Titolo della tesi: Role of RNA interactions in neuro-muscular development and pathology
The role of RNA interactions is crucial during complex processes such as cell differentiation in which many layers of molecular regulatory mechanism are orchestrated to promote the progression of developmental stages.
In particular we have characterized the molecular mechanism of two lncRNAs: we demonstrated that lncSMaRT is able to base pairs with its targets mRNAs, Mlx y and Spire1, mediating their translational repression and thus promoting murine skeletal muscle differentiation; moreover, we have described the functions of the multiple elements generated by the complex MN2 locus: two miRNAs (miR-384-5p and miR-325-3p) and a cytoplasmic lncRNA lncMN2-203 that synergistically cooperate to favor motor neurogenesis.
Moreover, the role of RNA interaction is often deregulated in pathological context. In neuro-muscular diseases we have characterized the role of RNA interactions focusing on Rhabdomyosarcoma and the motoneuron disease Amyotrophic Lateral Sclerosis (ALS).
Indeed, we demonstrated that in Rhabdomyosarcoma there is an augmented production of a class of peculiar lncRNAs, the covalently closed circular RNAs. Little is known about their biogenesis and alteration in cancer. We demonstrated that YTHDC1, the reader of the RNA epitranscriptomic modification N6 methyladenosine and the RNA helicase DDX5 are able to act in complex to regulate this process in this cancer type.
Furthermore, the role of RNA interactions is pivotal especially in the generation of membrane-less organelles that have often crucial implications in neurodegenerative diseases such as ALS. I have studied the interplay between the ALS associated FUS mutation P525L and the cytoplasmic membrane-less organelles Stress Granules (SGs). These condensates are generated in condition of oxidative stress and are important for storage of mRNAs when translation is stalled. We have characterized the first SG transcriptome in human neural system, and we have found that in presence of mutant FUS their physical properties and RNA composition are altered. Finally, we have studied the role of m6A in regulating these membrane-less organelles.