Model-based transcriptome engineering promotes a fermentative transcriptional state in yeast.
The ability to rationally manipulate the transcriptional states of cells would be of great use in medicine and bioengineering. We have developed an algorithm, NetSurgeon, which uses genome-wide gene-regulatory networks to identify interventions that force a cell toward a desired expression state. We first validated NetSurgeon extensively on existing datasets. Next, we used NetSurgeon to select transcription factor deletions aimed at improving ethanol production in Saccharomyces cerevisiae cultures that are catabolizing xylose. We reasoned that interventions that move the transcriptional state of cells using xylose toward that of cells producing large amounts of ethanol from glucose might improve xylose fermentation. Some of the interventions selected by NetSurgeon successfully promoted a fermentative transcriptional state in the absence of glucose, resulting in strains with a 2.7-fold increase in xylose import rates, a 4-fold improvement in xylose integration into central carbon metabolism, or a 1.3-fold increase in ethanol production rate. We conclude by presenting an integrated model of transcriptional regulation and metabolic flux that will enable future efforts aimed at improving xylose fermentation to prioritize functional regulators of central carbon metabolism.
Center for Genome Sciences and Systems Biology, Washington University in St. Louis, St. Louis, MO 63108.|Department of Computer Science and Engineering, Washington University in St. Louis, St. Louis, MO 63130.
Drew G
DG
Michael
Center for Genome Sciences and Systems Biology, Washington University in St. Louis, St. Louis, MO 63108.|Department of Computer Science and Engineering, Washington University in St. Louis, St. Louis, MO 63130.
Ezekiel J
EJ
Maier
Center for Genome Sciences and Systems Biology, Washington University in St. Louis, St. Louis, MO 63108.|Department of Computer Science and Engineering, Washington University in St. Louis, St. Louis, MO 63130.
Holly
H
Brown
Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110.
Stacey R
SR
Gish
Center for Genome Sciences and Systems Biology, Washington University in St. Louis, St. Louis, MO 63108.
Christopher
C
Fiore
Center for Genome Sciences and Systems Biology, Washington University in St. Louis, St. Louis, MO 63108.|Department of Electrical and Systems Engineering, Washington University in St. Louis, St. Louis, MO 63130.
Randall H
RH
Brown
Center for Genome Sciences and Systems Biology, Washington University in St. Louis, St. Louis, MO 63108; brent@wustl.edu.|Department of Computer Science and Engineering, Washington University in St. Louis, St. Louis, MO 63130.|Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110.
Michael R
MR
Brent
D000465:Algorithms; D000431:Ethanol / Q000378:metabolism; D005285:Fermentation; D017353:Gene Deletion; D053263:Gene Regulatory Networks; D005947:Glucose / Q000378:metabolism; D060847:Metabolic Engineering; D008957:Models, Genetic; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000254:growth & development*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*; D059467:Transcriptome; D014994:Xylose / Q000378:metabolism
D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors; D000431:Ethanol; D014994:Xylose; D005947:Glucose
Saccharomyces cerevisiae; engineering; gene-regulatory networks; regulatory systems biology; transcriptome