Susceptibility of the human pathways graphs to fragmentation by small sets of microRNAs.
BACKGROUND
MicroRNAs (miRNAs) are short sequences that negatively regulate gene expression. The current understanding of miRNA and their corresponding mRNA targets is primarily based on prediction programs. This study addresses the potential of a coordinated action of miRNAs to manipulate the human pathways. Specifically, we investigate the effectiveness of disrupting the topology of human pathway graphs through a regulation by miRNAs.


RESULTS
From a set of miRNA candidates that is associated with a pathway, an exhaustive search for all possible doubles and triplets (coined miR-Duo, miR-Trios) is performed. The impact of each miR-combination on the connectivity of the pathway graph was quantified. About 170 human pathways were tested, and the miR-Duos and miR-Trios were scored for their ability to disrupt these pathway graphs. We show that 75% of all pathways are effectively disconnected by a small number of pathway-specific miR-Trios. Only 15% of the human pathways are resistant to fragmentation by miR-Duos or miR-Trios. Significantly, the combination of the most effective miR-Trios is unique. Thus, a specific regulation of a pathway within the cell is guaranteed. The impact of the selected miR-Duo/Trios on various diseases is discussed.


CONCLUSIONS
The methodology presented shows that the synthesis of the topology of a network with a detailed understanding of the miRNAs' regulation is useful in exposing critical nodes of the network. We propose the miR-Trio approach as a basis for rationally designed perturbation experiments.


BACKGROUND
michall@cc.huji.ac.il


BACKGROUND
Supplementary data are available at Bioinformatics online.
School of Computer Science and Engineering, Institute of Life Sciences, Sudarsky Center for Computational Biology, The Hebrew University of Jerusalem, Jerusalem 91904, Israel.
Guy
G
Naamati
Yitzhak
Y
Friedman
Ohad
O
Balaga
Michal
M
Linial
D000465:Algorithms; D019295:Computational Biology / Q000379:methods*; D015870:Gene Expression; D053263:Gene Regulatory Networks; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics
D035683:MicroRNAs; D012333:RNA, Messenger