Download Transcriptional regulatory roles of G

P019
Transcriptional regulatory roles of G-quadruplex DNA
in promoters of genes involved in beta-adrenergic
signaling pathway
Wenhua Zhou1, Liming Ying2, Sian E Harding1
and Ramon Vilar Compte3
1
NHLI, Imperial College London, London, UK
2
Imperial College London, London, UK
3
Chemistry Department, Imperial College London,
London, UK
G-quadruplexes (G4s) are four-stranded DNA secondary structures
involved in a diverse range of biological processes. Although
the anti-cancer potential of G4s in oncogene promoters has
been extensively investigated, the functions of promoter G4s in
non-cancer-related genes are not known. 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. Our bioinformatics study has revealed that potential
G4-forming sequences are particularly enriched in the transcription
regulatory regions (TRRs) of cardiac function-related genes. Several
genes (adrenergic receptor beta-1 (ADRB1), adenylate cyclase 5
(AC5), and downstream human cardiac troponin I (TnIc)) involved
in beta-adrenergic signaling pathway which have conserved G4s
in their promoters were then selected and subjected to biophysical
characterization and gene expression studies. We found that TnIc
promoter G4s act cooperatively as enhancers in gene expression
regulation in HEK293 cells, when stabilized by a synthetic
G4-binding ligand, the first evidence of the biological significance
of promoter G4s in cardiac function-related genes. In addition,
our preliminary results with the study of human ADRB1 and AC5
indicate that transcription of these two genes are inhibited, in the
presence of the compound TMPyP4 which stabilize the G4s. Based
on these findings, we hypothesize that these conserved G4s found
in the promoters of ADRB1 and AC5 may be considered as potential
targets to inhibit corresponding gene transcription, providing cardiac
protective effects similar to beta-blockers.