美国麻省大学陈医学院Albertha J. M. Walhout研究组取得一项新突破。他们的最新研究提出了动物代谢重组的系统级设计原则。2025年2月26日出版的《自然》发表了这项成果。

本研究将蠕虫扰动序列（WPS）——一种结合全动物RNA干扰和RNA测序的高通量方法——应用于线虫线虫的约900个代谢基因。研究团队推导了一个代谢基因调控网络（mGRN），其中385个扰动通过超过110,000个相互作用与9,414个基因相连。mGRN具有高度模块化的结构，其中22个微扰仪连接44个基因表达程序。mGRN揭示了从简单的反应和通路补偿到重布线和更复杂的网络协调的不同转录重布线模式。利用代谢网络模型，该团队确定了转录重布线的设计原则，该团队将其命名为补偿-抑制（CR）模型。CR模型解释了代谢基因的大多数转录反应，并揭示了与能量和生物量相关的五个核心代谢功能的高水平补偿和抑制。研究组提供的初步证据表明，CR模型也可以解释人类细胞中的转录代谢重新布线。

研究人员表示，代谢调节对任何生物体都是至关重要的，可以通过转录激活或抑制代谢基因来实现。尽管已经报道了许多转录代谢重新布线的例子，但在任何动物身上都缺乏对代谢如何在代谢扰动下重新布线的系统级研究。

附：英文原文

Title: Systems-level design principles of metabolic rewiring in an animal

Author: Li, Xuhang, Zhang, Hefei, Hodder, Thomas, Wang, Wen, Myers, Chad L., Yilmaz, L. Safak, Walhout, Albertha J. M.

Issue&Volume: 2025-02-26

Abstract: The regulation of metabolism is vital to any organism and can be achieved by transcriptionally activating or repressing metabolic genes1,2,3. Although many examples of transcriptional metabolic rewiring have been reported4, a systems-level study of how metabolism is rewired in response to metabolic perturbations is lacking in any animal. Here we apply Worm Perturb-Seq (WPS)—a high-throughput method combining whole-animal RNA-interference and RNA-sequencing5—to around 900 metabolic genes in the nematode Caenorhabditis elegans. We derive a metabolic gene regulatory network (mGRN) in which 385 perturbations are connected to 9,414 genes by more than 110,000 interactions. The mGRN has a highly modular structure in which 22 perturbation clusters connect to 44 gene expression programs. The mGRN reveals different modes of transcriptional rewiring from simple reaction and pathway compensation to rerouting and more complex network coordination. Using metabolic network modelling, we identify a design principle of transcriptional rewiring that we name the compensation–repression (CR) model. The CR model explains most transcriptional responses in metabolic genes and reveals a high level of compensation and repression in five core metabolic functions related to energy and biomass. We provide preliminary evidence that the CR model may also explain transcriptional metabolic rewiring in human cells.

DOI: 10.1038/s41586-025-08636-5

Source: https://www.nature.com/articles/s41586-025-08636-5