title: Integrated in silico Analyses of Regulatory and Metabolic Networks of Synechococcus sp. PCC 7002 Reveal Relationships between Gene Centrality and Essentiality.
abstract: Cyanobacteria dynamically relay environmental inputs to intracellular adaptations through a coordinated adjustment of photosynthetic efficiency and carbon processing rates. The output of such adaptations is reflected through changes in transcriptional patterns and metabolic flux distributions that ultimately define growth strategy. To address interrelationships between metabolism and regulation, we performed integrative analyses of metabolic and gene co-expression networks in a model cyanobacterium, Synechococcus sp. PCC 7002. Centrality analyses using the gene co-expression network identified a set of key genes, which were defined here as "topologically important." Parallel in silico gene knock-out simulations, using the genome-scale metabolic network, classified what we termed as "functionally important" genes, deletion of which affected growth or metabolism. A strong positive correlation was observed between topologically and functionally important genes. Functionally important genes exhibited variable levels of topological centrality; however, the majority of topologically central genes were found to be functionally essential for growth. Subsequent functional enrichment analysis revealed that both functionally and topologically important genes in Synechococcus sp. PCC 7002 are predominantly associated with translation and energy metabolism, two cellular processes critical for growth. This research demonstrates how synergistic network-level analyses can be used for reconciliation of metabolic and gene expression data to uncover fundamental biological principles.
authors.affiliation: Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA 99352, USA. hyunseob.song@pnnl.gov.
authors.forename: Hyun-Seob
authors.initials: HS
authors.lastname: Song
authors.affiliation: Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA 99352, USA. ryan.mcclure@pnnl.gov.
authors.forename: Ryan S
authors.initials: RS
authors.lastname: McClure
authors.affiliation: Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA 99352, USA. hans.bernstein@pnnl.gov.
authors.forename: Hans C
authors.initials: HC
authors.lastname: Bernstein
authors.affiliation: Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA 99352, USA. christopher.overall@pnnl.gov.
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Overall
authors.affiliation: Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA 99352, USA. eric.hill@pnnl.gov.
authors.forename: Eric A
authors.initials: EA
authors.lastname: Hill
authors.affiliation: Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA 99352, USA. alex.beliaev@pnnl.gov.
authors.forename: Alexander S
authors.initials: AS
authors.lastname: Beliaev
references.citation: Phys Rev E Stat Nonlin Soft Matter Phys. 2012 Jan;85(1 Pt 2):016117
references.pmid: 22400635
references.citation: Mol Syst Biol. 2009;5:320
references.pmid: 19888215
references.citation: BMC Syst Biol. 2009 Oct 13;3:102
references.pmid: 19822021
references.citation: FEBS Lett. 2005 Aug 29;579(21):4642-6
references.pmid: 16095595
references.citation: Nat Biotechnol. 2008 Jun;26(6):659-67
references.pmid: 18536691
references.citation: Bioresour Technol. 2013 Apr;134:127-33
references.pmid: 23500569
references.citation: J Comput Biol. 2009 Feb;16(2):169-80
references.pmid: 19178137
references.citation: Front Microbiol. 2014 Sep 19;5:488
references.pmid: 25285095
references.citation: Proc Natl Acad Sci U S A. 2002 Nov 12;99(23):15112-7
references.pmid: 12415116
references.citation: Biophys J. 2006 Sep 15;91(6):2304-11
references.pmid: 16782788
references.citation: PLoS One. 2012;7(4):e34670
references.pmid: 22666308
references.citation: Environ Microbiol Rep. 2014 Feb;6(1):90-9
references.pmid: 24596266
references.citation: Nucleic Acids Res. 2013 Aug;41(14):e140
references.pmid: 23716638
references.citation: Front Microbiol. 2012 Apr 11;3:145
references.pmid: 22514553
references.citation: PLoS Biol. 2007 Jan;5(1):e8
references.pmid: 17214507
references.citation: BMC Microbiol. 2014 Jan 27;14:14
references.pmid: 24467879
references.citation: ISME J. 2014 Nov;8(11):2243-55
references.pmid: 24781900
references.citation: Microbiol Rev. 1993 Sep;57(3):725-49
references.pmid: 8246846
references.citation: PLoS One. 2013;8(2):e55871
references.pmid: 23409071
references.citation: Front Microbiol. 2012 Oct 11;3:354
references.pmid: 23087677
references.citation: Nat Biotechnol. 2010 Sep;28(9):977-82
references.pmid: 20802497
references.citation: Mol Biol Evol. 1999 Mar;16(3):332-46
references.pmid: 10331260
references.citation: Biophys J. 2005 Jan;88(1):L07-9
references.pmid: 15574705
references.citation: Proc Natl Acad Sci U S A. 2009 Apr 21;106(16):6477-82
references.pmid: 19346491
references.citation: Front Genet. 2014 Jul 02;5:191
references.pmid: 25071821
references.citation: Appl Environ Microbiol. 2011 Nov;77(21):7459-68
references.pmid: 21821760
references.citation: PLoS One. 2014 Nov 14;9(11):e112524
references.pmid: 25397773
references.citation: Nature. 2000 Jul 27;406(6794):378-82
references.pmid: 10935628
references.citation: Science. 1997 May 2;276(5313):707-12
references.pmid: 9115190
references.citation: Front Microbiol. 2011 Mar 07;2:41
references.pmid: 21779275
references.citation: Nat Protoc. 2010 Jan;5(1):93-121
references.pmid: 20057383