Genome-wide colonization of gene regulatory elements by G4 DNA motifs

G-quadruplex (or G4 DNA), a stable four-stranded structure found in guanine-rich regions, is implicated in the transcriptional regulation of genes involved in growth and development. Previous studies on the role of G4 DNA in gene regulation mostly focused on genomic regions proximal to transcription start sites (TSSs). To gain a more comprehensive understanding of the regulatory role of G4 DNA, we examined the landscape of potential G4 DNA (PG4Ms) motifs in the human genome and found that G4 motifs, not restricted to those found in the TSS-proximal regions, are bias toward gene-associated regions. Significantly, analyses of G4 motifs in seven types of well-known gene regulatory elements revealed a constitutive enrichment pattern and the clusters of G4 motifs tend to be colocalized with regulatory elements. Considering our analysis from a genome evolutionary perspective, we found evidence that the occurrence and accumulation of certain progenitors and canonical G4 DNA motifs within regulatory regions were progressively favored by natural selection. Our results suggest that G4 DNA motifs are ‘colonized’ in regulatory regions, supporting a likely genome-wide role of G4 DNA in gene regulation. We hypothesize that G4 DNA is a regulatory apparatus situated in regulatory elements, acting as a molecular switch that can modulate the role of the host functional regions, by transition in DNA structure.

[1]  Daekyu Sun,et al.  Evidence for the presence of a guanine quadruplex forming region within a polypurine tract of the hypoxia inducible factor 1alpha promoter. , 2005, Biochemistry.

[2]  Mi Zhou,et al.  CTCFBSDB: a CTCF-binding site database for characterization of vertebrate genomic insulators , 2007, Nucleic Acids Res..

[3]  Michael Q. Zhang,et al.  Analysis of the Vertebrate Insulator Protein CTCF-Binding Sites in the Human Genome , 2007, Cell.

[4]  Songnian Hu,et al.  A novel DNA sequence periodicity decodes nucleosome positioning , 2008, Nucleic acids research.

[5]  A. Phan,et al.  Propeller-type parallel-stranded G-quadruplexes in the human c-myc promoter. , 2004, Journal of the American Chemical Society.

[6]  N. Maizels,et al.  Gene function correlates with potential for G4 DNA formation in the human genome , 2006, Nucleic acids research.

[7]  N. Maizels,et al.  Dynamic roles for G4 DNA in the biology of eukaryotic cells , 2006, Nature Structural &Molecular Biology.

[8]  Eric Gilson,et al.  Insulator dynamics and the setting of chromatin domains , 2004, BioEssays : news and reviews in molecular, cellular and developmental biology.

[9]  Yiqiang Zhao,et al.  Extensive selection for the enrichment of G4 DNA motifs in transcriptional regulatory regions of warm blooded animals , 2007, FEBS letters.

[10]  Stephen Neidle,et al.  Quadruplex DNA crystal structures and drug design. , 2008, Biochimie.

[11]  N. Maizels,et al.  Conserved elements with potential to form polymorphic G-quadruplex structures in the first intron of human genes , 2008, Nucleic acids research.

[12]  Dustin E. Schones,et al.  High-Resolution Profiling of Histone Methylations in the Human Genome , 2007, Cell.

[13]  V. K. Yadav,et al.  Genome-Wide Analyses of Recombination Prone Regions Predict Role of DNA Structural Motif in Recombination , 2009, PloS one.

[14]  G. Dreyfuss,et al.  Specific binding of heterogeneous ribonucleoprotein particle protein K to the human c-myc promoter, in vitro. , 1993, The Journal of biological chemistry.

[15]  Tao Liu,et al.  CEAS: cis-regulatory element annotation system , 2009, Bioinform..

[16]  M. Fry,et al.  Formation and properties of hairpin and tetraplex structures of guanine-rich regulatory sequences of muscle-specific genes , 2005, Nucleic acids research.

[17]  M. Daly,et al.  Genome-wide mapping of DNase hypersensitive sites using massively parallel signature sequencing (MPSS). , 2005, Genome research.

[18]  Shankar Balasubramanian,et al.  G-quadruplexes in promoters throughout the human genome , 2006, Nucleic acids research.

[19]  H. Krutzsch,et al.  Cellular Nucleic Acid Binding Protein Regulates the CT Element of the Human c- myc Protooncogene (*) , 1995, The Journal of Biological Chemistry.

[20]  S. S. Smith,et al.  Hypermethylation of telomere-like foldbacks at codon 12 of the human c-Ha-ras gene and the trinucleotide repeat of the FMR-1 gene of fragile X. , 1994, Journal of molecular biology.

[21]  Julian Leon Huppert,et al.  G-quadruplexes: the beginning and end of UTRs , 2008, Nucleic acids research.

[22]  L. Hurley,et al.  Characterization of the G-quadruplexes in the duplex nuclease hypersensitive element of the PDGF-A promoter and modulation of PDGF-A promoter activity by TMPyP4 , 2007, Nucleic acids research.

[23]  Samer Khateb,et al.  Homodimeric MyoD Preferentially Binds Tetraplex Structures of Regulatory Sequences of Muscle-specific Genes* , 2005, Journal of Biological Chemistry.

[24]  Ning Li,et al.  Enrichment of G4 DNA motif in transcriptional regulatory region of chicken genome. , 2007, Biochemical and biophysical research communications.

[25]  V. K. Yadav,et al.  Evidence of genome-wide G4 DNA-mediated gene expression in human cancer cells , 2009, Nucleic acids research.

[26]  Oleg Kikin,et al.  GRSDB2 and GRS_UTRdb: databases of quadruplex forming G-rich sequences in pre-mRNAs and mRNAs , 2007, Nucleic Acids Res..

[27]  Steven Henikoff,et al.  Nucleosome destabilization in the epigenetic regulation of gene expression , 2008, Nature Reviews Genetics.

[28]  F. Johnson,et al.  In vivo veritas: using yeast to probe the biological functions of G-quadruplexes. , 2008, Biochimie.

[29]  Iris Cheung,et al.  Disruption of dog-1 in Caenorhabditis elegans triggers deletions upstream of guanine-rich DNA , 2002, Nature Genetics.

[30]  L. Hurley,et al.  G-quadruplex DNA: a potential target for anti-cancer drug design. , 2000, Trends in pharmacological sciences.

[31]  Francesca Chiaromonte,et al.  ESPERR: learning strong and weak signals in genomic sequence alignments to identify functional elements. , 2006, Genome research.

[32]  Javier Arsuaga,et al.  Genomic transcriptional response to loss of chromosomal supercoiling in Escherichia coli , 2004, Genome Biology.

[33]  Yan Xu,et al.  Formation of the G-quadruplex and i-motif structures in retinoblastoma susceptibility genes (Rb) , 2006, Nucleic acids research.

[34]  N. Maizels,et al.  Intracellular transcription of G-rich DNAs induces formation of G-loops, novel structures containing G4 DNA. , 2004, Genes & development.

[35]  Danzhou Yang,et al.  Structure of the Biologically Relevant G-Quadruplex in The c-MYC Promoter , 2006, Nucleosides, nucleotides & nucleic acids.

[36]  J. T. Kadonaga,et al.  *To whom correspondence should be addressed. E- , 2022 .

[37]  D. Bearss,et al.  Direct evidence for a G-quadruplex in a promoter region and its targeting with a small molecule to repress c-MYC transcription , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[38]  Mitali Mukerji,et al.  Genome-wide prediction of G4 DNA as regulatory motifs: role in Escherichia coli global regulation. , 2006, Genome research.

[39]  N. Galtier.  Gene conversion drives GC content evolution in mammalian histones. , 2003, Trends in genetics : TIG.

[40]  W. Rutter,et al.  Unusual DNA structure of the diabetes susceptibility locus IDDM2 and its effect on transcription by the insulin promoter factor Pur-1/MAZ. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[41]  Sarah W. Burge,et al.  Quadruplex DNA: sequence, topology and structure , 2006, Nucleic acids research.

[42]  Andrew Travers,et al.  DNA supercoiling — a global transcriptional regulator for enterobacterial growth? , 2005, Nature Reviews Microbiology.

[43]  L. Hurley,et al.  Deconvoluting the structural and drug-recognition complexity of the G-quadruplex-forming region upstream of the bcl-2 P1 promoter. , 2006, Journal of the American Chemical Society.

[44]  A. Phan,et al.  DNA architecture: from G to Z. , 2006, Current opinion in structural biology.

[45]  N. Maizels,et al.  G-rich proto-oncogenes are targeted for genomic instability in B-cell lymphomas. , 2007, Cancer research.

[46]  Stephan C. Schuster,et al.  Nucleosome organization in the Drosophila genome , 2008, Nature.

[47]  Shankar Balasubramanian,et al.  Prevalence of quadruplexes in the human genome , 2005, Nucleic acids research.

[48]  Ram Krishna Thakur,et al.  Genome-wide computational and expression analyses reveal G-quadruplex DNA motifs as conserved cis-regulatory elements in human and related species. , 2008, Journal of medicinal chemistry.

[49]  S. Jinks-Robertson.  The genome's best friend , 2002, Nature Genetics.

[50]  Ivan Ovcharenko,et al.  Predicting tissue-specific enhancers in the human genome. , 2006, Genome research.

[51]  F. Johnson,et al.  Genomic distribution and functional analyses of potential G-quadruplex-forming sequences in Saccharomyces cerevisiae , 2007, Nucleic acids research.

[52]  S. Cogoi,et al.  G-quadruplex formation within the promoter of the KRAS proto-oncogene and its effect on transcription , 2006, Nucleic acids research.

[53]  S. Neidle,et al.  The relationship of potential G-quadruplex sequences in cis-upstream regions of the human genome to SP1-binding elements , 2008, Nucleic acids research.

[54]  S. Neidle,et al.  Highly prevalent putative quadruplex sequence motifs in human DNA , 2005, Nucleic acids research.

[55]  H. Nakagama,et al.  Protein hnRNP A1 and its derivative Up1 unfold quadruplex DNA in the human KRAS promoter: implications for transcription , 2009, Nucleic acids research.

[56]  Roger A. Jones,et al.  An intramolecular G-quadruplex structure with mixed parallel/antiparallel G-strands formed in the human BCL-2 promoter region in solution. , 2006, Journal of the American Chemical Society.

[57]  Michael Fry,et al.  Tetraplex DNA and its interacting proteins. , 2007, Frontiers in bioscience : a journal and virtual library.

[58]  Laurence H. Hurley,et al.  Structures, folding patterns, and functions of intramolecular DNA G-quadruplexes found in eukaryotic promoter regions. , 2008, Biochimie.

[59]  Yiqiang Zhao,et al.  Genome-wide analysis reveals regulatory role of G4 DNA in gene transcription. , 2008, Genome research.

[60]  Z. Weng,et al.  High-Resolution Mapping and Characterization of Open Chromatin across the Genome , 2008, Cell.

[61]  Laurence D. Hurst,et al.  The evolution of isochores , 2001, Nature Reviews Genetics.

[62]  Tom H. Pringle,et al.  The human genome browser at UCSC. , 2002, Genome research.

[63]  S. S. Smith,et al.  Recognition of unusual DNA structures by human DNA (cytosine-5)methyltransferase. , 1991, Journal of molecular biology.

[64]  D. Haussler,et al.  Evolutionarily conserved elements in vertebrate, insect, worm, and yeast genomes. , 2005, Genome research.

[65]  J. Mergny,et al.  Telomerase downregulation induced by the G-quadruplex ligand 12459 in A549 cells is mediated by hTERT RNA alternative splicing. , 2004, Nucleic acids research.

[66]  A. Bird,et al.  Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals , 2003, Nature Genetics.

[67]  J. Shklover,et al.  Differential binding of quadruplex structures of muscle-specific genes regulatory sequences by MyoD, MRF4 and myogenin , 2008, Nucleic acids research.

[68]  Mark Gerstein,et al.  Pseudogene.org: a comprehensive database and comparison platform for pseudogene annotation , 2006, Nucleic Acids Res..

[69]  L. Hurley,et al.  Secondary DNA structures as molecular targets for cancer therapeutics. , 2001, Biochemical Society transactions.

[70]  P. Geyer,et al.  The role of insulator elements in defining domains of gene expression. , 1997, Current opinion in genetics & development.

[71]  J. Issa.  CpG island methylator phenotype in cancer , 2004, Nature Reviews Cancer.

[72]  Stephen Neidle,et al.  Quadruplex nucleic acids. , 2006 .

[73]  Stephen Neidle,et al.  A conserved quadruplex motif located in a transcription activation site of the human c-kit oncogene. , 2006, Biochemistry.

[74]  Irene K. Moore,et al.  The DNA-encoded nucleosome organization of a eukaryotic genome , 2009, Nature.

[75]  W. Gilbert,et al.  Formation of parallel four-stranded complexes by guanine-rich motifs in DNA and its implications for meiosis , 1988, Nature.

[76]  Haiyong Han,et al.  The cationic porphyrin TMPyP4 down-regulates c-MYC and human telomerase reverse transcriptase expression and inhibits tumor growth in vivo. , 2002, Molecular cancer therapeutics.

[77]  Laurence H. Hurley,et al.  Facilitation of a structural transition in the polypurine/polypyrimidine tract within the proximal promoter region of the human VEGF gene by the presence of potassium and G-quadruplex-interactive agents , 2005, Nucleic acids research.

[78]  William Stafford Noble,et al.  Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project , 2007, Nature.

[79]  Daniel J. Blankenberg,et al.  Galaxy: a platform for interactive large-scale genome analysis. , 2005, Genome research.

[80]  Victor G. Levitsky,et al.  Nucleosome formation potential of eukaryotic DNA: calculation and promoters analysis , 2001, Bioinform..

[81]  D. V. Von Hoff,et al.  Drug targeting of the c-MYC promoter to repress gene expression via a G-quadruplex silencer element. , 2006, Seminars in oncology.

[82]  John M. Greally,et al.  Epigenomics: beyond CpG islands , 2004, Nature Reviews Genetics.

[83]  Michael R. Green,et al.  Transcriptional regulatory elements in the human genome. , 2006, Annual review of genomics and human genetics.