The field of promoter prediction holds almost limitless potential, but has had very limited success. Instead of analyzing DMA sequence homology, we propose a novel method of eucaryotic promoter prediction based on the physical properties of DNA which arise from the local sequence. Using computer simulations with a nonlinear mathematical model, we predict the localized opening profile of a region of DNA. For several sample eucaryotic promoters, we have demonstrated that the dominant preferential opening positions predicted by the model (and verified by S1 nuclease digestion assays) correlate well with the experimentally-determined transcriptional start sites or major regulatory sites of the gene promoters. We hypothesize that these opening profiles can be applied more generally in seeking out novel gene promoters and transcriptionally significant sites in genomic DNA. Here we propose to further validate the use of nonlinear mathematical models to predict opening profiles as indicators for eukaryotic promoter prediction using known gene core promoters with experimentally-determined transcriptional start sites. We will also seek to apply the computational promoter prediction method in proof-of-concept studies on genes with unidentified promoters and transcriptional start sites. Finally, we plan to develop numerical techniques that allow application of our promoter prediction model on a genomic scale. The simulation-based analysis of DNA opening profiles shows great potential in the prediction of human gene promoters. This method is superior to previous prediction models in that it examines sequence-derived physical properties of DNA rather than sequence homology, however, further investigation is necessary to evaluate and expand the limits of applicability of this method. One of the strongest advantages of the computational model is that it can be used to evaluate opening profiles for any sequence of eukaryotic DNA with very little cost.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM073911-03
Application #
7223422
Study Section
Special Emphasis Panel (ZRG1-BDMA (01))
Program Officer
Li, Jerry
Project Start
2005-05-01
Project End
2009-04-30
Budget Start
2007-05-01
Budget End
2008-04-30
Support Year
3
Fiscal Year
2007
Total Cost
$282,611
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
Duan, Jubao; Shi, Jianxin; Fiorentino, Alessia et al. (2014) A rare functional noncoding variant at the GWAS-implicated MIR137/MIR2682 locus might confer risk to schizophrenia and bipolar disorder. Am J Hum Genet 95:744-53
Gelev, Vladimir; Zabolotny, Janice M; Lange, Martin et al. (2014) A new paradigm for transcription factor TFIIB functionality. Sci Rep 4:3664
Alexandrov, Boian S; Phipps, M Lisa; Alexandrov, Ludmil B et al. (2013) Specificity and heterogeneity of terahertz radiation effect on gene expression in mouse mesenchymal stem cells. Sci Rep 3:1184
Stoeckius, Marlon; Erat, Anna; Fujikawa, Tatsuya et al. (2012) Essential roles of Raf/extracellular signal-regulated kinase/mitogen-activated protein kinase pathway, YY1, and Ca2+ influx in growth arrest of human vascular smooth muscle cells by bilirubin. J Biol Chem 287:15418-26
Alexandrov, Boian S; Fukuyo, Yayoi; Lange, Martin et al. (2012) DNA breathing dynamics distinguish binding from nonbinding consensus sites for transcription factor YY1 in cells. Nucleic Acids Res 40:10116-23
Alexandrov, Boian S; Valtchinov, Vlad I; Alexandrov, Ludmil B et al. (2011) DNA dynamics is likely to be a factor in the genomic nucleotide repeats expansions related to diseases. PLoS One 6:e19800
Alexandrov, Boian S; Rasmussen, Kim Ø; Bishop, Alan R et al. (2011) Non-thermal effects of terahertz radiation on gene expression in mouse stem cells. Biomed Opt Express 2:2679-89
Alexandrov, B S; Gelev, V; Bishop, A R et al. (2010) DNA Breathing Dynamics in the Presence of a Terahertz Field. Phys Lett A 374:1214
Alexandrov, Boian S; Gelev, Vladimir; Yoo, Sang Wook et al. (2010) DNA dynamics play a role as a basal transcription factor in the positioning and regulation of gene transcription initiation. Nucleic Acids Res 38:1790-5
Kantorovitz, Miriam R; Rapti, Zoi; Gelev, Vladimir et al. (2010) Computing DNA duplex instability profiles efficiently with a two-state model: trends of promoters and binding sites. BMC Bioinformatics 11:604

Showing the most recent 10 out of 16 publications