Finding microRNA regulatory modules in human genome using rule induction

Background:MicroRNAs (miRNAs) are a class of small non-coding RNA molecules (20–24 nt), which are believed to participate in repression of gene expression. They play important roles in several biological processes (e.g. cell death and cell growth). Both experimental and computational approaches have been used to determine the function of miRNAs in cellular processes. Most efforts have concentrated on identification of miRNAs and their target genes. However, understanding the regulatory mechanism of miRNAs in the gene regulatory network is also essential to the discovery of functions of miRNAs in complex cellular systems. To understand the regulatory mechanism of miRNAs in complex cellular systems, we need to identify the functional modules involved in complex interactions between miRNAs and their target genes.Results:We propose a rule-based learning method to identify groups of miRNAs and target genes that are believed to participate cooperatively in the post-transcriptional gene regulation, so-called miRNA regulatory modules (MRMs). Applying our method to human genes and miRNAs, we found 79 MRMs. The MRMs are produced from multiple information sources, including miRNA-target binding information, gene expression and miRNA expression profiles. Analysis of two first MRMs shows that these MRMs consist of highly-related miRNAs and their target genes with respect to biological processes.Conclusion:The MRMs found by our method have high correlation in expression patterns of miRNAs as well as mRNAs. The mRNAs included in the same module shared similar biological functions, indicating the ability of our method to detect functionality-related genes. Moreover, review of the literature reveals that miRNAs in a module are involved in several types of human cancer.

[1]  Peng-Hui Wang,et al.  Altered Glycosylation in Cancer: Sialic Acids and Sialyltransferases , 2005 .

[2]  Peter A. Flach,et al.  Subgroup Discovery with CN2-SD , 2004, J. Mach. Learn. Res..

[3]  George P Cobb,et al.  microRNAs as oncogenes and tumor suppressors. , 2007, Developmental biology.

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

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

[6]  Y. Akao,et al.  MicroRNAs 143 and 145 are possible common onco-microRNAs in human cancers. , 2006, Oncology reports.

[7]  A. Ullrich,et al.  Molecular Portrait of Human Kidney Carcinomas: The cDNA Microarray Profiling of Kinases and Phosphatases Involved in the Cell Signaling Control , 2002, Molecular Biology.

[8]  R. Stephens,et al.  Unique microRNA molecular profiles in lung cancer diagnosis and prognosis. , 2006, Cancer cell.

[9]  Kristin C. Gunsalus,et al.  microRNA Target Predictions across Seven Drosophila Species and Comparison to Mammalian Targets , 2005, PLoS Comput. Biol..

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

[11]  James R. Brown,et al.  A computational view of microRNAs and their targets. , 2005, Drug discovery today.

[12]  T. Dalmay,et al.  MicroRNAs and cancer , 2008, Journal of internal medicine.

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

[14]  Chang-Zheng Chen,et al.  MicroRNAs as oncogenes and tumor suppressors. , 2005, The New England journal of medicine.

[15]  Lin He,et al.  MicroRNAs: small RNAs with a big role in gene regulation , 2004, Nature Reviews Genetics.

[16]  Stijn van Dongen,et al.  miRBase: microRNA sequences, targets and gene nomenclature , 2005, Nucleic Acids Res..

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

[18]  Ron Y. Pinter,et al.  A High-Throughput Approach for Associating microRNAs with Their Activity Conditions , 2005, RECOMB.

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

[20]  Stephen Safe,et al.  The oncogenic microRNA-27a targets genes that regulate specificity protein transcription factors and the G2-M checkpoint in MDA-MB-231 breast cancer cells. , 2007, Cancer research.

[21]  JOHANNES FÜRNKRANZ,et al.  Separate-and-Conquer Rule Learning , 1999, Artificial Intelligence Review.

[22]  K W Harder,et al.  Coexisting amplifications of the chromosome 1p32 genes (PTPRF and MYCL1) encoding protein tyrosine phosphatase LAR and L-myc in a small cell lung cancer line. , 1995, Genomics.

[23]  Arndt Borkhardt,et al.  High expression of precursor microRNA‐155/BIC RNA in children with Burkitt lymphoma , 2004, Genes, chromosomes & cancer.

[24]  Stijn van Dongen,et al.  miRBase: tools for microRNA genomics , 2007, Nucleic Acids Res..

[25]  G. Rubin,et al.  Computational identification of Drosophila microRNA genes , 2003, Genome Biology.

[26]  Michael Z Michael,et al.  Reduced accumulation of specific microRNAs in colorectal neoplasia. , 2003, Molecular cancer research : MCR.

[27]  Carlos Caldas,et al.  MicroRNA expression profiling of human breast cancer identifies new markers of tumour subtype , 2007 .

[28]  C. Croce,et al.  Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[29]  C. Croce,et al.  A microRNA expression signature of human solid tumors defines cancer gene targets , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[30]  C. Croce,et al.  MicroRNA gene expression deregulation in human breast cancer. , 2005, Cancer research.

[31]  Leonard D. Goldstein,et al.  MicroRNA expression profiling of human breast cancer identifies new markers of tumor subtype , 2007, Genome Biology.

[32]  Minchen Chien,et al.  Prognostic Values of microRNAs in Colorectal Cancer , 2006, Biomarker insights.

[33]  Sung-Liang Yu,et al.  MicroRNA signature predicts survival and relapse in lung cancer. , 2008, Cancer cell.

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

[35]  Tu Bao Ho,et al.  Computational discovery of transcriptional regulatory rules , 2005, ECCB/JBI.

[36]  T Chaplin,et al.  MicroRNA miR-181a correlates with morphological sub-class of acute myeloid leukaemia and the expression of its target genes in global genome-wide analysis , 2007, Leukemia.

[37]  F. Slack,et al.  The let-7 microRNA represses cell proliferation pathways in human cells. , 2007, Cancer research.

[38]  Peter Clark,et al.  The CN2 Induction Algorithm , 1989, Machine Learning.

[39]  T. Tuschl,et al.  Identification of Novel Genes Coding for Small Expressed RNAs , 2001, Science.

[40]  Oliver Hobert,et al.  miRNAs Play a Tune , 2007, Cell.

[41]  S. Lowe,et al.  A microRNA polycistron as a potential human oncogene , 2005, Nature.

[42]  Byoung-Tak Zhang,et al.  BIOINFORMATICS ORIGINAL PAPER doi:10.1093/bioinformatics/btm045 Data and text mining Discovery of microRNA–mRNA modules via population-based probabilistic learning , 2007 .

[43]  H. Horvitz,et al.  MicroRNA expression profiles classify human cancers , 2005, Nature.

[44]  Yitzhak Pilpel,et al.  Differentially Regulated Micro-RNAs and Actively Translated Messenger RNA Transcripts by Tumor Suppressor p53 in Colon Cancer , 2006, Clinical Cancer Research.

[45]  Giovanni De Micheli,et al.  Prediction of regulatory modules comprising microRNAs and target genes , 2005, ECCB/JBI.

[46]  Masakazu Yamamoto,et al.  Non-coding MicroRNAs hsa-let-7g and hsa-miR-181b are Associated with Chemoresponse to S-1 in Colon Cancer. , 2006, Cancer genomics & proteomics.

[47]  David N. Louis,et al.  ANOVA, a putative astrocytic RNA-binding protein gene that maps to chromosome 19q13.3 , 1997, Neurogenetics.

[48]  Miao Sun,et al.  MicroRNA and cancer: Current status and prospective , 2006, International journal of cancer.

[49]  M. Ashburner,et al.  Gene Ontology: tool for the unification of biology , 2000, Nature Genetics.

[50]  W. Gerald,et al.  Endogenous human microRNAs that suppress breast cancer metastasis , 2008, Nature.

[51]  C. Croce,et al.  Frequent deletions and down-regulation of micro- RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[52]  Brendan J. Frey,et al.  Detecting MicroRNA Targets by Linking Sequence, MicroRNA and Gene Expression Data , 2006, RECOMB.