Homotypic regulatory clusters in Drosophila.

Cis-regulatory modules (CRMs) are transcription regulatory DNA segments (approximately 1 Kb range) that control the expression of developmental genes in higher eukaryotes. We analyzed clustering of known binding motifs for transcription factors (TFs) in over 60 known CRMs from 20 Drosophila developmental genes, and we present evidence that each type of recognition motif forms significant clusters within the regulatory regions regulated by the corresponding TF. We demonstrate how a search with a single binding motif can be applied to explore gene regulatory networks and to discover coregulated genes in the genome. We also discuss the potential of the clustering method in interpreting the differential response of genes to various levels of transcriptional regulators.

[1]  B. Matthews,et al.  Kinetic studies on Cro repressor-operator DNA interaction. , 1987, Journal of molecular biology.

[2]  P. V. von Hippel,et al.  Selection of DNA binding sites by regulatory proteins. Statistical-mechanical theory and application to operators and promoters. , 1987, Journal of molecular biology.

[3]  C. Nüsslein-Volhard,et al.  The bicoid protein determines position in the Drosophila embryo in a concentration-dependent manner , 1988, Cell.

[4]  C. Nüsslein-Volhard,et al.  A gradient of bicoid protein in Drosophila embryos , 1988, Cell.

[5]  Wolfgang Driever,et al.  Determination of spatial domains of zygotic gene expression in the Drosophila embryo by the affinity of binding sites for the bicoid morphogen , 1989, Nature.

[6]  G. Rubin,et al.  Definition of cis-acting elements regulating expression of the Drosophila melanogaster ninaE opsin gene by oligonucleotide-directed mutagenesis. , 1989, Genetics.

[7]  G. Rubin,et al.  Analysis of cis-acting requirements of the Rh3 and Rh4 genes reveals a bipartite organization to rhodopsin promoters in Drosophila melanogaster. , 1990, Genes & development.

[8]  R. Palmiter,et al.  Spatial and temporal control elements of the Drosophila engrailed gene. , 1990, Genes & development.

[9]  P. Lu,et al.  Lac repressor-operator interaction: DNA length dependence. , 1990, Biochimica et biophysica acta.

[10]  V. Pirrotta,et al.  Interactions of the Drosophila gap gene giant with maternal and zygotic pattern-forming genes. , 1991, Development.

[11]  M. Levine,et al.  Spatial regulation of the gap gene giant during Drosophila development. , 1991, Development.

[12]  M. Levine,et al.  Regulation of a segmentation stripe by overlapping activators and repressors in the Drosophila embryo. , 1991, Science.

[13]  M. Levine,et al.  Regulation of even‐skipped stripe 2 in the Drosophila embryo. , 1992, The EMBO journal.

[14]  B. Pugh,et al.  Evidence for Functional Binding and Stable Sliding of the TATA Binding Protein on Nonspecific DNA (*) , 1995, The Journal of Biological Chemistry.

[15]  Alexander E. Kel,et al.  Eukaryotic promoter recognition by binding sites for transcription factors , 1995, Comput. Appl. Biosci..

[16]  Michael S. Waterman,et al.  Introduction to computational biology , 1995 .

[17]  Q. Gao,et al.  orthodenticle regulation during embryonic head development in Drosophila , 1996, Mechanisms of Development.

[18]  M. Levine,et al.  Regulation of two pair-rule stripes by a single enhancer in the Drosophila embryo. , 1996, Developmental biology.

[19]  D Kosman,et al.  Concentration-dependent patterning by an ectopic expression domain of the Drosophila gap gene knirps. , 1997, Development.

[20]  T. Maniatis,et al.  Common themes in the function of transcription and splicing enhancers. , 1997, Current opinion in cell biology.

[21]  E. Davidson,et al.  The hardwiring of development: organization and function of genomic regulatory systems. , 1997, Development.

[22]  K. Roeder,et al.  A statistical model for locating regulatory regions in genomic DNA. , 1997, Journal of molecular biology.

[23]  A. Wagner,et al.  A computational genomics approach to the identification of gene networks. , 1997, Nucleic acids research.

[24]  J. Fickett,et al.  Identification of regulatory regions which confer muscle-specific gene expression. , 1998, Journal of molecular biology.

[25]  Nikolay A. Kolchanov,et al.  GeneNet: a gene network database and its automated visualization , 1998, Bioinform..

[26]  Alexander V. Spirov,et al.  Graphical interface to the genetic network database GeNet , 1998, Bioinform..

[27]  N. Patel,et al.  Functional analysis of eve stripe 2 enhancer evolution in Drosophila: rules governing conservation and change. , 1998, Development.

[28]  Q Gao,et al.  Targeting gene expression to the head: the Drosophila orthodenticle gene is a direct target of the Bicoid morphogen. , 1998, Development.

[29]  Frank Klawonn,et al.  Transcription regulatory region analysis using signal detection and fuzzy clustering , 1998, Bioinform..

[30]  M. Fujioka,et al.  Analysis of an even-skipped rescue transgene reveals both composite and discrete neuronal and early blastoderm enhancers, and multi-stripe positioning by gap gene repressor gradients. , 1999, Development.

[31]  H. Krause,et al.  Kinetic analysis of segmentation gene interactions in Drosophila embryos. , 1999, Development.

[32]  Andreas Wagner,et al.  Genes regulated cooperatively by one or more transcription factors and their identification in whole eukaryotic genomes , 1999, Bioinform..

[33]  M. Fujioka,et al.  The even-skipped locus is contained in a 16-kb chromatin domain. , 1999, Developmental biology.

[34]  G M Rubin,et al.  A brief history of Drosophila's contributions to genome research. , 2000, Science.

[35]  R. Guigó,et al.  An assessment of gene prediction accuracy in large DNA sequences. , 2000, Genome research.

[36]  N. Patel,et al.  Evidence for stabilizing selection in a eukaryotic enhancer element , 2000, Nature.

[37]  Anna G. Nazina,et al.  A conserved regulatory element present in all Drosophila rhodopsin genes mediates Pax6 functions and participates in the fine-tuning of cell-specific expression , 2001, Mechanisms of Development.

[38]  S Wallenstein,et al.  Nonoverlapping clusters: approximate distribution and application to molecular biology. , 2001, Biometrics.

[39]  Peter W. Markstein,et al.  Genome-wide analysis of clustered Dorsal binding sites identifies putative target genes in the Drosophila embryo , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[40]  Martin C. Frith,et al.  Detection of cis -element clusters in higher eukaryotic DNA , 2001, Bioinform..

[41]  Anna G. Nazina,et al.  Extraction of functional binding sites from unique regulatory regions: the Drosophila early developmental enhancers. , 2002, Genome research.

[42]  G. Rubin,et al.  Exploiting transcription factor binding site clustering to identify cis-regulatory modules involved in pattern formation in the Drosophila genome , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[43]  G. Stormo,et al.  Identification of a novel cis-regulatory element involved in the heat shock response in Caenorhabditis elegans using microarray gene expression and computational methods. , 2002, Genome research.