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Nucleic Acids Res. 2013 Aug;41(15):7220-30. doi: 10.1093/nar/gkt511. Epub 2013 Jun 12.

Unravelling the hidden DNA structural/physical code provides novel insights on promoter location.

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Institute for Research in Biomedicine (IRB Barcelona), Barcelona 08028, Spain, Joint IRB-BSC Research Program on Computational Biology, Barcelona 08028, Spain, Bioinformatics and Genomics Group, Center for Genomic Regulation and Universitat Pompeu Fabra, Barcelona 08003, Spain, Barcelona Supercomputing Center, Barcelona 08034, Spain and Department of Biochemistry and Molecular Biology, University of Barcelona, Barcelona 08028, Spain.


Although protein recognition of DNA motifs in promoter regions has been traditionally considered as a critical regulatory element in transcription, the location of promoters, and in particular transcription start sites (TSSs), still remains a challenge. Here we perform a comprehensive analysis of putative core promoter sequences relative to non-annotated predicted TSSs along the human genome, which were defined by distinct DNA physical properties implemented in our ProStar computational algorithm. A representative sampling of predicted regions was subjected to extensive experimental validation and analyses. Interestingly, the vast majority proved to be transcriptionally active despite the lack of specific sequence motifs, indicating that physical signaling is indeed able to detect promoter activity beyond conventional TSS prediction methods. Furthermore, highly active regions displayed typical chromatin features associated to promoters of housekeeping genes. Our results enable to redefine the promoter signatures and analyze the diversity, evolutionary conservation and dynamic regulation of human core promoters at large-scale. Moreover, the present study strongly supports the hypothesis of an ancient regulatory mechanism encoded by the intrinsic physical properties of the DNA that may contribute to the complexity of transcription regulation in the human genome.

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