title: Inferring causal metabolic signals that regulate the dynamic TORC1-dependent transcriptome.
abstract: Cells react to nutritional cues in changing environments via the integrated action of signaling, transcriptional, and metabolic networks. Mechanistic insight into signaling processes is often complicated because ubiquitous feedback loops obscure causal relationships. Consequently, the endogenous inputs of many nutrient signaling pathways remain unknown. Recent advances for system-wide experimental data generation have facilitated the quantification of signaling systems, but the integration of multi-level dynamic data remains challenging. Here, we co-designed dynamic experiments and a probabilistic, model-based method to infer causal relationships between metabolism, signaling, and gene regulation. We analyzed the dynamic regulation of nitrogen metabolism by the target of rapamycin complex 1 (TORC1) pathway in budding yeast. Dynamic transcriptomic, proteomic, and metabolomic measurements along shifts in nitrogen quality yielded a consistent dataset that demonstrated extensive re-wiring of cellular networks during adaptation. Our inference method identified putative downstream targets of TORC1 and putative metabolic inputs of TORC1, including the hypothesized glutamine signal. The work provides a basis for further mechanistic studies of nitrogen metabolism and a general computational framework to study cellular processes.
authors.affiliation: Department of Biology, Institute of Molecular Systems Biology, ETH Zurich, Zurich, Switzerland.
authors.forename: Ana Paula
authors.initials: AP
authors.lastname: Oliveira
authors.affiliation: Department of Biosystems Science and Engineering and SIB Swiss Institute of Bioinformatics, ETH Zurich, Basel, Switzerland.
authors.forename: Sotiris
authors.initials: S
authors.lastname: Dimopoulos
authors.affiliation: Department of Computer Science, ETH Zurich, Zurich, Switzerland.
authors.forename: Alberto Giovanni
authors.initials: AG
authors.lastname: Busetto
authors.affiliation: Department of Biology, Institute of Molecular Systems Biology, ETH Zurich, Zurich, Switzerland.
authors.forename: Stefan
authors.initials: S
authors.lastname: Christen
authors.affiliation: Department of Biology, Institute of Biochemistry, ETH Zurich, Zurich, Switzerland.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Dechant
authors.affiliation: Department of Biology, Institute of Molecular Systems Biology, ETH Zurich, Zurich, Switzerland.
authors.forename: Laura
authors.initials: L
authors.lastname: Falter
authors.affiliation: Department of Computer Science, ETH Zurich, Zurich, Switzerland.
authors.forename: Morteza
authors.initials: M
authors.lastname: Haghir Chehreghani
authors.affiliation: Department of Biology, Institute of Molecular Systems Biology, ETH Zurich, Zurich, Switzerland.
authors.forename: Szymon
authors.initials: S
authors.lastname: Jozefczuk
authors.affiliation: Department of Biology, Institute of Molecular Systems Biology, ETH Zurich, Zurich, Switzerland.
authors.forename: Christina
authors.initials: C
authors.lastname: Ludwig
authors.affiliation: Department of Biology, Institute of Molecular Systems Biology, ETH Zurich, Zurich, Switzerland.
authors.forename: Florian
authors.initials: F
authors.lastname: Rudroff
authors.affiliation: Department of Biology, Institute of Molecular Systems Biology, ETH Zurich, Zurich, Switzerland.
authors.forename: Juliane Caroline
authors.initials: JC
authors.lastname: Schulz
authors.affiliation: Biozentrum, University of Basel, Basel, Switzerland.
authors.forename: Asier
authors.initials: A
authors.lastname: González
authors.affiliation: Biozentrum, University of Basel, Basel, Switzerland UMR5240 MAP, Université Lyon 1, Villeurbanne, France.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Soulard
authors.affiliation: Biozentrum, University of Basel, Basel, Switzerland.
authors.forename: Daniele
authors.initials: D
authors.lastname: Stracka
authors.affiliation: Department of Biology, Institute of Molecular Systems Biology, ETH Zurich, Zurich, Switzerland Faculty of Science, University of Zurich, Zurich, Switzerland.
authors.forename: Ruedi
authors.initials: R
authors.lastname: Aebersold
authors.affiliation: Department of Computer Science, ETH Zurich, Zurich, Switzerland.
authors.forename: Joachim M
authors.initials: JM
authors.lastname: Buhmann
authors.affiliation: Biozentrum, University of Basel, Basel, Switzerland.
authors.forename: Michael N
authors.initials: MN
authors.lastname: Hall
authors.affiliation: Department of Biology, Institute of Biochemistry, ETH Zurich, Zurich, Switzerland.
authors.forename: Matthias
authors.initials: M
authors.lastname: Peter
authors.affiliation: Department of Biology, Institute of Molecular Systems Biology, ETH Zurich, Zurich, Switzerland sauer@ethz.ch joerg.stelling@bsse.ethz.ch.
authors.forename: Uwe
authors.initials: U
authors.lastname: Sauer
authors.affiliation: Department of Biosystems Science and Engineering and SIB Swiss Institute of Bioinformatics, ETH Zurich, Basel, Switzerland sauer@ethz.ch joerg.stelling@bsse.ethz.ch.
authors.forename: Jörg
authors.initials: J
authors.lastname: Stelling
mesh_terms: D015984:Causality; D002453:Cell Cycle; D003198:Computer Simulation; D003470:Culture Media / Q000494:pharmacology; D015966:Gene Expression Regulation, Fungal; D018698:Glutamic Acid / Q000378:metabolism; D005973:Glutamine / Q000378:metabolism; D055442:Metabolome; D008954:Models, Biological; D009584:Nitrogen / Q000378:metabolism; D011336:Probability; D020543:Proteome; D012331:RNA, Fungal / Q000096:biosynthesis* / Q000235:genetics; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism*; D059467:Transcriptome
chemical_list: D003470:Culture Media; D020543:Proteome; D012331:RNA, Fungal; D029701:Saccharomyces cerevisiae Proteins; C561842:TORC1 protein complex, S cerevisiae; D014157:Transcription Factors; D005973:Glutamine; D018698:Glutamic Acid; D009584:Nitrogen
keywords: causal inference; network motifs; nutrient signaling; target of rapamycin pathway