title: Genome-wide gene expression and RNA half-life measurements allow predictions of regulation and metabolic behavior in Methanosarcina acetivorans.
abstract: While a few studies on the variations in mRNA expression and half-lives measured under different growth conditions have been used to predict patterns of regulation in bacterial organisms, the extent to which this information can also play a role in defining metabolic phenotypes has yet to be examined systematically. Here we present the first comprehensive study for a model methanogen.
  
  
  
  We use expression and half-life data for the methanogen Methanosarcina acetivorans growing on fast- and slow-growth substrates to examine the regulation of its genes. Unlike Escherichia coli where only small shifts in half-lives were observed, we found that most mRNA have significantly longer half-lives for slow growth on acetate compared to fast growth on methanol or trimethylamine. Interestingly, half-life shifts are not uniform across functional classes of enzymes, suggesting the existence of a selective stabilization mechanism for mRNAs. Using the transcriptomics data we determined whether transcription or degradation rate controls the change in transcript abundance. Degradation was found to control abundance for about half of the metabolic genes underscoring its role in regulating metabolism. Genes involved in half of the metabolic reactions were found to be differentially expressed among the substrates suggesting the existence of drastically different metabolic phenotypes that extend beyond just the methanogenesis pathways. By integrating expression data with an updated metabolic model of the organism (iST807) significant differences in pathway flux and production of metabolites were predicted for the three growth substrates.
  
  
  
  This study provides the first global picture of differential expression and half-lives for a class II methanogen, as well as provides the first evidence in a single organism that drastic genome-wide shifts in RNA half-lives can be modulated by growth substrate. We determined which genes in each metabolic pathway control the flux and classified them as regulated by transcription (e.g. transcription factor) or degradation (e.g. post-transcriptional modification). We found that more than half of genes in metabolism were controlled by degradation. Our results suggest that M. acetivorans employs extensive post-transcriptional regulation to optimize key metabolic steps, and more generally that degradation could play a much greater role in optimizing an organism's metabolism than previously thought.
authors.affiliation: Department of Chemistry, University of Illinois at Urbana-Champaign, 505 S Mathews Ave, Urbana, 60801, IL, USA.
authors.forename: Joseph R
authors.identifier: 0000-0003-0989-5288
authors.initials: JR
authors.lastname: Peterson
authors.affiliation: Center for Biophysics and Computational Biology, University of Illinois at Urbana-Champaign, 1110 W Green St, Urbana, 60801, IL, USA.
authors.forename: ShengShee
authors.initials: S
authors.lastname: Thor
authors.affiliation: Department of Chemistry, University of Illinois at Urbana-Champaign, 505 S Mathews Ave, Urbana, 60801, IL, USA.
authors.forename: Lars
authors.initials: L
authors.lastname: Kohler
authors.affiliation: Department of Microbiology, University of Illinois at Urbana-Champaign, 601 S Goodwin AveIL, Urbana, 60801, USA.
authors.forename: Petra R A
authors.initials: PR
authors.lastname: Kohler
authors.affiliation: Department of Microbiology, University of Illinois at Urbana-Champaign, 601 S Goodwin AveIL, Urbana, 60801, USA.|Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, 1206 W Gregory DrIL, Urbana, 60801, USA.
authors.forename: William W
authors.initials: WW
authors.lastname: Metcalf
authors.affiliation: Department of Chemistry, University of Illinois at Urbana-Champaign, 505 S Mathews Ave, Urbana, 60801, IL, USA. zan@illinois.edu.|Center for Biophysics and Computational Biology, University of Illinois at Urbana-Champaign, 1110 W Green St, Urbana, 60801, IL, USA. zan@illinois.edu.|Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, 1206 W Gregory DrIL, Urbana, 60801, USA. zan@illinois.edu.|Beckman Institute, University of Illinois at Urbana-Champaign, 405 N Mathews Ave, Urbana, 60801, IL, USA. zan@illinois.edu.
authors.forename: Zaida
authors.initials: Z
authors.lastname: Luthey-Schulten
mesh_terms: D003609:Dactinomycin / Q000494:pharmacology; D015870:Gene Expression; D020745:Genome, Archaeal; D006207:Half-Life; D053858:Metabolic Networks and Pathways; D000432:Methanol / Q000378:metabolism; D017020:Methanosarcina / Q000145:classification / Q000235:genetics* / Q000378:metabolism; D008954:Models, Biological; D010641:Phenotype; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D012313:RNA / Q000302:isolation & purification / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D017423:Sequence Analysis, RNA; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D011500:Protein Synthesis Inhibitors; D012333:RNA, Messenger; D003609:Dactinomycin; D012313:RNA; D000432:Methanol
keywords: Degradational regulatory control; Differential pathway usage; Genome scale metabolic modeling; Metabolic phenotype; Methanogens; RNA half–lives