title: A C. elegans genome-scale microRNA network contains composite feedback motifs with high flux capacity.
abstract: MicroRNAs (miRNAs) and transcription factors (TFs) are primary metazoan gene regulators. Whereas much attention has focused on finding the targets of both miRNAs and TFs, the transcriptional networks that regulate miRNA expression remain largely unexplored. Here, we present the first genome-scale Caenorhabditis elegans miRNA regulatory network that contains experimentally mapped transcriptional TF --> miRNA interactions, as well as computationally predicted post-transcriptional miRNA --> TF interactions. We find that this integrated miRNA network contains 23 miRNA <--> TF composite feedback loops in which a TF that controls a miRNA is itself regulated by that same miRNA. By rigorous network randomizations, we show that such loops occur more frequently than expected by chance and, hence, constitute a genuine network motif. Interestingly, miRNAs and TFs in such loops are heavily regulated and regulate many targets. This "high flux capacity" suggests that loops provide a mechanism of high information flow for the coordinate and adaptable control of miRNA and TF target regulons.
authors.affiliation: Program in Gene Function and Expression, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
authors.forename: Natalia J
authors.initials: NJ
authors.lastname: Martinez
authors.forename: Maria C
authors.initials: MC
authors.lastname: Ow
authors.forename: M Inmaculada
authors.initials: MI
authors.lastname: Barrasa
authors.forename: Molly
authors.initials: M
authors.lastname: Hammell
authors.forename: Reynaldo
authors.initials: R
authors.lastname: Sequerra
authors.forename: Lynn
authors.initials: L
authors.lastname: Doucette-Stamm
authors.forename: Frederick P
authors.initials: FP
authors.lastname: Roth
authors.forename: Victor R
authors.initials: VR
authors.lastname: Ambros
authors.forename: Albertha J M
authors.initials: AJ
authors.lastname: Walhout
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D017173:Caenorhabditis elegans / Q000196:embryology / Q000235:genetics*; D016678:Genome; D035683:MicroRNAs / Q000235:genetics*; D016133:Polymerase Chain Reaction; D014158:Transcription, Genetic
chemical_list: D035683:MicroRNAs
references.citation: Nat Methods. 2008 Sep;5(9):813-9
references.pmid: 19160516
references.citation: Cell. 2006 Dec 15;127(6):1193-207
references.pmid: 17174894
references.citation: Science. 2000 Jan 7;287(5450):116-22
references.pmid: 10615043
references.citation: Proc Natl Acad Sci U S A. 2004 Apr 20;101(16):5934-9
references.pmid: 15079056
references.citation: Cell. 2006 Jun 16;125(6):1193-205
references.pmid: 16777607
references.citation: Methods Enzymol. 2000;328:575-92
references.pmid: 11075367
references.citation: RNA. 2004 Oct;10(10):1507-17
references.pmid: 15383676
references.citation: Cell. 2005 Dec 2;123(5):819-31
references.pmid: 16325577
references.citation: Genome Res. 2006 Dec;16(12):1445-54
references.pmid: 17053092
references.citation: Genes Dev. 2003 Apr 15;17(8):991-1008
references.pmid: 12672692
references.citation: Nat Rev Genet. 2004 May;5(5):396-400
references.pmid: 15143321
references.citation: Development. 1994 Sep;120(9):2359-68
references.pmid: 7956818
references.citation: CSH Protoc. 2006 Oct 01;2006(5):
references.pmid: 22485967
references.citation: Genome Res. 2004 Oct;14(10B):2093-101
references.pmid: 15489331
references.citation: Curr Biol. 2003 May 13;13(10):807-18
references.pmid: 12747828
references.citation: Cell. 2005 Sep 23;122(6):947-56
references.pmid: 16153702
references.citation: Dev Cell. 2005 Sep;9(3):415-22
references.pmid: 16139229
references.citation: Nat Rev Genet. 2007 Jun;8(6):450-61
references.pmid: 17510665
references.citation: Genome Biol. 2005;6(13):R110
references.pmid: 16420670
references.citation: Development. 2003 Apr;130(8):1621-34
references.pmid: 12620986
references.citation: Cell. 2008 May 30;133(5):903-15
references.pmid: 18510933
references.citation: Cell. 2005 Mar 11;120(5):635-47
references.pmid: 15766527
references.citation: Genes Dev. 2007 Feb 15;21(4):436-49
references.pmid: 17322403
references.citation: Nat Genet. 2002 May;31(1):64-8
references.pmid: 11967538
references.citation: Nat Rev Mol Cell Biol. 2005 May;6(5):376-85
references.pmid: 15852042
references.citation: Genome Res. 2007 Jul;17(7):1061-71
references.pmid: 17513831
references.citation: Dev Biol. 2003 Jul 15;259(2):364-79
references.pmid: 12871707
references.citation: PLoS Genet. 2007 Dec;3(12):e215
references.pmid: 18085825
references.citation: Genes Dev. 2007 Sep 15;21(18):2277-82
references.pmid: 17761811
references.citation: Cell. 1993 Dec 3;75(5):843-54
references.pmid: 8252621
references.citation: BMC Genomics. 2007 Jan 18;8:21
references.pmid: 17233892
references.citation: Cell. 1993 Dec 3;75(5):855-62
references.pmid: 8252622
references.citation: Nat Genet. 2006 Jun;38 Suppl:S20-4
references.pmid: 16736020
references.citation: Genes Dev. 1997 Oct 15;11(20):2679-90
references.pmid: 9334330
references.citation: RNA. 2004 Oct;10(10):1586-94
references.pmid: 15337850
references.citation: Nat Methods. 2007 Aug;4(8):659-64
references.pmid: 17589517
references.citation: J Biol Chem. 2007 Jan 26;282(4):2135-43
references.pmid: 17135249
references.citation: Dev Biol. 2004 Jan 15;265(2):478-90
references.pmid: 14732406
references.citation: Proc Natl Acad Sci U S A. 2005 Aug 30;102(35):12449-54
references.pmid: 16099833
references.citation: Genome Res. 2003 Nov;13(11):2498-504
references.pmid: 14597658
references.citation: RNA. 2005 Mar;11(3):241-7
references.pmid: 15701730
references.citation: BMC Genomics. 2007 Jan 23;8:27
references.pmid: 17244357
references.citation: Nature. 2004 Aug 12;430(7001):785-9
references.pmid: 15306811
references.citation: Proc Natl Acad Sci U S A. 2006 Feb 21;103(8):2746-51
references.pmid: 16477010
references.citation: Science. 2007 Aug 31;317(5842):1220-4
references.pmid: 17761882
references.citation: Genetics. 1994 Oct;138(2):303-16
references.pmid: 7828815
references.citation: EMBO J. 2004 Oct 13;23(20):4051-60
references.pmid: 15372072
references.citation: Nature. 2000 Jan 20;403(6767):339-42
references.pmid: 10659857
references.citation: Nature. 2000 Oct 5;407(6804):651-4
references.pmid: 11034217
references.citation: Cell. 2005 Jan 14;120(1):15-20
references.pmid: 15652477
references.citation: PLoS Comput Biol. 2007 Jul;3(7):e131
references.pmid: 17630826
references.citation: Science. 2002 Oct 25;298(5594):840-3
references.pmid: 12399594
references.citation: Development. 1999 Jan;126(1):97-107
references.pmid: 9834189
references.citation: Genes Dev. 2007 Aug 1;21(15):1882-94
references.pmid: 17652178
references.citation: Nature. 2001 May 3;411(6833):41-2
references.pmid: 11333967
references.citation: Curr Biol. 2006 Mar 7;16(5):460-71
references.pmid: 16458514
references.citation: Cell. 2005 Dec 16;123(6):1133-46
references.pmid: 16337999
references.citation: Mol Cell. 2007 Jun 8;26(5):753-67
references.pmid: 17560377
references.citation: Nucleic Acids Res. 2006 Jan 1;34(Database issue):D140-4
references.pmid: 16381832
references.citation: Cell. 2004 Jan 23;116(2):281-97
references.pmid: 14744438
references.citation: Nat Methods. 2006 Nov;3(11):881-6
references.pmid: 17060911
references.citation: Genes Dev. 2008 Sep 15;22(18):2520-34
references.pmid: 18794349
references.citation: Science. 2005 Dec 16;310(5755):1817-21
references.pmid: 16308420
references.citation: Genome Biol. 2003;5(1):R1
references.pmid: 14709173
references.citation: Science. 2002 Oct 25;298(5594):824-7
references.pmid: 12399590
references.citation: Nature. 2004 Sep 2;431(7004):99-104
references.pmid: 15343339
references.citation: Phys Rev E Stat Nonlin Soft Matter Phys. 2003 Aug;68(2 Pt 2):026127
references.pmid: 14525069
references.citation: Bioinformatics. 2004 Jul 22;20(11):1746-58
references.pmid: 15001476
references.citation: Science. 2005 Nov 25;310(5752):1330-3
references.pmid: 16239437