title: Pluralistic and stochastic gene regulation: examples, models and consistent theory.
abstract: We present a theory of pluralistic and stochastic gene regulation. To bridge the gap between empirical studies and mathematical models, we integrate pre-existing observations with our meta-analyses of the ENCODE ChIP-Seq experiments. Earlier evidence includes fluctuations in levels, location, activity, and binding of transcription factors, variable DNA motifs, and bursts in gene expression. Stochastic regulation is also indicated by frequently subdued effects of knockout mutants of regulators, their evolutionary losses/gains and massive rewiring of regulatory sites. We report wide-spread pluralistic regulation in ≈800 000 tightly co-expressed pairs of diverse human genes. Typically, half of ≈50 observed regulators bind to both genes reproducibly, twice more than in independently expressed gene pairs. We also examine the largest set of co-expressed genes, which code for cytoplasmic ribosomal proteins. Numerous regulatory complexes are highly significant enriched in ribosomal genes compared to highly expressed non-ribosomal genes. We could not find any DNA-associated, strict sense master regulator. Despite major fluctuations in transcription factor binding, our machine learning model accurately predicted transcript levels using binding sites of 20+ regulators. Our pluralistic and stochastic theory is consistent with partially random binding patterns, redundancy, stochastic regulator binding, burst-like expression, degeneracy of binding motifs and massive regulatory rewiring during evolution.
authors.affiliation: Department of Statistics, University of Nebraska, Lincoln, NE 68583-0963, USA Department of Biochemistry, University of Nebraska, Lincoln, NE 68588-0665, USA.
authors.forename: Elisa N
authors.initials: EN
authors.lastname: Salas
authors.affiliation: Department of Statistics, University of Nebraska, Lincoln, NE 68583-0963, USA.
authors.forename: Jiang
authors.initials: J
authors.lastname: Shu
authors.affiliation: Department of Statistics, University of Nebraska, Lincoln, NE 68583-0963, USA.
authors.forename: Matyas F
authors.initials: MF
authors.lastname: Cserhati
authors.affiliation: Department of Biochemistry, University of Nebraska, Lincoln, NE 68588-0665, USA.
authors.forename: Donald P
authors.initials: DP
authors.lastname: Weeks
authors.affiliation: Department of Statistics, University of Nebraska, Lincoln, NE 68583-0963, USA Department of Biochemistry, University of Nebraska, Lincoln, NE 68588-0665, USA sladunga@unl.edu.
authors.forename: Istvan
authors.initials: I
authors.lastname: Ladunga
mesh_terms: D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D047369:Chromatin Immunoprecipitation; D004247:DNA / Q000378:metabolism; D005786:Gene Expression Regulation; D015894:Genome, Human; D006801:Humans; D000069550:Machine Learning; D051379:Mice; D008957:Models, Genetic; D012269:Ribosomal Proteins / Q000235:genetics; D013269:Stochastic Processes
chemical_list: D012269:Ribosomal Proteins; D004247:DNA
references.citation: Nucleic Acids Res. 2010 Apr;38(6):1805-20
references.pmid: 20026583
references.citation: Immunity. 2008 Oct 17;29(4):565-77
references.pmid: 18848473
references.citation: Nature. 2012 Sep 6;489(7414):91-100
references.pmid: 22955619
references.citation: Nat Genet. 2000 May;25(1):110-4
references.pmid: 10802668
references.citation: Nucleic Acids Res. 2015 Jan;43(Database issue):D1113-6
references.pmid: 25361974
references.citation: EMBO J. 2006 Jul 26;25(14):3357-66
references.pmid: 16810319
references.citation: Genes Dev. 1989 Mar;3(3):293-303
references.pmid: 2498162
references.citation: Nucleic Acids Res. 2014 Jan;42(Database issue):D926-32
references.pmid: 24304889
references.citation: Nature. 2010 Apr 22;464(7292):1187-91
references.pmid: 20237471
references.citation: J Biol Chem. 2013 Jun 14;288(24):17508-19
references.pmid: 23625919
references.citation: Cell. 2012 Sep 28;151(1):56-67
references.pmid: 23021215
references.citation: Mol Cell Biol. 2004 Dec;24(24):10826-34
references.pmid: 15572685
references.citation: Enzyme. 1990;44(1-4):83-92
references.pmid: 2133661
references.citation: Nat Rev Genet. 2004 Feb;5(2):101-13
references.pmid: 14735121
references.citation: Nucleic Acids Res. 2011 Jun;39(11):e76
references.pmid: 21486752
references.citation: Science. 2011 Jun 10;332(6035):1322-6
references.pmid: 21659605
references.citation: Cell Rep. 2014 Jul 10;8(1):94-102
references.pmid: 24981865
references.citation: Mol Cell Proteomics. 2009 Feb;8(2):215-25
references.pmid: 18723842
references.citation: PLoS Comput Biol. 2012;8(4):e1002480
references.pmid: 22511863
references.citation: Nature. 2008 Jan 31;451(7178):535-40
references.pmid: 18172436
references.citation: Trends Biochem Sci. 1998 Jun;23(6):208-12
references.pmid: 9644974
references.citation: J Biol Chem. 2010 Dec 31;285(53):42013-22
references.pmid: 20943654
references.citation: Mol Cell. 2009 Apr 10;34(1):3-11
references.pmid: 19362532
references.citation: Cold Spring Harb Perspect Med. 2014 Feb 01;4(2):null
references.pmid: 24492846
references.citation: Nature. 2005 Jan 27;433(7024):434-8
references.pmid: 15647753
references.citation: Genes Dev. 2008 Jul 15;22(14):1921-33
references.pmid: 18628398
references.citation: Blood. 2005 Sep 1;106(5):1519-24
references.pmid: 15914558
references.citation: Adv Bioinformatics. 2008;2008:420747
references.pmid: 19956698
references.citation: J Exp Med. 2012 Dec 17;209(13):2467-83
references.pmid: 23230003
references.citation: Mol Cell. 2011 Nov 4;44(3):410-23
references.pmid: 22055187
references.citation: Nat Struct Mol Biol. 2008 Apr;15(4):364-72
references.pmid: 18327268
references.citation: Plant Cell. 2012 May;24(5):1860-75
references.pmid: 22634764
references.citation: Cell. 2013 Jul 18;154(2):452-64
references.pmid: 23870131
references.citation: Science. 2014 Nov 21;346(6212):1007-12
references.pmid: 25411453
references.citation: Nature. 2012 Sep 6;489(7414):57-74
references.pmid: 22955616
references.citation: Cell. 2006 Aug 25;126(4):663-76
references.pmid: 16904174
references.citation: Science. 2002 Aug 16;297(5584):1183-6
references.pmid: 12183631
references.citation: Genome Res. 2012 Sep;22(9):1813-31
references.pmid: 22955991
references.citation: Nat Rev Genet. 2009 Apr;10 (4):252-63
references.pmid: 19274049
references.citation: J Stem Cell Res Ther. 2013 May 4;3:null
references.pmid: 23885309
references.citation: J Biol Chem. 2013 Nov 15;288(46):33156-70
references.pmid: 24089523
references.citation: Nat Rev Genet. 2011 Apr;12 (4):277-82
references.pmid: 21386863
references.citation: Bull Math Biol. 2004 Mar;66(2):301-40
references.pmid: 14871568
references.citation: Cancer Cell. 2009 Nov 6;16(5):369-77
references.pmid: 19878869
references.citation: Am J Hum Genet. 2014 Apr 3;94(4):559-73
references.pmid: 24702953
references.citation: Nat Rev Mol Cell Biol. 2011 Jun 23;12 (7):453-9
references.pmid: 21697902
references.citation: PLoS Biol. 2015 Jul 07;13(7):e1002195
references.pmid: 26151137
references.citation: Science. 2007 Dec 21;318(5858):1917-20
references.pmid: 18029452
references.citation: Nature. 2003 Jul 10;424(6945):147-51
references.pmid: 12853946
references.citation: Nature. 2014 Nov 20;515(7527):355-64
references.pmid: 25409824
references.citation: Science. 1988 Oct 21;242(4877):405-11
references.pmid: 3175662
references.citation: Exp Cell Res. 2012 Nov 1;318(18):2365-76
references.pmid: 22814251
references.citation: Curr Biol. 2004 Sep 21;14(18):1650-6
references.pmid: 15380067
references.citation: Am J Hum Genet. 2007 Apr;80(4):800-4
references.pmid: 17357085
references.citation: Bioinformatics. 2013 Sep 15;29(18):2311-9
references.pmid: 23821649
references.citation: Cell Rep. 2013 May 30;3(5):1476-82
references.pmid: 23643537
references.citation: Biochim Biophys Acta. 2015 May;1849(5):469-83
references.pmid: 24933113
references.citation: Proc Natl Acad Sci U S A. 2003 Mar 4;100(5):2374-9
references.pmid: 12606710
references.citation: PLoS Genet. 2014 Dec 18;10(12):e1004890
references.pmid: 25521328
references.citation: Curr Biol. 2001 Jul 10;11(13):1044-9
references.pmid: 11470409
references.citation: Mol Cell Biol. 2004 Jan;24(1):294-305
references.pmid: 14673163
references.citation: Proc Natl Acad Sci U S A. 2013 May 7;110(19):7678-83
references.pmid: 23610421
references.citation: J Clin Invest. 2008 Sep;118(9):3065-74
references.pmid: 18725988
references.citation: Science. 2013 Feb 1;339(6119):584-7
references.pmid: 23372015
references.citation: Mol Cell Biol. 1999 Aug;19(8):5393-404
references.pmid: 10409730
references.citation: Br J Cancer. 2013 Jul 9;109(1):76-82
references.pmid: 23807161
references.citation: Biochim Biophys Acta. 2012 Jul;1819(7):657-66
references.pmid: 22484099
references.citation: Cell. 2012 Sep 28;151(1):68-79
references.pmid: 23021216
references.citation: Nucleic Acids Res. 2014 Feb;42(4):2224-34
references.pmid: 24288374
references.citation: Proteins. 2007 Jul 1;68(1):403-7
references.pmid: 17410582
references.citation: Cold Spring Harb Symp Quant Biol. 1961;26:389-401
references.pmid: 14475415
references.citation: Science. 2011 Jun 10;332(6035):1317-22
references.pmid: 21659604
references.citation: Mol Cell. 2009 Sep 24;35(6):741-53
references.pmid: 19782025
references.citation: Wiley Interdiscip Rev Dev Biol. 2015 Mar-Apr;4(2):59-84
references.pmid: 25704908
references.citation: EMBO J. 2006 Jun 21;25(12):2723-34
references.pmid: 16724113
references.citation: Biochem Soc Trans. 2010 Oct;38(5):1257-64
references.pmid: 20863295
references.citation: Nat Rev Genet. 2009 Mar;10(3):184-94
references.pmid: 19223927
references.citation: BMC Bioinformatics. 2009 Dec 30;10:450
references.pmid: 20042075
references.citation: Nucleic Acids Res. 2012 Jul;40(13):6353-66
references.pmid: 22457068
references.citation: Nat Genet. 2009 May;41(5):553-62
references.pmid: 19377474
references.citation: Biochim Biophys Acta. 2014 Dec;1839(12):1373-84
references.pmid: 24859457
references.citation: Proc Natl Acad Sci U S A. 2009 May 19;106(20):8204-8
references.pmid: 19420219
references.citation: Monogr Endocrinol. 1978;11:1-140
references.pmid: 109750
references.citation: Blood Cells Mol Dis. 2004 Jan-Feb;32(1):143-54
references.pmid: 14757430
references.citation: Proc Natl Acad Sci U S A. 2014 Jul 15;111(28):10185-90
references.pmid: 24946805
references.citation: Genes Dev. 2010 Sep 15;24(18):2013-8
references.pmid: 20801935
references.citation: Mol Cell Biol. 2006 Jul;26(13):4853-62
references.pmid: 16782874
references.citation: Cell. 1996 Jul 12;86(1):47-57
references.pmid: 8689686
references.citation: Trends Genet. 2010 Jan;26(1):21-8
references.pmid: 19944475
references.citation: Cell. 1988 Jul 1;54(1):83-93
references.pmid: 3383244
references.citation: Annu Rev Genet. 2000;34:77-137
references.pmid: 11092823
references.citation: Mol Cell. 2010 Oct 22;40(2):179-204
references.pmid: 20965415
references.citation: Eur J Biochem. 1997 Jun 15;246(3):581-601
references.pmid: 9219514
references.citation: Mol Cell. 2013 Mar 7;49(5):773-82
references.pmid: 23473598
references.citation: Health Technol Assess. 2015 Feb;19(11):1-138
references.pmid: 25671821