Over-represented sequences located on 3' UTRs are potentially involved in regulatory functions

Eukaryotic gene expression must be coordinated for the proper functioning of biological processes. This coordination can be achieved both at the transcriptional and post-transcriptional levels. In both cases, regulatory sequences placed at either promoter regions or on UTRs function as markers recognized by regulators that can then activate or repress different groups of genes according to necessity. While regulatory sequences involved in transcription are quite well documented, there is a lack of information on sequence elements involved in post-transcriptional regulation. We used a statistical over-representation method to identify novel regulatory elements located on UTRs. An exhaustive search approach was used to calculate the frequency of all possible n-mers (short nucleotide sequences) in 16,160 human genes of NCBI RefSeq sequences and to identify any peculiar usage of n-mers on UTRs. After a stringent filtering process, we identified 2,772 highly over-represented n-mers on 3’ UTRs. We provide evidence that these n-mers are potentially involved in regulatory functions. Identified n-mers overlap with previously identified binding sites for HuR and TIA-1 and, ARE and GRE sequences. We determine also that n-mers overlap with predicted miRNA target sites. Finally, a method to cluster n-mer groups allowed the identification of putative gene networks.

[1]  G. Karypis,et al.  Conserved GU-rich elements mediate mRNA decay by binding to CUG-binding protein 1. , 2008, Molecular cell.

[2]  Liqing Zhang,et al.  Housekeeping and tissue-specific genes differ in simple sequence repeats in the 5'-UTR region. , 2008, Gene.

[3]  J. Keene RNA regulons: coordination of post-transcriptional events , 2007, Nature Reviews Genetics.

[4]  Michele Caselle,et al.  Identification of candidate regulatory sequences in mammalian 3' UTRs by statistical analysis of oligonucleotide distributions , 2007, BMC Bioinformatics.

[5]  M. Esteller,et al.  Aberrant Regulation of Messenger RNA 3′-Untranslated Region in Human Cancer , 2007, Cellular oncology : the official journal of the International Society for Cellular Oncology.

[6]  Shankar Balasubramanian,et al.  An RNA G-quadruplex in the 5' UTR of the NRAS proto-oncogene modulates translation. , 2007, Nature chemical biology.

[7]  E. Korn,et al.  Stage‐specific alterations of the genome, transcriptome, and proteome during colorectal carcinogenesis , 2007, Genes, chromosomes & cancer.

[8]  N. Sonenberg,et al.  mTOR, translation initiation and cancer , 2006, Oncogene.

[9]  Hélène Touzet,et al.  Predicting transcription factor binding sites using local over-representation and comparative genomics , 2006, BMC Bioinformatics.

[10]  T. Rouault The role of iron regulatory proteins in mammalian iron homeostasis and disease , 2006, Nature chemical biology.

[11]  A. Whetton,et al.  Systematic Proteome and Transcriptome Analysis of Stem Cell Populations , 2006, Cell cycle.

[12]  A. Méreau,et al.  Mammalian CELF/Bruno-like RNA-binding proteins: molecular characteristics and biological functions. , 2006, Biochimie.

[13]  Aristotelis Tsirigos,et al.  Short blocks from the noncoding parts of the human genome have instances within nearly all known genes and relate to biological processes. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[14]  A. Admon,et al.  Molecular phenotype of zebrafish ovarian follicle by serial analysis of gene expression and proteomic profiling, and comparison with the transcriptomes of other animals , 2006, BMC Genomics.

[15]  V. Polunovsky,et al.  The Cap-Dependent Translation Apparatus Integrates and Amplifies Cancer Pathways , 2006, RNA biology.

[16]  Alexander E. Kel,et al.  TRANSFAC® and its module TRANSCompel®: transcriptional gene regulation in eukaryotes , 2005, Nucleic Acids Res..

[17]  Geppino Falco,et al.  Identification and Functional Outcome of mRNAs Associated with RNA-Binding Protein TIA-1 , 2005, Molecular and Cellular Biology.

[18]  Graziano Pesole,et al.  uAUG and uORFs in human and rodent 5'untranslated mRNAs. , 2005, Gene.

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

[20]  A. Willis,et al.  The implications of structured 5' untranslated regions on translation and disease. , 2005, Seminars in cell & developmental biology.

[21]  M. Gorospe,et al.  HuR: Post-Transcriptional Paths to Malignancy , 2005, RNA biology.

[22]  A. Willis,et al.  Aberrant regulation of translation initiation in tumorigenesis. , 2003, Current molecular medicine.

[23]  S. Kuersten,et al.  The power of the 3′ UTR: translational control and development , 2003, Nature Reviews Genetics.

[24]  S. Tenenbaum,et al.  Eukaryotic mRNPs may represent posttranscriptional operons. , 2002, Molecular cell.

[25]  C. Gissi,et al.  Untranslated regions of mRNAs , 2002, Genome Biology.

[26]  L. Timchenko,et al.  Molecular Basis for Impaired Muscle Differentiation in Myotonic Dystrophy , 2001, Molecular and Cellular Biology.

[27]  S. Gygi,et al.  Correlation between Protein and mRNA Abundance in Yeast , 1999, Molecular and Cellular Biology.

[28]  D. Zacharias,et al.  Minimum CAG repeat in the human calmodulin-1 gene 5' untranslated region is required for full expression. , 1998, Biochimica et biophysica acta.

[29]  M. Kozak Structural features in eukaryotic mRNAs that modulate the initiation of translation. , 1991, The Journal of biological chemistry.

[30]  Ali S. Hadi,et al.  Finding Groups in Data: An Introduction to Chster Analysis , 1991 .

[31]  E. Marcotte,et al.  Absolute protein expression profiling estimates the relative contributions of transcriptional and translational regulation , 2007, Nature Biotechnology.

[32]  M. Gorospe,et al.  Global analysis of HuR-regulated gene expression in colon cancer systems of reducing complexity. , 2004, Gene expression.

[33]  A. W. van der Velden,et al.  The role of the 5' untranslated region of an mRNA in translation regulation during development. , 1999, The international journal of biochemistry & cell biology.

[34]  A E Willis,et al.  Translational control of growth factor and proto-oncogene expression. , 1999, The international journal of biochemistry & cell biology.