title: Possible regulatory roles of promoter g-quadruplexes in cardiac function-related genes - human TnIc as a model.
abstract: G-quadruplexes (G4s) are four-stranded DNA secondary structures, which are involved in a diverse range of biological processes. Although the anti-cancer potential of G4s in oncogene promoters has been thoroughly investigated, the functions of promoter G4s in non-cancer-related genes are not well understood. We have explored the possible regulatory roles of promoter G4s in cardiac function-related genes using both computational and a wide range of experimental approaches. According to our bioinformatics results, it was found that potential G4-forming sequences are particularly enriched in the transcription regulatory regions (TRRs) of cardiac function-related genes. Subsequently, the promoter of human cardiac troponin I (TnIc) was chosen as a model, and G4s found in this region were subjected to biophysical characterisations. The chromosome 19 specific minisatellite G4 sequence (MNSG4) and near transcription start site (TSS) G4 sequence (-80 G4) adopt anti-parallel and parallel structures respectively in 100 mM KCl, with stabilities comparable to those of oncogene G4s. It was also found that TnIc G4s act cooperatively as enhancers in gene expression regulation in HEK293 cells, when stabilised by a synthetic G4-binding ligand. This study provides the first evidence of the biological significance of promoter G4s in cardiac function-related genes. The feasibility of using a single ligand to target multiple G4s in a particular gene has also been discussed.
authors: Molecular Medicine, National Heart and Lung Institute, Imperial College London, London, United Kingdom.
authors: Wenhua
authors: W
authors: Zhou
authors: Kogularamanan
authors: K
authors: Suntharalingam
authors: Nigel J
authors: NJ
authors: Brand
authors: Paul J R
authors: PJ
authors: Barton
authors: Ramon
authors: R
authors: Vilar
authors: Liming
authors: L
authors: Ying
mesh_terms: D001921:Brain / Q000378:metabolism; D019295:Computational Biology / Q000379:methods; D004247:DNA / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D054856:G-Quadruplexes; D005786:Gene Expression Regulation; D015894:Genome, Human / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D007700:Kinetics; D008024:Ligands; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D018598:Minisatellite Repeats / Q000235:genetics; D008957:Models, Genetic; D009206:Myocardium / Q000378:metabolism; D009690:Nucleic Acid Conformation; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics*; D013816:Thermodynamics; D024363:Transcription Initiation Site; D019210:Troponin I / Q000235:genetics*
chemical_list: D008024:Ligands; D019210:Troponin I; D004247:DNA; D008156:Luciferases