title: Pseudo-transition Analysis Identifies the Key Regulators of Dynamic Metabolic Adaptations from Steady-State Data.
abstract: Hundreds of molecular-level changes within central metabolism allow a cell to adapt to the changing environment. A primary challenge in cell physiology is to identify which of these molecular-level changes are active regulatory events. Here, we introduce pseudo-transition analysis, an approach that uses multiple steady-state observations of (13)C-resolved fluxes, metabolites, and transcripts to infer which regulatory events drive metabolic adaptations following environmental transitions. Pseudo-transition analysis recapitulates known biology and identifies an unexpectedly sparse, transition-dependent regulatory landscape: typically a handful of regulatory events drive adaptation between carbon sources, with transcription mainly regulating TCA cycle flux and reactants regulating EMP pathway flux. We verify these observations using time-resolved measurements of the diauxic shift, demonstrating that some dynamic transitions can be approximated as monotonic shifts between steady-state extremes. Overall, we show that pseudo-transition analysis can explore the vast regulatory landscape of dynamic transitions using relatively few steady-state data, thereby guiding time-consuming, hypothesis-driven molecular validations.
authors.affiliation: Institute of Molecular Systems Biology, ETH Zurich, Zurich 8093, Switzerland; Systems Biology Graduate School, Zurich 8057, Switzerland. Electronic address: gerosa@fas.harvard.edu.
authors.forename: Luca
authors.initials: L
authors.lastname: Gerosa
authors.affiliation: Institute of Molecular Systems Biology, ETH Zurich, Zurich 8093, Switzerland; Systems Biology Graduate School, Zurich 8057, Switzerland.
authors.forename: Bart R B
authors.initials: BR
authors.lastname: Haverkorn van Rijsewijk
authors.affiliation: Institute of Molecular Systems Biology, ETH Zurich, Zurich 8093, Switzerland; Systems Biology Graduate School, Zurich 8057, Switzerland.
authors.forename: Dimitris
authors.initials: D
authors.lastname: Christodoulou
authors.affiliation: Institute of Molecular Systems Biology, ETH Zurich, Zurich 8093, Switzerland; Systems Biology Graduate School, Zurich 8057, Switzerland.
authors.forename: Karl
authors.initials: K
authors.lastname: Kochanowski
authors.affiliation: Institute of Molecular Systems Biology, ETH Zurich, Zurich 8093, Switzerland.
authors.forename: Thomas S B
authors.initials: TS
authors.lastname: Schmidt
authors.affiliation: Institute of Molecular Systems Biology, ETH Zurich, Zurich 8093, Switzerland.
authors.forename: Elad
authors.initials: E
authors.lastname: Noor
authors.affiliation: Institute of Molecular Systems Biology, ETH Zurich, Zurich 8093, Switzerland. Electronic address: sauer@imsb.biol.ethz.ch.
authors.forename: Uwe
authors.initials: U
authors.lastname: Sauer
keywords: computational biology; metabolism; metabolomics; regulation network; transcription factor