Weak seed-pairing stability and high target-site abundance decrease the proficiency of lsy-6 and other microRNAs

被引:751
作者
Garcia, David M. [1 ,2 ,3 ]
Baek, Daehyun [1 ,2 ,3 ,4 ,5 ]
Shin, Chanseok [1 ,2 ,3 ,6 ]
Bell, George W. [1 ]
Grimson, Andrew [1 ,2 ,3 ]
Bartel, David P. [1 ,2 ,3 ]
机构
[1] Whitehead Inst Biomed Res, Cambridge, MA 02142 USA
[2] MIT, Howard Hughes Med Inst, Cambridge, MA USA
[3] MIT, Dept Biol, Cambridge, MA USA
[4] Seoul Natl Univ, Sch Biol Sci, Seoul, South Korea
[5] Seoul Natl Univ, Bioinformat Inst, Seoul, South Korea
[6] Seoul Natl Univ, Dept Agr Biotechnol, Seoul, South Korea
基金
美国国家卫生研究院;
关键词
MAMMALIAN MICRORNAS; GENE-EXPRESSION; DETERMINANTS; RECOGNITION; IMPACT; BIOGENESIS; PREDICTION; MECHANISM; SIRNAS; RNAS;
D O I
10.1038/nsmb.2115
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Most metazoan microRNAs (miRNAs) target many genes for repression, but the nematode lsy-6 miRNA is much less proficient. Here we show that the low proficiency of lsy-6 can be recapitulated in HeLa cells and that miR-23, a mammalian miRNA, also has low proficiency in these cells. Reporter results and array data indicate two properties of these miRNAs that impart low proficiency: their weak predicted seed-pairing stability (SPS) and their high target-site abundance (TA). These two properties also explain differential propensities of small interfering RNAs (siRNAs) to repress unintended targets. Using these insights, we expand the TargetScan tool for quantitatively predicting miRNA regulation (and siRNA off-targeting) to model differential miRNA (and siRNA) proficiencies, thereby improving prediction performance. We propose that siRNAs designed to have both weaker SPS and higher TA will have fewer off-targets without compromised on-target activity.
引用
收藏
页码:1139 / U75
页数:9
相关论文
共 55 条
[1]   The functions of animal microRNAs [J].
Ambros, V .
NATURE, 2004, 431 (7006) :350-355
[2]   Molecular basis for target RNA recognition and cleavage by human RISC [J].
Ameres, Stefan Ludwig ;
Martinez, Javier ;
Schroeder, Renee .
CELL, 2007, 130 (01) :101-112
[3]   Experimental validation of the importance of seed complement frequency to siRNA specificity [J].
Anderson, Emily M. ;
Birmingham, Amanda ;
Baskerville, Scott ;
Reynolds, Angela ;
Maksimova, Elena ;
Leake, Devin ;
Fedorov, Yuriy ;
Karpilow, Jon ;
Khvorova, Anastasia .
RNA, 2008, 14 (05) :853-861
[4]   Target mRNA abundance dilutes microRNA and siRNA activity [J].
Arvey, Aaron ;
Larsson, Erik ;
Sander, Chris ;
Leslie, Christina S. ;
Marks, Debora S. .
MOLECULAR SYSTEMS BIOLOGY, 2010, 6
[5]   The impact of microRNAs on protein output [J].
Baek, Daehyun ;
Villen, Judit ;
Shin, Chanseok ;
Camargo, Fernando D. ;
Gygi, Steven P. ;
Bartel, David P. .
NATURE, 2008, 455 (7209) :64-U38
[6]   MicroRNAs: Target Recognition and Regulatory Functions [J].
Bartel, David P. .
CELL, 2009, 136 (02) :215-233
[7]   Micromanagers of gene expression: the potentially widespread influence of metazoan microRNAs [J].
Bartel, DP ;
Chen, CZ .
NATURE REVIEWS GENETICS, 2004, 5 (05) :396-400
[8]   MicroRNAs: Genomics, biogenesis, mechanism, and function (Reprinted from Cell, vol 116, pg 281-297, 2004) [J].
Bartel, David P. .
CELL, 2007, 131 (04) :11-29
[9]   DNA methylation patterns and epigenetic memory [J].
Bird, A .
GENES & DEVELOPMENT, 2002, 16 (01) :6-21
[10]   Principles of MicroRNA-target recognition [J].
Brennecke, J ;
Stark, A ;
Russell, RB ;
Cohen, SM .
PLOS BIOLOGY, 2005, 3 (03) :404-418