title: Genome-wide dissection of microRNA functions and cotargeting networks using gene set signatures.
abstract: MicroRNAs are emerging as important regulators of diverse biological processes and pathologies in animals and plants. Though hundreds of human microRNAs are known, only a few have known functions. Here, we predict human microRNA functions by using a new method that systematically assesses the statistical enrichment of several microRNA-targeting signatures in annotated gene sets such as signaling networks and protein complexes. Some of our top predictions are supported by published experiments, yet many are entirely new or provide mechanistic insights to known phenotypes. Our results indicate that coordinated microRNA targeting of closely connected genes is prevalent across pathways. We use the same method to infer which microRNAs regulate similar targets and provide the first genome-wide evidence of pervasive cotargeting, in which a handful of "hub" microRNAs are involved in a majority of cotargeting relationships. Our method and analyses pave the way to systematic discovery of microRNA functions.
authors.affiliation: Graduate Program in Biophysics, Harvard University, Cambridge, MA 02138, USA. jt08@post.harvard.edu
authors.forename: John S
authors.initials: JS
authors.lastname: Tsang
authors.forename: Margaret S
authors.initials: MS
authors.lastname: Ebert
authors.forename: Alexander
authors.initials: A
authors.lastname: van Oudenaarden
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000818:Animals; D006332:Cardiomegaly / Q000235:genetics / Q000503:physiopathology; D020869:Gene Expression Profiling; D053263:Gene Regulatory Networks; D006801:Humans; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D046912:Multiprotein Complexes; D015398:Signal Transduction / Q000235:genetics
chemical_list: D020413:3' Untranslated Regions; D035683:MicroRNAs; D046912:Multiprotein Complexes
references.citation: Gene Expr Patterns. 2009 Apr;9(4):193-9
references.pmid: 19135553
references.citation: Nat Cell Biol. 2009 Jun;11(6):705-16
references.pmid: 19465924
references.citation: Mol Cell Biol. 2007 Mar;27(6):2240-52
references.pmid: 17242205
references.citation: EMBO Rep. 2008 Jun;9(6):582-9
references.pmid: 18483486
references.citation: Genes Dev. 2008 Apr 1;22(7):894-907
references.pmid: 18381893
references.citation: Biochem Biophys Res Commun. 2008 Feb 22;366(4):922-6
references.pmid: 18086561
references.citation: Science. 2005 Dec 16;310(5755):1817-21
references.pmid: 16308420
references.citation: Cell. 2008 Apr 18;133(2):217-22
references.pmid: 18423194
references.citation: Nat Genet. 2005 May;37(5):495-500
references.pmid: 15806104
references.citation: Nat Genet. 2004 Oct;36(10):1090-8
references.pmid: 15448693
references.citation: Cell. 2007 Dec 14;131(6):1109-23
references.pmid: 18083101
references.citation: Nat Rev Genet. 2004 May;5(5):396-400
references.pmid: 15143321
references.citation: Cell. 2009 Jan 9;136(1):26-36
references.pmid: 19135886
references.citation: J Biol Chem. 2008 Oct 31;283(44):29897-903
references.pmid: 18708351
references.citation: Mol Cell. 2007 Jul 6;27(1):91-105
references.pmid: 17612493
references.citation: Genes Dev. 2008 Sep 15;22(18):2535-49
references.pmid: 18794350
references.citation: Genome Biol. 2008;9(8):R127
references.pmid: 18700987
references.citation: Science. 2007 Apr 27;316(5824):604-8
references.pmid: 17463289
references.citation: BMC Cancer. 2008 Sep 21;8:266
references.pmid: 18803879
references.citation: Proc Natl Acad Sci U S A. 2008 Mar 11;105(10):3903-8
references.pmid: 18308936
references.citation: Biochem Biophys Res Commun. 2003 Jun 13;305(4):806-10
references.pmid: 12767901
references.citation: Gene Expr Patterns. 2009 Feb;9(2):109-13
references.pmid: 18977315
references.citation: Semin Immunol. 2005 Apr;17(2):155-65
references.pmid: 15737576
references.citation: Cell Res. 2008 May;18(5):549-57
references.pmid: 18379589
references.citation: Nature. 2005 Dec 1;438(7068):685-9
references.pmid: 16258535
references.citation: Nat Genet. 2006 Jun;38 Suppl:S8-13
references.pmid: 16736023
references.citation: J Biol Chem. 2008 Nov 7;283(45):31079-86
references.pmid: 18790736
references.citation: Cell. 2008 Mar 7;132(5):875-86
references.pmid: 18329372
references.citation: Nat Rev Mol Cell Biol. 2006 Aug;7(8):589-600
references.pmid: 16936699
references.citation: Nat Genet. 2000 May;25(1):25-9
references.pmid: 10802651
references.citation: Mol Cell. 2007 Jun 8;26(5):745-52
references.pmid: 17540599
references.citation: Nat Neurosci. 2009 Apr;12(4):399-408
references.pmid: 19287386
references.citation: PLoS One. 2009 Jun 09;4(6):e5848
references.pmid: 19513126
references.citation: Hum Mutat. 2009 Mar;30(3):328-33
references.pmid: 19067360
references.citation: Nucleic Acids Res. 2008 Jan;36(Database issue):D154-8
references.pmid: 17991681
references.citation: J Biol Chem. 2009 Feb 27;284(9):5731-41
references.pmid: 19073608
references.citation: Cell Cycle. 2008 Mar 15;7(6):759-64
references.pmid: 18344688
references.citation: Biochem Biophys Res Commun. 2006 Oct 13;349(1):59-68
references.pmid: 16934749
references.citation: Cell Cycle. 2007 Jul 1;6(13):1586-93
references.pmid: 17554199
references.citation: N Engl J Med. 2005 Oct 27;353(17):1793-801
references.pmid: 16251535
references.citation: J Immunol. 2009 Apr 15;182(8):4994-5002
references.pmid: 19342679
references.citation: Cancer Res. 2007 Aug 15;67(16):7713-22
references.pmid: 17699775
references.citation: Mol Cell. 2007 Jun 8;26(5):731-43
references.pmid: 17540598
references.citation: Nature. 2008 Sep 4;455(7209):58-63
references.pmid: 18668040
references.citation: Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50
references.pmid: 16199517
references.citation: Nature. 2005 Jun 9;435(7043):834-8
references.pmid: 15944708
references.citation: Circ Res. 2007 Feb 16;100(3):416-24
references.pmid: 17234972
references.citation: Cancer Res. 2008 May 15;68(10):3566-72
references.pmid: 18483236
references.citation: Diabetes. 2009 May;58(5):1050-7
references.pmid: 19188425
references.citation: Cell. 2005 Jan 14;120(1):15-20
references.pmid: 15652477
references.citation: Cell. 2007 Apr 6;129(1):147-61
references.pmid: 17382377
references.citation: Nucleic Acids Res. 2008 Sep;36(16):5391-404
references.pmid: 18701644
references.citation: Annu Rev Neurosci. 2004;27:509-47
references.pmid: 15217342
references.citation: Nature. 2008 Feb 28;451(7182):1125-9
references.pmid: 18278031
references.citation: Nucleic Acids Res. 2008 Jan;36(Database issue):D646-50
references.pmid: 17965090
references.citation: Nat Cell Biol. 2008 May;10(5):593-601
references.pmid: 18376396
references.citation: Nat Med. 2008 Nov;14(11):1271-7
references.pmid: 18931683
references.citation: Annu Rev Cell Dev Biol. 2007;23:175-205
references.pmid: 17506695
references.citation: Oncogene. 2009 Jan 8;28(1):140-5
references.pmid: 18836483
references.citation: Nat Med. 2007 May;13(5):613-8
references.pmid: 17468766
references.citation: Proc Natl Acad Sci U S A. 2008 Sep 2;105(35):13027-32
references.pmid: 18723672
references.citation: Nature. 2007 Jun 28;447(7148):1130-4
references.pmid: 17554337
references.citation: BMC Bioinformatics. 2003 Jan 13;4:2
references.pmid: 12525261
references.citation: Proc Natl Acad Sci U S A. 2003 Aug 5;100(16):9440-5
references.pmid: 12883005
references.citation: J Biol Chem. 2008 May 30;283(22):14910-4
references.pmid: 18411277
references.citation: Nucleic Acids Res. 2000 Jan 1;28(1):27-30
references.pmid: 10592173
references.citation: Cancer Res. 2005 Jul 15;65(14):6029-33
references.pmid: 16024602
references.citation: Osteoarthritis Cartilage. 2009 Apr;17(4):464-72
references.pmid: 19008124
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: Proc Natl Acad Sci U S A. 2008 Sep 16;105(37):13906-11
references.pmid: 18784367
references.citation: PLoS One. 2009 Aug 28;4(8):e6816
references.pmid: 19714243
references.citation: Nature. 2008 Sep 4;455(7209):64-71
references.pmid: 18668037
references.citation: Proc Natl Acad Sci U S A. 2006 Aug 15;103(33):12481-6
references.pmid: 16885212
references.citation: J Biol Chem. 2009 Jun 5;284(23):15676-84
references.pmid: 19342382
references.citation: Genes Dev. 2007 Apr 1;21(7):744-9
references.pmid: 17403776