A large-scale analysis of mRNA polyadenylation of human and mouse genes

mRNA polyadenylation is a critical cellular process in eukaryotes. It involves 3′ end cleavage of nascent mRNAs and addition of the poly(A) tail, which plays important roles in many aspects of the cellular metabolism of mRNA. The process is controlled by various cis-acting elements surrounding the cleavage site, and their binding factors. In this study, we surveyed genome regions containing cleavage sites [herein called poly(A) sites], for 13 942 human and 11 155 mouse genes. We found that a great proportion of human and mouse genes have alternative polyadenylation (∼54 and 32%, respectively). The conservation of alternative polyadenylation type or polyadenylation configuration between human and mouse orthologs is statistically significant, indicating that alternative polyadenylation is widely employed by these two species to produce alternative gene transcripts. Genes belonging to several functional groups, indicated by their Gene Ontology annotations, are biased with respect to polyadenylation configuration. Many poly(A) sites harbor multiple cleavage sites (51.25% human and 46.97% mouse sites), leading to heterogeneous 3′ end formation for transcripts. This implies that the cleavage process of polyadenylation is largely imprecise. Different types of poly(A) sites, with regard to their relative locations in a gene, are found to have distinct nucleotide composition in surrounding genomic regions. This large-scale study provides important insights into the mechanism of polyadenylation in mammalian species and represents a genomic view of the regulation of gene expression by alternative polyadenylation.

[1]  Christina Gloeckner,et al.  Modern Applied Statistics With S , 2003 .

[2]  J. Alwine,et al.  Definition of the upstream efficiency element of the simian virus 40 late polyadenylation signal by using in vitro analyses , 1992, Molecular and cellular biology.

[3]  G. Edwalds-Gilbert,et al.  Alternative poly(A) site selection in complex transcription units: means to an end? , 1997, Nucleic acids research.

[4]  Jeffrey Wilusz,et al.  Downstream sequence elements with different affinities for the hnRNP H/H' protein influence the processing efficiency of mammalian polyadenylation signals. , 2002, Nucleic acids research.

[5]  T. Shenk,et al.  A 64 kd nuclear protein binds to RNA segments that include the AAUAAA polyadenylation motif , 1988, Cell.

[6]  D Gautheret,et al.  Identification of alternate polyadenylation sites and analysis of their tissue distribution using EST data. , 2001, Genome research.

[7]  Jack E. Tabaska,et al.  Detection of polyadenylation signals in human DNA sequences. , 1999, Gene.

[8]  S. Peltz,et al.  Interrelationships of the pathways of mRNA decay and translation in eukaryotic cells. , 1996, Annual review of biochemistry.

[9]  D. Gautheret,et al.  Sequence determinants in human polyadenylation site selection , 2003, BMC Genomics.

[10]  J. Wilusz,et al.  Auxiliary downstream elements are required for efficient polyadenylation of mammalian pre-mRNAs. , 1998, Nucleic acids research.

[11]  L. Minvielle-Sebastia,et al.  A comparison of mammalian and yeast pre-mRNA 3'-end processing. , 1997, Current opinion in cell biology.

[12]  J. Wilusz,et al.  Cleavage site determinants in the mammalian polyadenylation signal. , 1995, Nucleic acids research.

[13]  T. Maniatis,et al.  An extensive network of coupling among gene expression machines , 2002, Nature.

[14]  Jeffrey Wilusz,et al.  Upstream Elements Present in the 3′-Untranslated Region of Collagen Genes Influence the Processing Efficiency of Overlapping Polyadenylation Signals* , 2002, The Journal of Biological Chemistry.

[15]  Kathryn A. O’Donnell,et al.  An mRNA Surveillance Mechanism That Eliminates Transcripts Lacking Termination Codons , 2002, Science.

[16]  J. Steitz,et al.  Overexpression of HuR, a nuclear–cytoplasmic shuttling protein, increases the in vivo stability of ARE‐containing mRNAs , 1998, The EMBO journal.

[17]  M. Edmonds,et al.  A history of poly A sequences: from formation to factors to function. , 2002, Progress in nucleic acid research and molecular biology.

[18]  E. Wahle,et al.  The mechanism of 3' cleavage and polyadenylation of eukaryotic pre-mRNA. , 1997, Progress in nucleic acid research and molecular biology.

[19]  Y. Benjamini,et al.  Controlling the false discovery rate: a practical and powerful approach to multiple testing , 1995 .

[20]  M. Wollerton,et al.  The upstream sequence element of the C2 complement poly(A) signal activates mRNA 3' end formation by two distinct mechanisms. , 1998, Genes & development.

[21]  B. Graveley,et al.  CPSF recognition of an HIV-1 mRNA 3'-processing enhancer: multiple sequence contacts involved in poly(A) site definition. , 1995, Genes & development.

[22]  J. Manley,et al.  Mechanism and regulation of mRNA polyadenylation. , 1997, Genes & development.

[23]  J. Manley,et al.  The Polyadenylation Factor CstF-64 Regulates Alternative Processing of IgM Heavy Chain Pre-mRNA during B Cell Differentiation , 1996, Cell.

[24]  M. Wickens,et al.  Point mutations in AAUAAA and the poly (A) addition site: effects on the accuracy and efficiency of cleavage and polyadenylation in vitro. , 1990, Nucleic acids research.

[25]  G. Shaw,et al.  A conserved AU sequence from the 3′ untranslated region of GM-CSF mRNA mediates selective mRNA degradation , 1986, Cell.

[26]  Eric C. Rouchka,et al.  UTR Reconstruction and Analysis Using Genomically Aligned EST Sequences , 2000, ISMB.

[27]  A. Shyu,et al.  RNA stabilization by the AU‐rich element binding protein, HuR, an ELAV protein , 1998, The EMBO journal.

[28]  Victor V. Solovyev,et al.  SpliceDB: database of canonical and non-canonical mammalian splice sites , 2001, Nucleic Acids Res..

[29]  C. Y. Chen,et al.  Unraveling a cytoplasmic role for hnRNP D in the in vivo mRNA destabilization directed by the AU-rich element. , 1999, Genes & development.

[30]  R. Amann,et al.  Predictive Identification of Exonic Splicing Enhancers in Human Genes , 2022 .

[31]  A. Sachs,et al.  Poly(A) Tail Length Control in Saccharomyces cerevisiae Occurs by Message-Specific Deadenylation , 1998, Molecular and Cellular Biology.

[32]  D. Gautheret,et al.  Patterns of variant polyadenylation signal usage in human genes. , 2000, Genome research.

[33]  W. J. Kent,et al.  BLAT--the BLAST-like alignment tool. , 2002, Genome research.

[34]  Jing Zhao,et al.  Formation of mRNA 3′ Ends in Eukaryotes: Mechanism, Regulation, and Interrelationships with Other Steps in mRNA Synthesis , 1999, Microbiology and Molecular Biology Reviews.

[35]  D. Hovorun,et al.  Downstream elements of mammalian pre-mRNA polyadenylation signals: primary, secondary and higher-order structures. , 2003, Nucleic acids research.

[36]  Nick Proudfoot,et al.  New perspectives on connecting messenger RNA 3' end formation to transcription. , 2004, Current opinion in cell biology.

[37]  J. Wilusz,et al.  ELAV proteins stabilize deadenylated intermediates in a novel in vitro mRNA deadenylation/degradation system. , 1999, Genes & development.

[38]  C. Y. Chen,et al.  AU-rich elements: characterization and importance in mRNA degradation. , 1995, Trends in biochemical sciences.

[39]  M. Wickens,et al.  Life and death in the cytoplasm: messages from the 3' end. , 1997, Current opinion in genetics & development.

[40]  C. MacDonald,et al.  Reexamining the polyadenylation signal: were we wrong about AAUAAA? , 2002, Molecular and Cellular Endocrinology.

[41]  E Pauws,et al.  Heterogeneity in polyadenylation cleavage sites in mammalian mRNA sequences: implications for SAGE analysis. , 2001, Nucleic acids research.

[42]  I. Mattaj,et al.  The influence of 5′ and 3′ end structures on pre-mRNA metabolism , 1995, Journal of Cell Science.

[43]  J. Manley,et al.  Strange bedfellows: polyadenylation factors at the promoter. , 2003, Genes & development.

[44]  Hongyu Zhang,et al.  Alignment of BLAST High-scoring Segment Pairs Based on the Longest Increasing Subsequence Algorithm , 2003, Bioinform..

[45]  C R Cantor,et al.  In silico detection of control signals: mRNA 3'-end-processing sequences in diverse species. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[46]  K. Neugebauer,et al.  On the importance of being co-transcriptional , 2002, Journal of Cell Science.