Target mRNA abundance dilutes microRNA and siRNA activity.
Post-transcriptional regulation by microRNAs and siRNAs depends not only on characteristics of individual binding sites in target mRNA molecules, but also on system-level properties such as overall molecular concentrations. We hypothesize that an intracellular pool of microRNAs/siRNAs faced with a larger number of available predicted target transcripts will downregulate each individual target gene to a lesser extent. To test this hypothesis, we analyzed mRNA expression change from 178 microRNA and siRNA transfection experiments in two cell lines. We find that downregulation of particular genes mediated by microRNAs and siRNAs indeed varies with the total concentration of available target transcripts. We conclude that to interpret and design experiments involving gene regulation by small RNAs, global properties, such as target mRNA abundance, need to be considered in addition to local determinants. We propose that analysis of microRNA/siRNA targeting would benefit from a more quantitative definition, rather than simple categorization of genes as 'target' or 'not a target.' Our results are important for understanding microRNA regulation and may also have implications for siRNA design and small RNA therapeutics.
Arvey
Aaron
A
Computational Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
Larsson
Erik
E
Sander
Chris
C
Leslie
Christina S
CS
Marks
Debora S
DS
D015536:Down-Regulation; D006367:HeLa Cells; D006801:Humans; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008957:Models, Genetic; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
D035683:MicroRNAs; D012333:RNA, Messenger; D034741:RNA, Small Interfering
Nat Methods. 2008 Sep;5(9):813-9
19160516
Nature. 2005 Feb 17;433(7027):769-73
15685193
RNA. 2008 May;14(5):853-61
18367722
Mol Cell. 2007 Jul 6;27(1):91-105
17612493
Nat Struct Mol Biol. 2004 Jul;11(7):599-606
15170178
Nat Genet. 2007 Aug;39(8):1033-7
17643101
PLoS Comput Biol. 2009 Dec;5(12):e1000598
20011106
PLoS Biol. 2004 Nov;2(11):e363
15502875
Biotechniques. 2008 Jul;45(1):81-94
18611170
Nucleic Acids Res. 2010 Jan;38(1):239-52
19850724
Nat Methods. 2007 Apr;4(4):337-44
17351622
Mol Cell Biol. 2007 Mar;27(6):2240-52
17242205
Nat Biotechnol. 2009 Jun;27(6):549-55
19465925
Nature. 2008 Sep 4;455(7209):58-63
18668040
RNA. 2006 Jul;12(7):1179-87
16682560
Nat Rev Genet. 2008 Feb;9(2):102-14
18197166
Cell. 2005 Jan 14;120(1):15-20
15652477
Nat Methods. 2008 Jul;5(7):621-8
18516045
Cell. 2003 Dec 26;115(7):787-98
14697198
Genome Biol. 2006;7 Suppl 1:S12.1-14
16925834
Nature. 2007 Jun 28;447(7148):1130-4
17554337
Cell. 2005 Dec 16;123(6):1133-46
16337999
PLoS Genet. 2006 Sep 8;2(9):e140
16965178
PLoS Biol. 2003 Dec;1(3):E60
14691535
Science. 2005 Dec 16;310(5755):1817-21
16308420
Genome Biol. 2003;5(1):R1
14709173
Nat Methods. 2007 Sep;4(9):721-6
17694064