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Nucleic Acids Research Advance Access published online on October 15, 2008
Nucleic Acids Research, doi:10.1093/nar/gkn712
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© 2008 The Author(s) This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Gene regulation, Chromatin and Epigenetics

Analysis of regulatory network topology reveals functionally distinct classes of microRNAs

Xueping Yu1, Jimmy Lin1, Donald J. Zack1,2,3,4, Joshua T. Mendell4,5 and Jiang Qian1,*

1Wilmer Institute, 2Department of Molecular Biology and Genetics, 3Department of Neuroscience, 4McKusick-Nathans Institute of Genetic Medicine and 5Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA

*To whom correspondence should be addressed. Tel: 443 287 3882; Fax: 410 502 5382; Email: jiang.qian{at}jhmi.edu

Received June 11, 2008. Revised September 2, 2008. Accepted September 30, 2008.

MicroRNAs (miRNAs) negatively regulate the expression of target genes at the post-transcriptional level. Little is known about the crosstalk between miRNAs and transcription factors (TFs). Here we provide data suggesting that the interaction patterns between TFs and miRNAs can influence the biological functions of miRNAs. From this global survey, we find that a regulated feedback loop, in which two TFs regulate each other and one miRNA regulates both of the factors, is the most significantly overrepresented network motif. Mathematical modeling shows that the miRNA in this motif stabilizes the feedback loop to resist environmental perturbation, providing one mechanism to explain the robustness of developmental programs that is contributed by miRNAs. Furthermore, on the basis of a network motif profile analysis, we demonstrate the existence of two classes of miRNAs with distinct network topological properties. The first class of miRNAs is regulated by a large number of TFs, whereas the second is regulated by only a few TFs. The differential expression level of the two classes of miRNAs in embryonic developmental stages versus adult tissues suggests that the two classes may have fundamentally different biological functions. Our results demonstrate that the TFs and miRNAs extensively interact with each other and the biological functions of miRNAs may be wired in the regulatory network topology.


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