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Title: OptRAM: In-silico strain design via integrative regulatory-metabolic network modeling

Abstract

The ultimate goal of metabolic engineering is to produce desired compounds on an industrial scale in a cost effective manner. To address challenges in metabolic engineering, computational strain optimization algorithms based on genome-scale metabolic models have increasingly been used to aid in overproducing products of interest. However, most of these strain optimization algorithms utilize a metabolic network alone, with few approaches providing strategies that also include transcriptional regulation. Moreover previous integrated approaches generally require a pre-existing regulatory network. In this study, we developed a novel strain design algorithm, named OptRAM (Optimization of Regulatory And Metabolic Networks), which can identify combinatorial optimization strategies including overexpression, knockdown or knockout of both metabolic genes and transcription factors. OptRAM is based on our previous IDREAM integrated network framework, which makes it able to deduce a regulatory network from data. OptRAM uses simulated annealing with a novel objective function, which can ensure a favorable coupling between desired chemical and cell growth. The other advance we propose is a systematic evaluation metric of multiple solutions, by considering the essential genes, flux variation, and engineering manipulation cost. We applied OptRAM to generate strain designs for succinate, 2,3-butanediol, and ethanol overproduction in yeast, which predicted high minimum predictedmore » target production rate compared with other methods and previous literature values. Moreover, most of the genes and TFs proposed to be altered by OptRAM in these scenarios have been validated by modification of the exact genes or the target genes regulated by the TFs, for overproduction of these desired compounds by in vivo experiments cataloged in the LASER database. Particularly, we successfully validated the predicted strain optimization strategy for ethanol production by fermentation experiment. As a result, OptRAM can provide a useful approach that leverages an integrated transcriptional regulatory network and metabolic network to guide metabolic engineering applications.« less

Authors:
 [1];  [2];  [2];  [2];  [2];  [3]; ORCiD logo [2]; ORCiD logo [2];  [4]
  1. Shanghai Jiao Tong Univ., Shanghai (China); Univ. of Michigan, Ann Arbor, MI (United States)
  2. Shanghai Jiao Tong Univ., Shanghai (China)
  3. Institute for Systems Biology, Seattle, WA (United States)
  4. CPERI (Greece)
Publication Date:
Research Org.:
Center for Advanced Bioenergy and Bioproducts Innovation (CABBI), Urbana, IL (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Biological and Environmental Research (BER) (SC-23)
OSTI Identifier:
1503681
Grant/Contract Number:  
SC0018420
Resource Type:
Accepted Manuscript
Journal Name:
PLoS Computational Biology (Online)
Additional Journal Information:
Journal Name: PLoS Computational Biology (Online); Journal Volume: 15; Journal Issue: 3; Journal ID: ISSN 1553-7358
Publisher:
Public Library of Science
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; ethanol; metabolic networks; gene regulation; gene regulatory networks; Saccharomyces cerevisiae; gene expression; transcriptional control; simulated annealing

Citation Formats

Shen, Fangzhou, Sun, Renliang, Yao, Jie, Li, Jian, Liu, Qian, Price, Nathan D., Liu, Chenguang, Wang, Zhuo, and Ouzounis, Christos A. OptRAM: In-silico strain design via integrative regulatory-metabolic network modeling. United States: N. p., 2019. Web. doi:10.1371/journal.pcbi.1006835.
Shen, Fangzhou, Sun, Renliang, Yao, Jie, Li, Jian, Liu, Qian, Price, Nathan D., Liu, Chenguang, Wang, Zhuo, & Ouzounis, Christos A. OptRAM: In-silico strain design via integrative regulatory-metabolic network modeling. United States. doi:10.1371/journal.pcbi.1006835.
Shen, Fangzhou, Sun, Renliang, Yao, Jie, Li, Jian, Liu, Qian, Price, Nathan D., Liu, Chenguang, Wang, Zhuo, and Ouzounis, Christos A. Fri . "OptRAM: In-silico strain design via integrative regulatory-metabolic network modeling". United States. doi:10.1371/journal.pcbi.1006835. https://www.osti.gov/servlets/purl/1503681.
@article{osti_1503681,
title = {OptRAM: In-silico strain design via integrative regulatory-metabolic network modeling},
author = {Shen, Fangzhou and Sun, Renliang and Yao, Jie and Li, Jian and Liu, Qian and Price, Nathan D. and Liu, Chenguang and Wang, Zhuo and Ouzounis, Christos A.},
abstractNote = {The ultimate goal of metabolic engineering is to produce desired compounds on an industrial scale in a cost effective manner. To address challenges in metabolic engineering, computational strain optimization algorithms based on genome-scale metabolic models have increasingly been used to aid in overproducing products of interest. However, most of these strain optimization algorithms utilize a metabolic network alone, with few approaches providing strategies that also include transcriptional regulation. Moreover previous integrated approaches generally require a pre-existing regulatory network. In this study, we developed a novel strain design algorithm, named OptRAM (Optimization of Regulatory And Metabolic Networks), which can identify combinatorial optimization strategies including overexpression, knockdown or knockout of both metabolic genes and transcription factors. OptRAM is based on our previous IDREAM integrated network framework, which makes it able to deduce a regulatory network from data. OptRAM uses simulated annealing with a novel objective function, which can ensure a favorable coupling between desired chemical and cell growth. The other advance we propose is a systematic evaluation metric of multiple solutions, by considering the essential genes, flux variation, and engineering manipulation cost. We applied OptRAM to generate strain designs for succinate, 2,3-butanediol, and ethanol overproduction in yeast, which predicted high minimum predicted target production rate compared with other methods and previous literature values. Moreover, most of the genes and TFs proposed to be altered by OptRAM in these scenarios have been validated by modification of the exact genes or the target genes regulated by the TFs, for overproduction of these desired compounds by in vivo experiments cataloged in the LASER database. Particularly, we successfully validated the predicted strain optimization strategy for ethanol production by fermentation experiment. As a result, OptRAM can provide a useful approach that leverages an integrated transcriptional regulatory network and metabolic network to guide metabolic engineering applications.},
doi = {10.1371/journal.pcbi.1006835},
journal = {PLoS Computational Biology (Online)},
number = 3,
volume = 15,
place = {United States},
year = {2019},
month = {3}
}

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