This project stems from gaps still present in the etiopathogenesis of MS. A plausible role by the recently described transient RNA s (trRNAs) may contribute to fill these gaps. Regulatory tr-RNA share some features: erratic time dynamics; highly contextual expression (in time and tissues); propensity to respond to non-genetic `cues¿ converging on DNA regulatory regions. The transient transcriptome has a half-life of minutes, compared to stable RNA (mRNAs, long-noncoding RNAs, and micro-RNAs) that last at least hours. Transient transcriptomes include enhancer RNAs (eRNA), short intergenic non-coding RNAs (sincRNA - promoter-associated RNAs within 10 Kbp of a GENCODE mRNA transcription start site) and antisense RNAs.
Our working hypothesis is that genomic regions coding for trRNA are significantly enriched of genetic variants associated to MS, and significantly enriched of binding motifs for non-genetic `drivers¿ capable of tuning the regulation exerted by trRNA physiologically or with a pathogenic outcome, as it may be in MS. The research plan will include the following steps:
-Implementing maps of genomic regions coding for trRNA, with special reference to eRNA and sincRNA, from as many tissues as possible;
-Matching between genomic regions coding trRNA (categorized according to their tissue expression) and genomic regions resulting from genomewide association studies on MS;
-Verifying whether the genomic regions coding for trRNA are significantly enriched of DNA-binding sites for ¿transductors¿ of adaptive/pathogenic cues such as vitamin D receptor, activation-induced cytidine deaminase, aryl hydrocarbon receptor, and Epstein Barr virus nuclear antigens (EBNA2 and EBNA3C).
The availability of advanced genomic annotations and bioinformatics tools, as well as the recent published TT-seq protocol to map the human transient transcriptome, make the working hypothesis testable in silico (the present project) and, if confirmed, in ex-vivo experiments in MS patients.
