Identification of phylogenetically conserved microRNA cis-regulatory elements across 12 Drosophila species

MOTIVATION MicroRNAs are a class of endogenous small RNAs that play regulatory roles. Intergenic miRNAs are believed to be transcribed independently, but the transcriptional control of these crucial regulators is still poorly understood. RESULTS In this work, phylogenetic footprinting is used to identify conserved cis-regulatory elements (CCEs) surrounding intergenic miRNAs in Drosophila. With a two-step strategy that takes advantage of both alignment-based and motif-based methods, we identified CCEs that are conserved across the 12 fly species. When compared with TRANSFAC database, these CCEs are significantly enriched in known transcription factor binding sites (TFBSs). Moreover, several TFs that play essential roles in Drosophila development (e.g. Adf-1, Abd-B, Sd, Prd, Ubx, Zen and En) are found to be preferentially regulating the miRNA genes. Further analysis revealed many over-represented cis-regulatory modules (CRMs) composed of multiple known TFBSs, motif pairs with significant distance constraints and a number of novel motifs, many of which preferentially occur near the transcription start site of protein-coding genes. Additionally, a number of putative miRNA-TF regulatory feedback loops were also detected. AVAILABILITY Supplementary Material and the Perl scripts performing two-step phylogenetic footprinting are available at http://bioinfo.au.tsinghua.edu.cn/member/xwwang/mircisreg

[1]  D. Guhathakurta,et al.  Computational identification of transcriptional regulatory elements in DNA sequence , 2006, Nucleic acids research.

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

[3]  Shane T. Jensen,et al.  MicroRNA promoter element discovery in Arabidopsis. , 2006, RNA.

[4]  Sanghyuk Lee,et al.  MicroRNA genes are transcribed by RNA polymerase II , 2004, The EMBO journal.

[5]  Xueping Yu,et al.  Genome-wide prediction and characterization of interactions between transcription factors in Saccharomyces cerevisiae , 2006, Nucleic acids research.

[6]  Melanie A. Huntley,et al.  Evolution of genes and genomes on the Drosophila phylogeny , 2007, Nature.

[7]  Lior Pachter,et al.  Whole-genome alignments and polytopes for comparative genomics , 2006 .

[8]  Michael Q. Zhang,et al.  BMC Bioinformatics Methodology article Statistical significance of cis-regulatory modules , 2007 .

[9]  Mathieu Blanchette,et al.  FootPrinter3: phylogenetic footprinting in partially alignable sequences , 2006, Nucleic Acids Res..

[10]  Yong Zhao,et al.  Serum response factor regulates a muscle-specific microRNA that targets Hand2 during cardiogenesis , 2005, Nature.

[11]  V. Ambros,et al.  Mesodermally expressed Drosophila microRNA-1 is regulated by Twist and is required in muscles during larval growth. , 2005, Genes & development.

[12]  Ziheng Yang,et al.  PAML: a program package for phylogenetic analysis by maximum likelihood , 1997, Comput. Appl. Biosci..

[13]  D. Zack,et al.  Computational analysis of tissue-specific combinatorial gene regulation: predicting interaction between transcription factors in human tissues , 2006, Nucleic acids research.

[14]  Oliver Hobert,et al.  MicroRNAs acting in a double-negative feedback loop to control a neuronal cell fate decision. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[15]  Martin Fussenegger,et al.  Impact of RNA interference on gene networks. , 2006, Metabolic engineering.

[16]  Xin Chen,et al.  The TRANSFAC system on gene expression regulation , 2001, Nucleic Acids Res..

[17]  M. Levine,et al.  Spatial regulation of microRNA gene expression in the Drosophila embryo. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[18]  Fei Li,et al.  MicroRNA identification based on sequence and structure alignment , 2005, Bioinform..

[19]  M. Goodman,et al.  Embryonic epsilon and gamma globin genes of a prosimian primate (Galago crassicaudatus). Nucleotide and amino acid sequences, developmental regulation and phylogenetic footprints. , 1988, Journal of molecular biology.

[20]  A. van Oudenaarden,et al.  MicroRNA-mediated feedback and feedforward loops are recurrent network motifs in mammals. , 2007, Molecular cell.

[21]  Kathryn A. O’Donnell,et al.  c-Myc-regulated microRNAs modulate E2F1 expression , 2005, Nature.

[22]  Weixiong Zhang,et al.  Characterization and Identification of MicroRNA Core Promoters in Four Model Species , 2007, PLoS Comput. Biol..

[23]  M. Blanchette,et al.  Discovery of regulatory elements by a computational method for phylogenetic footprinting. , 2002, Genome research.

[24]  G. Rubin,et al.  Exploiting transcription factor binding site clustering to identify cis-regulatory modules involved in pattern formation in the Drosophila genome , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[25]  R. Tjian,et al.  Adf-1 Is a Nonmodular Transcription Factor That Contains a TAF-Binding Myb-Like Motif , 1998, Molecular and Cellular Biology.

[26]  G. Hannon,et al.  Control of translation and mRNA degradation by miRNAs and siRNAs. , 2006, Genes & development.

[27]  David A. Nix,et al.  Large-Scale Turnover of Functional Transcription Factor Binding Sites in Drosophila , 2006, PLoS Comput. Biol..

[28]  Alessandro Fatica,et al.  A Minicircuitry Comprised of MicroRNA-223 and Transcription Factors NFI-A and C/EBPα Regulates Human Granulopoiesis , 2005, Cell.

[29]  Zhihua Li,et al.  Regulatory Circuit of Human MicroRNA Biogenesis , 2007, PLoS Comput. Biol..

[30]  C. Burge,et al.  Patterns of flanking sequence conservation and a characteristic upstream motif for microRNA gene identification. , 2004, RNA.

[31]  H. Kishino,et al.  Dating of the human-ape splitting by a molecular clock of mitochondrial DNA , 2005, Journal of Molecular Evolution.

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

[33]  Yu Wang,et al.  Significant sequence similarities in promoters and precursors of Arabidopsis thaliana non-conserved microRNAs , 2006, Bioinform..

[34]  B. Cullen,et al.  Human microRNAs are processed from capped, polyadenylated transcripts that can also function as mRNAs. , 2004, RNA.

[35]  N. Rajewsky,et al.  The evolution of gene regulation by transcription factors and microRNAs , 2007, Nature Reviews Genetics.

[36]  Casey M. Bergman,et al.  Identifying cis-regulatory modules by combining comparative and compositional analysis of DNA , 2006, Bioinform..

[37]  Oliver Hobert,et al.  Early Embryonic Programming of Neuronal Left/Right Asymmetry in C. elegans , 2006, Current Biology.

[38]  S. Salzberg,et al.  Computational identification of developmental enhancers: conservation and function of transcription factor binding-site clusters in Drosophila melanogaster and Drosophila pseudoobscura , 2004, Genome Biology.

[39]  Jing Chen,et al.  GenomeTrafac: a whole genome resource for the detection of transcription factor binding site clusters associated with conventional and microRNA encoding genes conserved between mouse and human gene orthologs , 2006, Nucleic Acids Res..

[40]  Vincent De Guire,et al.  An E2F/miR-20a Autoregulatory Feedback Loop* , 2007, Journal of Biological Chemistry.

[41]  D. Haussler,et al.  Human-mouse alignments with BLASTZ. , 2003, Genome research.

[42]  Oliver Hobert,et al.  MicroRNAs act sequentially and asymmetrically to control chemosensory laterality in the nematode , 2004, Nature.

[43]  Lior Pachter,et al.  MAVID: constrained ancestral alignment of multiple sequences. , 2003, Genome research.

[44]  Zhe Han,et al.  MicroRNA1 influences cardiac differentiation in Drosophila and regulates Notch signaling. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

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

[46]  B. Davidson,et al.  RNA polymerase III transcribes human microRNAs , 2006, Nature Structural &Molecular Biology.

[47]  Xin Li,et al.  A microRNA Mediates EGF Receptor Signaling and Promotes Photoreceptor Differentiation in the Drosophila Eye , 2005, Cell.

[48]  Martin Tompa,et al.  Discovery of regulatory elements in vertebrates through comparative genomics , 2005, Nature Biotechnology.

[49]  Yoko Fukuda,et al.  An Evolutionarily Conserved Mechanism for MicroRNA-223 Expression Revealed by MicroRNA Gene Profiling , 2007, Cell.

[50]  Mathieu Blanchette,et al.  FootPrinter: a program designed for phylogenetic footprinting , 2003, Nucleic Acids Res..

[51]  M. Goodman,et al.  Embryonic ε and γ globin genes of a prosimian primate (Galago crassicaudatus): Nucleotide and amino acid sequences, developmental regulation and phylogenetic footprints , 1988 .