Alu elements contain many binding sites for transcription factors and may play a role in regulation of developmental processes

BackgroundThe human genome contains over one million Alu repeat elements whose distribution is not uniform. While metabolism-related genes were shown to be enriched with Alu, in structural genes Alu elements are under-represented. Such observations led researchers to suggest that Alu elements were involved in gene regulation and were selected to be present in some genes and absent from others. This hypothesis is gaining strength due to findings that indicate involvement of Alu elements in a variety of functions; for example, Alu sequences were found to contain several functional transcription factor (TF) binding sites (BSs). We performed a search for new putative BSs on Alu elements, using a database of Position Specific Score Matrices (PSSMs). We searched consensus Alu sequences as well as specific Alu elements that appear on the 5 Kbp regions upstream to the transcription start site (TSS) of about 14000 genes.ResultsWe found that the upstream regions of the TSS are enriched with Alu elements, and the Alu consensus sequences contain dozens of putative BSs for TFs. Hence several TFs have Alu-associated BSs upstream of the TSS of many genes. For several TFs most of the putative BSs reside on Alu; a few of these were previously found and their association with Alu was also reported. In four cases the fact that the identified BSs resided on Alu went unnoticed, and we report this association for the first time. We found dozens of new putative BSs. Interestingly, many of the corresponding TFs are associated with early markers of development, even though the upstream regions of development-related genes are Alu-poor, compared with translational and protein biosynthesis related genes, which are Alu-rich. Finally, we found a correlation between the mouse B1 and human Alu densities within the corresponding upstream regions of orthologous genes.ConclusionWe propose that evolution used transposable elements to insert TF binding motifs into promoter regions. We observed enrichment of biosynthesis genes with Alu-associated BSs of developmental TFs. Since development and cell proliferation (of which biosynthesis is an essential component) were proposed to be opposing processes, these TFs possibly play inhibitory roles, suppressing proliferation during differentiation.

[1]  Xin Chen,et al.  TRANSFAC: an integrated system for gene expression regulation , 2000, Nucleic Acids Res..

[2]  J. Murray,et al.  Pitx2 Regulates Procollagen Lysyl Hydroxylase (Plod) Gene Expression , 2001, The Journal of cell biology.

[3]  V. Babich,et al.  Association of some potential hormone response elements in human genes with the Alu family repeats. , 1999, Gene.

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

[5]  Valer Gotea,et al.  Transposable elements as a significant source of transcription regulating signals. , 2006, Gene.

[6]  Mouse Genome Sequencing Consortium.  Initial sequencing and comparative analysis of the mouse genome , 2002, Nature.

[7]  M. G. Kidwell,et al.  PERSPECTIVE: TRANSPOSABLE ELEMENTS, PARASITIC DNA, AND GENOME EVOLUTION , 2001, Evolution; international journal of organic evolution.

[8]  T. Werner,et al.  MatInd and MatInspector: new fast and versatile tools for detection of consensus matches in nucleotide sequence data. , 1995, Nucleic acids research.

[9]  Thomas Brand,et al.  Heart development: molecular insights into cardiac specification and early morphogenesis. , 2003, Developmental biology.

[10]  G. Glazko,et al.  Origin of a substantial fraction of human regulatory sequences from transposable elements. , 2003, Trends in genetics : TIG.

[11]  Thierry Heidmann,et al.  LINE-mediated retrotransposition of marked Alu sequences , 2003, Nature Genetics.

[12]  L. N. van de Lagemaat,et al.  Retroelement distributions in the human genome: variations associated with age and proximity to genes. , 2002, Genome research.

[13]  M. Batzer,et al.  Alu repeats and human genomic diversity , 2002, Nature Reviews Genetics.

[14]  John M. Greally,et al.  Short interspersed transposable elements (SINEs) are excluded from imprinted regions in the human genome , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[15]  M. Guerin,et al.  A CYP7A promoter binding factor site and Alu repeat in the distal promoter region are implicated in regulation of human CETP gene expression Published, JLR Papers in Press, February 16, 2003. DOI 10.1194/jlr.M200423-JLR200 , 2003, Journal of Lipid Research.

[16]  P. Deininger,et al.  Identification of a New Subclass of Alu DNA Repeats Which Can Function as Estrogen Receptor-dependent Transcriptional Enhancers (*) , 1995, The Journal of Biological Chemistry.

[17]  C. Schmid,et al.  Specific Alu Binding Protein from Human Sperm Chromatin Prevents DNA Methylation (*) , 1995, The Journal of Biological Chemistry.

[18]  H. Hamdi,et al.  Alu-mediated phylogenetic novelties in gene regulation and development. , 2000, Journal of molecular biology.

[19]  Maria Stepanova,et al.  A comparative analysis of relative occurrence of transcription factor binding sites in vertebrate genomes and gene promoter areas , 2005, Bioinform..

[20]  J. Brosius,et al.  RNAs from all categories generate retrosequences that may be exapted as novel genes or regulatory elements. , 1999, Gene.

[21]  F. Alt,et al.  Defective DNA-dependent protein kinase activity is linked to V(D)J recombination and DNA repair defects associated with the murine scid mutation , 1995, Cell.

[22]  Colin N. Dewey,et al.  Initial sequencing and comparative analysis of the mouse genome. , 2002 .

[23]  J. Jurka,et al.  Repbase Update, a database of eukaryotic repetitive elements , 2005, Cytogenetic and Genome Research.

[24]  Gordon Vansant,et al.  An Alu Element in the Myeloperoxidase Promoter Contains a Composite SP1-Thyroid Hormone-Retinoic Acid Response Element* , 1996, The Journal of Biological Chemistry.

[25]  Youngsook Lee,et al.  PITX2 Isoform-specific Regulation of Atrial Natriuretic Factor Expression , 2003, Journal of Biological Chemistry.

[26]  Ellen V Rothenberg,et al.  Molecular genetics of T cell development. , 2005, Annual review of immunology.

[27]  Samir K. Brahmachari,et al.  ALU-ring elements in the primate genomes , 2005, Genetica.

[28]  C. A. Dunn,et al.  Impact of transposable elements on the evolution of mammalian gene regulation , 2005, Cytogenetic and Genome Research.

[29]  E. Levanon,et al.  Identification of RNA editing sites in the SNP database , 2005, Nucleic acids research.

[30]  D. Cavener,et al.  Comparison of the consensus sequence flanking translational start sites in Drosophila and vertebrates. , 1987, Nucleic acids research.

[31]  V. Kapitonov,et al.  The age of Alu subfamilies , 2004, Journal of Molecular Evolution.

[32]  Suzhen Li,et al.  Induction of human liver X receptor alpha gene expression via an autoregulatory loop mechanism. , 2002, Molecular endocrinology.

[33]  Identification and characterization of an Alu-containing, T-cell-specific enhancer located in the last intron of the human CD8 alpha gene , 1993 .

[34]  Kaushal Kumar,et al.  Comparative analysis of chromatin landscape in regulatory regions of human housekeeping and tissue specific genes , 2005, BMC Bioinformatics.

[35]  D. A. Kramerov,et al.  B1 and related SINEs in mammalian genomes. , 2003, Gene.

[36]  A. Skoultchi,et al.  Coordinating cell proliferation and differentiation. , 2001, Current opinion in genetics & development.

[37]  R. Britten,et al.  Evolutionary selection against change in many Alu repeat sequences interspersed through primate genomes. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[38]  Xun Gu,et al.  Novel PAX6 binding sites in the human genome and the role of repetitive elements in the evolution of gene regulation. , 2002, Genome research.

[39]  P. Kavathas,et al.  RepetitiveAluElements form a Cruciform Structure that Regulates the Function of the Human CD8α T Cell-specific En hancer , 1995 .

[40]  Suzhen Li,et al.  Induction of Human Liver X Receptor α Gene Expression Via an Autoregulatory Loop Mechanism , 2002 .

[41]  Carl W. Schmid,et al.  Standardized nomenclature for Alu repeats , 2004, Journal of Molecular Evolution.

[42]  T. Matise,et al.  Widespread RNA editing of embedded alu elements in the human transcriptome. , 2004, Genome research.

[43]  V. Babich,et al.  Clusters of regulatory signals for RNA polymerase II transcription associated with Alu family repeats and CpG islands in human promoters. , 2004, Genomics.

[44]  P. Kavathas,et al.  Identification and characterization of an Alu-containing, T-cell-specific enhancer located in the last intron of the human CD8 alpha gene , 1993, Molecular and cellular biology.

[45]  Deepak Grover,et al.  Nonrandom distribution of alu elements in genes of various functional categories: insight from analysis of human chromosomes 21 and 22. , 2003, Molecular biology and evolution.

[46]  H. Kazazian.  Mobile Elements: Drivers of Genome Evolution , 2004, Science.

[47]  N. Kakazu,et al.  Cloning and Characterization of LUN, a Novel RING Finger Protein That Is Highly Expressed in Lung and Specifically Binds to a Palindromic Sequence* , 2001, The Journal of Biological Chemistry.

[48]  Alexander Rich,et al.  Widespread A-to-I RNA Editing of Alu-Containing mRNAs in the Human Transcriptome , 2004, PLoS biology.

[49]  Zhijun Duan,et al.  Targets of the transcriptional repressor oncoprotein Gfi-1 , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[50]  Michael Q. Zhang.  Computational prediction of eukaryotic protein-coding genes , 2002, Nature Reviews Genetics.

[51]  International Human Genome Sequencing Consortium.  Initial sequencing and analysis of the human genome , 2001, Nature.

[52]  Brad T. Sherman,et al.  DAVID: Database for Annotation, Visualization, and Integrated Discovery , 2003, Genome Biology.

[53]  W F Reynolds,et al.  The consensus sequence of a major Alu subfamily contains a functional retinoic acid response element. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[54]  W. Li,et al.  A novel Pax-6 binding site in rodent B1 repetitive elements: coevolution between developmental regulation and repeated elements? , 2000, Gene.

[55]  P. Kavathas,et al.  Repetitive Alu elements form a cruciform structure that regulates the function of the human CD8 alpha T cell-specific enhancer. , 1995, Journal of molecular biology.

[56]  Samir K. Brahmachari,et al.  Alu repeat analysis in the complete human genome: trends and variations with respect to genomic composition , 2004, Bioinform..

[57]  D. Landsman,et al.  Transposable elements donate lineage-specific regulatory sequences to host genomes , 2005, Cytogenetic and Genome Research.