Inferring metabolic objectives and trade-offs in single cells during embryogenesis.

Cell systems Pub Date : 2025-01-15 Epub Date: 2025-01-07 DOI:10.1016/j.cels.2024.12.005
Da-Wei Lin, Ling Zhang, Jin Zhang, Sriram Chandrasekaran
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Abstract

While proliferating cells optimize their metabolism to produce biomass, the metabolic objectives of cells that perform non-proliferative tasks are unclear. The opposing requirements for optimizing each objective result in a trade-off that forces single cells to prioritize their metabolic needs and optimally allocate limited resources. Here, we present single-cell optimization objective and trade-off inference (SCOOTI), which infers metabolic objectives and trade-offs in biological systems by integrating bulk and single-cell omics data, using metabolic modeling and machine learning. We validated SCOOTI by identifying essential genes from CRISPR-Cas9 screens in embryonic stem cells, and by inferring the metabolic objectives of quiescent cells, during different cell-cycle phases. Applying this to embryonic cell states, we observed a decrease in metabolic entropy upon development. We further uncovered a trade-off between glutathione and biosynthetic precursors in one-cell zygote, two-cell embryo, and blastocyst cells, potentially representing a trade-off between pluripotency and proliferation. A record of this paper's transparent peer review process is included in the supplemental information.

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推断胚胎发生过程中单细胞的代谢目标和权衡。
当增殖细胞优化其代谢以产生生物量时,执行非增殖任务的细胞的代谢目标尚不清楚。优化每个目标的相反要求导致权衡,迫使单个细胞优先考虑其代谢需求并优化分配有限的资源。在这里,我们提出了单细胞优化目标和权衡推理(SCOOTI),它通过整合大量和单细胞组学数据,使用代谢建模和机器学习来推断生物系统中的代谢目标和权衡。我们通过从胚胎干细胞的CRISPR-Cas9筛选中鉴定必需基因,并通过推断静止细胞在不同细胞周期阶段的代谢目的来验证SCOOTI。将此应用于胚胎细胞状态,我们观察到发育过程中代谢熵的减少。我们进一步揭示了谷胱甘肽和单细胞受精卵、双细胞胚胎和囊胚细胞中生物合成前体之间的权衡,可能代表了多能性和增殖之间的权衡。本文的透明同行评议过程记录包含在补充信息中。
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