The discovery and characterization of functional long noncoding RNAs (lncRNAs) updated the notion that proteins are the unique determinants for cellular phenotypes, revealing the requirement of these transcripts in cell growth, differentiation, apoptosis, organ development and function. Our lab contributed to advance the field through the identification of Charme (Chromatin architect of muscle expression), a muscle-restricted and evolutionary conserved lncRNA contributing to myogenesis through the regulation of myoblasts fusion and contraction genes. The expression of many of these Charme targets was found altered in human cardiomyopathies. In line with this, Charme null mice (CharmeKO) showed reduced lifespan as a consequence of muscle hyperplasia and a pronounced phenotype of cardiac remodeling at developmental onset. The mechanistic understanding of Charme mode-of-action required extensive efforts and still call for high-level competences, technological applications and model systems to be deepened further. We know that in muscle, the functional isoform (pCharme) retains an evolutionary conserved and long-sized intron (intron-1) of 11 kb in length. pCharme functions in myotubes as a chromatin architect lncRNA, which controls the expression of its direct targets by influencing their 3-dimensional genomic proximity. This epigenetic control is in line with emerging studies indicating that lncRNAs can act as modular scaffolds for chromatin regulators to shape the formation of chromosome territories where co-regulated gene expression occurs. The project proposed here aims to clarify the contribution of RNA-protein interactions to Charme-mediated epigenetic regulation. Although intron-1 mutations produce in vivo phenotypes similar to Charme ablation, evidences supporting the contribution of this region to the lncRNA chromatin performance are still preliminary and requires more investigation.
