. Therefore, it remains unclear whether and how human genetic interaction networks are rewired in response to changing environmental conditions. Here, we developed a framework for mapping context-specific genetic interactions, enabling us to measure the plasticity of human genetic architecture upon environmental challenge for ∼250,000 interactions, using cell cycle interruption, genotoxic perturbation, and nutrient deprivation as archetypes. We discover large-scale rewiring of human gene relationships across conditions, highlighted by dramatic shifts in the functional connections of epigenetic regulators (TIP60), cell cycle regulators (PP2A), and glycolysis metabolism. Our study demonstrates that upon environmental perturbation, intra-complex genetic rewiring is rare while inter-complex rewiring is common, suggesting a modular and flexible evolutionary genetic strategy that allows a limited number of human genes to enable adaptation to a large number of environmental conditions.
Citation Format: Luke Gilbert, Ben Herken. Environmental challenge rewires functional connections among human genes [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Expanding and Translating Cancer Synthetic Vulnerabilities; 2024 Jun 10-13; Montreal, Quebec, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(6 Suppl):Abstract nr IA021.
期刊介绍:
Molecular Cancer Therapeutics will focus on basic research that has implications for cancer therapeutics in the following areas: Experimental Cancer Therapeutics, Identification of Molecular Targets, Targets for Chemoprevention, New Models, Cancer Chemistry and Drug Discovery, Molecular and Cellular Pharmacology, Molecular Classification of Tumors, and Bioinformatics and Computational Molecular Biology. The journal provides a publication forum for these emerging disciplines that is focused specifically on cancer research. Papers are stringently reviewed and only those that report results of novel, timely, and significant research and meet high standards of scientific merit will be accepted for publication.