Model-based transcriptome engineering promotes a fermentative transcriptional state in yeast
Drew G. Michael,Ezekiel J. Maier,Holly Brown,Stacey R. Gish,Christopher Fiore,Randall H. Brown,Michael R. Brent +6 more
TL;DR: An integrated model of transcriptional regulation and metabolic flux is presented that will enable future efforts aimed at improving xylose fermentation to prioritize functional regulators of central carbon metabolism.
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Abstract: 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.
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Eliza J. R. Peterson,Rebeca Bailo,Alissa C. Rothchild,Mario L. Arrieta-Ortiz,Amardeep Kaur,Min Pan,Dat Mai,Abrar A. Abidi,Charlotte Cooper,Alan Aderem,Apoorva Bhatt,Nitin S. Baliga,Nitin S. Baliga,Nitin S. Baliga +13 more
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d-Xylose consumption by nonrecombinant Saccharomyces cerevisiae: A review.
TL;DR: The genome of this yeast has all the genes required forxylose transport and metabolism through the xylose reductase, xylitol dehydrogenase, and xylulokinase pathway, but there seems to be problems in their kinetic properties and/or required expression.
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Rewired cellular signaling coordinates sugar and hypoxic responses for anaerobic xylose fermentation in yeast.
Kevin S. Myers,Nicholas M. Riley,Matthew E. MacGilvray,Trey K. Sato,Mick McGee,Justin Heilberger,Joshua J. Coon,Audrey P. Gasch,Audrey P. Gasch +8 more
TL;DR: A picture of the metabolic logic behind anaerobic xylose flux is presented and it is suggested that widespread cellular remodeling, rather than individual metabolic changes, is an important goal for metabolic engineering.
Pentose Metabolism in Saccharomyces cerevisiae: The Need to Engineer Global Regulatory Systems
TL;DR: The engineering strategies that are employed for pentose assimilation in this yeast are reviewed, and compared with metabolism and regulation of native sugar, galactose, to identify missing links in xylose and arabinose utilization.
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Dual threshold optimization and network inference reveal convergent evidence from TF binding locations and TF perturbation responses.
Yiming Kang,Nikhil R. Patel,Christian A. Shively,Pamela Samantha Recio,Xuhua Chen,Bernd Wranik,Griffin Kim,R. Scott McIsaac,Robi D. Mitra,Michael R. Brent +9 more
TL;DR: Dual Threshold Optimization, a new method for setting significance thresholds on binding and response data, is introduced and improved, and the combination of dual threshold optimization and network inference greatly expands the high-confidence TF network map in both yeast and human.
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