title: Protein-DNA binding dynamics predict transcriptional response to nutrients in archaea.
abstract: Organisms across all three domains of life use gene regulatory networks (GRNs) to integrate varied stimuli into coherent transcriptional responses to environmental pressures. However, inferring GRN topology and regulatory causality remains a central challenge in systems biology. Previous work characterized TrmB as a global metabolic transcription factor in archaeal extremophiles. However, it remains unclear how TrmB dynamically regulates its ∼100 metabolic enzyme-coding gene targets. Using a dynamic perturbation approach, we elucidate the topology of the TrmB metabolic GRN in the model archaeon Halobacterium salinarum. Clustering of dynamic gene expression patterns reveals that TrmB functions alone to regulate central metabolic enzyme-coding genes but cooperates with various regulators to control peripheral metabolic pathways. Using a dynamical model, we predict gene expression patterns for some TrmB-dependent promoters and infer secondary regulators for others. Our data suggest feed-forward gene regulatory topology for cobalamin biosynthesis. In contrast, purine biosynthesis appears to require TrmB-independent regulators. We conclude that TrmB is an important component for mediating metabolic modularity, integrating nutrient status and regulating gene expression dynamics alone and in concert with secondary regulators.
authors.affiliation: Department of Biology, Duke University, Durham, NC 27708, USA and Center for Systems Biology, Institute for Genome Science and Policy, Duke University, Durham, NC 27708, USA.
authors.forename: Horia
authors.initials: H
authors.lastname: Todor
authors.forename: Kriti
authors.initials: K
authors.lastname: Sharma
authors.forename: Adrianne M C
authors.initials: AM
authors.lastname: Pittman
authors.forename: Amy K
authors.initials: AK
authors.lastname: Schmid
mesh_terms: D019843:Archaeal Proteins / Q000378:metabolism*; D019848:Gene Expression Regulation, Archaeal; D053263:Gene Regulatory Networks; D005947:Glucose / Q000378:metabolism; D019617:Halobacterium salinarum / Q000235:genetics* / Q000378:metabolism; D017866:Phosphotransferases (Paired Acceptors) / Q000235:genetics; D011401:Promoter Regions, Genetic; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D019843:Archaeal Proteins; D014157:Transcription Factors; D017866:Phosphotransferases (Paired Acceptors); C022509:pyruvate, water dikinase; D005947:Glucose
references.citation: J Biol Chem. 2007 Nov 16;282(46):33659-33670
references.pmid: 17875647
references.citation: Mol Syst Biol. 2009;5:285
references.pmid: 19536208
references.citation: BMC Bioinformatics. 2003 Sep 11;4:41
references.pmid: 12969510
references.citation: BMC Syst Biol. 2010 May 14;4:64
references.pmid: 20470417
references.citation: Nucleic Acids Res. 2004 Jan 02;32(1):143-50
references.pmid: 14704351
references.citation: Biochemistry. 1978 Sep 19;17(19):4004-10
references.pmid: 708691
references.citation: J Proteome Res. 2012 Oct 5;11(10):4823-33
references.pmid: 22639831
references.citation: Genome Res. 2009 Jan;19(1):79-91
references.pmid: 18836036
references.citation: PLoS One. 2009;4(3):e4777
references.pmid: 19274099
references.citation: Arch Microbiol. 2008 Sep;190(3):247-56
references.pmid: 18470695
references.citation: J Bacteriol. 1993 Nov;175(22):7200-8
references.pmid: 8226666
references.citation: Mol Syst Biol. 2010 Jul;6:393
references.pmid: 20664639
references.citation: Curr Opin Microbiol. 2005 Dec;8(6):695-705
references.pmid: 16256419
references.citation: PLoS One. 2011 Mar 22;6(3):e18086
references.pmid: 21445366
references.citation: Proc Natl Acad Sci U S A. 2002 Nov 12;99(23):14913-8
references.pmid: 12403819
references.citation: Mol Syst Biol. 2009;5:294
references.pmid: 19690563
references.citation: Nat Rev Genet. 2007 Jun;8(6):450-61
references.pmid: 17510665
references.citation: PLoS Comput Biol. 2010 Jun 03;6(6):e1000802
references.pmid: 20532205
references.citation: Biol Chem Hoppe Seyler. 1990 Jun;371(6):515-9
references.pmid: 2117936
references.citation: Nucleic Acids Res. 2011 Apr;39(7):2519-33
references.pmid: 21109526
references.citation: Cell. 2007 Dec 28;131(7):1354-65
references.pmid: 18160043
references.citation: Nat Genet. 2002 May;31(1):64-8
references.pmid: 11967538
references.citation: J Biol Chem. 2003 Jul 11;278(28):25417-27
references.pmid: 12654928
references.citation: Mol Syst Biol. 2009;5:282
references.pmid: 19536205
references.citation: Science. 1997 Oct 24;278(5338):631-7
references.pmid: 9381173
references.citation: J Biol Chem. 2003 Jan 10;278(2):983-90
references.pmid: 12426307
references.citation: Mol Microbiol. 2006 Apr;60(2):287-98
references.pmid: 16573681
references.citation: PLoS One. 2011;6(6):e20081
references.pmid: 21673794
references.citation: Mol Biol Evol. 2006 Oct;23(10):1931-6
references.pmid: 16840361
references.citation: Nucleic Acids Res. 2011 Aug;39(15):6456-64
references.pmid: 21572102
references.citation: J Bacteriol. 2005 Mar;187(5):1659-67
references.pmid: 15716436
references.citation: Mol Microbiol. 2007 Jul;65(2):305-18
references.pmid: 17587231
references.citation: Genome Res. 2007 Oct;17(10):1399-413
references.pmid: 17785531
references.citation: Nucleic Acids Res. 2001 May 1;29(9):e45
references.pmid: 11328886
references.citation: Nat Rev Genet. 2010 Jul;11(7):487-98
references.pmid: 20548290
references.citation: Nat Biotechnol. 2008 Mar;26(3):317-25
references.pmid: 18278033
references.citation: J Bacteriol. 2004 Apr;186(7):2179-94
references.pmid: 15028704
references.citation: J Bacteriol. 1999 Jun;181(12):3810-5
references.pmid: 10368157
references.citation: J Biol Chem. 2003 Oct 17;278(42):41148-59
references.pmid: 12869542
references.citation: Nat Protoc. 2008;3(4):698-709
references.pmid: 18388953
references.citation: Nature. 2004 Sep 2;431(7004):99-104
references.pmid: 15343339
references.citation: J Bacteriol. 2007 Oct;189(19):6936-44
references.pmid: 17644597