Dottorato in GENETICA E BIOLOGIA MOLECOLARE

Titolo della tesi: Role of trans-acting long non-coding RNAs in physiology and pathology

Long non-coding RNAs are pivotal regulators of gene expression. They have been found to play a role in different biological processes and several modes of action have been described. An interesting field in which lncRNA have been studied is the one concerning the planning and execution of voluntary movement. They have been in fact extensively studied during muscular differentiation, in homeostasis and pathology, in order to understand their contribution to muscle formation and maintenance, and they are currently under characterization in physiological and pathological aspects of motor neuron, the unit which is aimed to transport the signal which coordinates the muscle action. In this context I have studied two trans-acting lncRNAs. The first one, DUXAP8 has been found aberrantly expressed in a Duchenne muscular dystrophy patient. Its expression causes the unexpected silencing of a splicing factor, Celf2a, through the deposition of repressive histone marks. As a consequence, there is a compaction of chromatin which impedes the binding of the skeletal myogenesis master regulator MyoD, involved as well in regulation of the splicing factor. The absence of Celf2a favours a natural occurring exon 45 skipping in patient myotubes, resulting in a partial restoration of Dystrophin expression, sufficient to ameliorate the condition of the patient. For what concerns motor neuron, it has been identified a new player in physiological differentiation that is characterized by the presence of a small open reading frame coding for a micropeptide, which seems to be involved in processes taking place in motor neuron membrane.