The lncRNA Charme regulates skeletal muscle differentiation and heart development

The current view of coordinated gene expression suggests the existence of chromosome territories acting as discrete regulatory units. By Next-Generation RNA sequencing on murine myoblasts and differentiated myotubes, we recently identified an atlas of novel lncRNAs expressed at different stages during in vitro skeletal muscle differentiation (Ballarino et al, MCB 2015). Within this collection, the attention towards lnc-405, renamed as Charme (for Chromatin architect of muscle expression) was prioritized based on several peculiarities (Ballarino et al., submitted). At variance with most characterized lncRNAs, Charme is an abundant and highly conserved non-coding transcript specifically required for in vitro differentiation of myoblasts into myotubes. Mechanistically, we found that, in the nucleus, Charme acts as a structural RNA, which contributes to the formation of Chromosomal territories where coordinated expression of pro-myogenic genes occurs. In line with this, Charme knock-down produces the disassembly of specific chromosomal loops and the downregulation of myogenic genes therein contained, including genes linked to cardiomyopathies (Ballarino et al., submitted). Indeed, genetic ablation of Charme in vivo produces a macroscopic pathological phenotype in which the global architecture of the murine heart is altered. Moreover, we identified a human highly conserved Charme counterpart which regulates the same subset of target genes. Altogether, these data show that Charme regulates the chromosomal architecture and the expression of myogenic loci controlling muscle differentiation and heart remodelling