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Recent publications in the journal Nature highlight a critical advancement in the exploration of the intricate workings of metabolic networks. The research, led by Dr. Marian Walhout, who holds the Maroun Semaan Chair in Biomedical Research and leads the systems biology department, addresses essential metabolic questions that have been at the forefront of scientific inquiry for over a decade.
Dr. Walhout explains that living organisms continuously assess their nutrient availability and adapt their metabolism accordingly, ensuring efficient biomass and energy production. This metabolism is orchestrated through a complex series of chemical reactions forming the metabolic network. The focus of Walhout’s laboratory is to elucidate how these reactions integrate and what transpires when typical information flows within the network are disrupted. Central inquiries include whether cells can identify alternative pathways within this metabolic framework and the mechanisms enabling such adaptability. Insights from this research are crucial, as various health issues, including cancer, diabetes, and obesity, are linked to metabolic dysfunction.
Although specific reactions and pathways have been scrutinized extensively, identifying which reactions are active—or ‘carrying flux’—in any given cell at a specific time has posed challenges. The first paper released today, titled “Systems-level design principles of metabolic rewiring in an animal,” adopts a systems-level perspective to dissect the principles guiding metabolic flow alterations in response to disruptions. The accompanying paper, “A systems-level, semi-quantitative landscape of metabolic flux in C. elegans,” utilizes insights from the first study to map the ‘natural’ organization of metabolic circuits within an organism, annotating which reactions function and which are suppressed under baseline conditions.
Both studies utilized a pioneering technique known as “Worm Perturb-Seq” (WPS), which enables the individual depletion of approximately 900 metabolic genes in the model organism C. elegans. This innovative method employs RNA sequencing to illuminate how fluctuations in various areas of the metabolic network impact gene expression. The findings indicate that gene expression can inform us about how organisms negotiate changes to their metabolic status. The comprehensive analysis revealed a high-level model in which depletion of ‘core’ metabolic functions leads to compensatory responses from other related genes, while some core functions face repression. This “compensation-repression” (CR) model suggests a strategic regulatory mechanism employed by the worm to maintain metabolic balance, which preliminary human data suggests may also be relevant to understanding metabolic disruptions in humans.
“The analysis of the WPS data provided compelling insights into the adaptive rewiring of metabolism through the compensation-repression model,” Walhout remarked. “By reformulating metabolic questions into a genomics context, we constructed a ‘wiring map’ of adult worm metabolism, yielding numerous new revelations.”
Co-first author and postdoctoral researcher Hefei Zhang, PhD, expressed enthusiasm about the predictive power of their findings. “I found it most exciting that the majority of our predictions were corroborated through isotope tracing experiments, reinforcing the reliability of our approach to predict metabolic network wiring based on molecular phenotypes,” he stated.
Notable revelations from the research include the organism’s utilization of RNA as a carbon source and employing amino acids to energize the tricarboxylic acid cycle. Interestingly, carbohydrates such as glucose, commonly believed to be the primary energy source, were found to have a relatively secondary role in energy production within the worm.
Dr. Walhout emphasized that WPS and the findings from these studies lay a robust groundwork for future metabolic studies in various organisms, including humans, offering potential insights into healthy metabolism and disorders linked to metabolic irregularities.
Xuhang Li, a PhD candidate and co-first author on both studies, noted, “These findings collectively usher in a new paradigm for examining metabolism through genomics, facilitating a comprehensive understanding of metabolic dynamics.”
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