MicroRNAs preferentially target the genes with high transcriptional regulation complexity.

Over the past few years, microRNAs (miRNAs) have emerged as a new prominent class of gene regulatory factors that negatively regulate expression of approximately one-third of the genes in animal genomes at post-transcriptional level. However, it is still unclear why some genes are regulated by miRNAs but others are not, i.e. what principles govern miRNA regulation in animal genomes. In this study, we systematically analyzed the relationship between transcription factors (TFs) and miRNAs in gene regulation. We found that the genes with more TF-binding sites have a higher probability of being targeted by miRNAs and have more miRNA-binding sites on average. This observation reveals that the genes with higher cis-regulation complexity are more coordinately regulated by TFs at the transcriptional level and by miRNAs at the post-transcriptional level. This is a potentially novel discovery of mechanism for coordinated regulation of gene expression. Gene ontology analysis further demonstrated that such coordinated regulation is more popular in the developmental genes.

[1]  Pei-shan Wu,et al.  Biochemical and Biophysical Research Communications , 1960, Nature.

[2]  C. Burge,et al.  Conserved Seed Pairing, Often Flanked by Adenosines, Indicates that Thousands of Human Genes are MicroRNA Targets , 2005, Cell.

[3]  T. Tuschl,et al.  Mechanisms of gene silencing by double-stranded RNA , 2004, Nature.

[4]  G. Hannon,et al.  RNase III enzymes and the initiation of gene silencing , 2004, Nature Structural &Molecular Biology.

[5]  Anton J. Enright,et al.  Human MicroRNA Targets , 2004, PLoS biology.

[6]  C. Lawrence,et al.  Human-mouse genome comparisons to locate regulatory sites , 2000, Nature Genetics.

[7]  Georg Haberer,et al.  Transcriptional Similarities, Dissimilarities, and Conservation of cis-Elements in Duplicated Genes of Arabidopsis1[w] , 2004, Plant Physiology.

[8]  Sean R. Eddy,et al.  Rfam: annotating non-coding RNAs in complete genomes , 2004, Nucleic Acids Res..

[9]  Sandya Liyanarachchi,et al.  Genome-wide analysis of core promoter elements from conserved human and mouse orthologous pairs , 2006, BMC Bioinformatics.

[10]  R. Russell,et al.  Principles of MicroRNA–Target Recognition , 2005, PLoS biology.

[11]  N. Rajewsky microRNA target predictions in animals , 2006, Nature Genetics.

[12]  C. Burge,et al.  The Widespread Impact of Mammalian MicroRNAs on mRNA Repression and Evolution , 2005, Science.

[13]  Anton J. Enright,et al.  MicroRNA targets in Drosophila , 2003, Genome Biology.

[14]  N. Rajewsky,et al.  Silencing of microRNAs in vivo with ‘antagomirs’ , 2005, Nature.

[15]  K. Gunsalus,et al.  Combinatorial microRNA target predictions , 2005, Nature Genetics.

[16]  Edwin Wang,et al.  Global analysis of microRNA target gene expression reveals that miRNA targets are lower expressed in mature mouse and Drosophila tissues than in the embryos , 2006, Nucleic acids research.

[17]  D. Bartel MicroRNAs Genomics, Biogenesis, Mechanism, and Function , 2004, Cell.

[18]  Nicola J. Rinaldi,et al.  Transcriptional regulatory code of a eukaryotic genome , 2004, Nature.

[19]  T. Speed,et al.  GOstat: find statistically overrepresented Gene Ontologies within a group of genes. , 2004, Bioinformatics.

[20]  S. Hammond,et al.  MicroRNAs as oncogenes. , 2006, Current opinion in genetics & development.

[21]  Cristian I. Castillo-Davis,et al.  cis-Regulatory and protein evolution in orthologous and duplicate genes. , 2004, Genome research.

[22]  Christoph Dieterich,et al.  Ab initio identification of putative human transcription factor binding sites by comparative genomics , 2005, BMC Bioinformatics.

[23]  Megan F. Cole,et al.  Core Transcriptional Regulatory Circuitry in Human Embryonic Stem Cells , 2005, Cell.

[24]  V. Kim MicroRNA biogenesis: coordinated cropping and dicing , 2005, Nature Reviews Molecular Cell Biology.

[25]  J. Castle,et al.  Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs , 2005, Nature.

[26]  X. Gu,et al.  Expression divergence between duplicate genes. , 2005, Trends in genetics : TIG.

[27]  Sin Lam Tan,et al.  Computational method for discovery of estrogen responsive genes. , 2004, Nucleic acids research.

[28]  N. Rajewsky,et al.  Cell-type-specific signatures of microRNAs on target mRNA expression. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[29]  Julius Brennecke,et al.  Identification of Drosophila MicroRNA Targets , 2003, PLoS biology.

[30]  K. Lindblad-Toh,et al.  Systematic discovery of regulatory motifs in human promoters and 3′ UTRs by comparison of several mammals , 2005, Nature.

[31]  A. Hatzigeorgiou,et al.  A combined computational-experimental approach predicts human microRNA targets. , 2004, Genes & development.

[32]  R. Russell,et al.  Animal MicroRNAs Confer Robustness to Gene Expression and Have a Significant Impact on 3′UTR Evolution , 2005, Cell.

[33]  Michael Q. Zhang,et al.  DNA motifs in human and mouse proximal promoters predict tissue-specific expression. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[34]  Q. Cui,et al.  Principles of microRNA regulation of a human cellular signaling network , 2006, Molecular systems biology.

[35]  Ting Wang,et al.  Identifying the conserved network of cis-regulatory sites of a eukaryotic genome. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[36]  Satoru Miyano,et al.  Combining microarrays and biological knowledge for estimating gene networks via Bayesian networks , 2003, Computational Systems Bioinformatics. CSB2003. Proceedings of the 2003 IEEE Bioinformatics Conference. CSB2003.

[37]  Xun Gu,et al.  How much expression divergence after yeast gene duplication could be explained by regulatory motif evolution? , 2004, Trends in genetics : TIG.

[38]  V. Ambros The functions of animal microRNAs , 2004, Nature.

[39]  Inna Dubchak,et al.  Dissimilatory Metabolism of Nitrogen Oxides in Bacteria: Comparative Reconstruction of Transcriptional Networks , 2005, PLoS Comput. Biol..

[40]  B. Cullen Transcription and processing of human microRNA precursors. , 2004, Molecular cell.