Thesis title: Evolutionary conservation of lncRNAs-mediated epigenetic circuitries in cardiac development and pathologies
Tissue-specific long non-coding RNAs (lncRNA) play essential functions in the regulation of cell proliferation and differentiation. Their dysregulation was often linked with neuromuscular and cardiovascular diseases, although the knowledge concerning their modes of action is still far from complete. Among them, nuclear lncRNAs are generally associated with chromatin, where they were shown to contribute to the formation of higher-order chromatin structures (Statello et al., 2021). This is the case of Charme, an abundant and highly conserved lncRNA previously identified in my host lab (Ballarino et al., 2015) and specifically expressed in skeletal myotubes and cardiomyocytes (CM) (Ballarino et al., 2018). My thesis work starts with the observation that in mice the functional loss of the nuclear Charme activities impacts on myogenic differentiation and triggers cardiac remodeling (Desideri et al., 2020). With this knowledge, we aimed to deeply examine the function of the lncRNA in heart development and to characterize its role from an evolutionary perspective, in both the murine and human cardiac biology. In particular, we found that, in mice, the nuclear isoform of Charme (pCharme) acts as an “architect” lncRNA by supervising the chromatin localization of MATR3, a DNA/RNA-binding protein whose mutation has been linked to neuromuscular and cardiovascular diseases. Specifically, in the nucleus, pCharme and MATR3 form ribonucleoprotein condensates that are crucial for the developmental expression of genes involved in the regulation of CMs proliferation/maturation balance. Disruption of these condensates in CharmeKO animals causes a substantial remodeling of the cardiac muscle. Intriguingly, we also found that the human syntenic gene, hsCharme, shares several features and a similar tissue specificity with its murine counterpart. Using the highly adaptable IPSCs system, we could observe that, in the nucleus, the lncRNA plays a conserved role in sustaining human CM maturation. Finally, we found that in human the expression of hsCharme was significantly altered in different types of cardiomyopathies. Since the World Health Organization classify cardiomyopathies among the most prevalent and fatal diseases in humans, understanding the role that hsCharme plays in a pathological context could be extremely important, especially in cases when a clear genetic cause was not identified, as it holds potential as a novel therapeutic tool.