Grant: Project Grant

The Encyclopedia of DNA Elements (ENCODE) and the Functional Annotation Of Mouse (FANTOM) consortiums reported that there are far more transcripts than initially anticipated. Surprisingly, it turned out that coding transcripts represent only <3% of the total genome, whereas the majority of other transcripts have no coding potential. The existence of the large number of noncoding transcripts has been disregarded as junk DNA and transcript noises for some time, but increasing evidence suggests that a significant part of such noncoding transcripts are in fact functionally active RNA molecules. Importantly, the biological function of noncoding RNAs is thus primarily determined by their structure and their interactions with protein partners. Among these non-coding RNAs are riboswitches, which are structured elements typically found in the 5' untranslated regions of mRNAs. Riboswitches regulate gene expression by altering their structure upon binding to small cellular metabolites. Similarly to the majority of non-coding RNAs, very little information is known regarding how the structure of riboswitches is used to modulate genetic expression. As a result, it is imperative to employ novel high-resolution methods to characterize RNA structures under conditions closer to the in vivo context, most preferably allowing to study the structure of nascent transcripts. A major goal of our research is to unravel the molecular mechanisms by which riboswitches perform ligand binding during their transcription (i.e., co-transcriptionally) to control gene expression. Our research could be used to design novel general antimicrobial drugs based on riboswitch ligand analogs, which would be selectively toxic to bacteria carrying these RNAs. The knowledge obtained from this research will also be generally applicable to study more complex systems, such as long non-coding RNAs associated to cardiovascular diseases and several types of cancer.