Deficiency in the nuclear long noncoding RNA Charme causes myogenic defects and heart remodeling in mice

Abstract

Myogenesis is a highly regulated process that involves the conversion of progenitor cells into multinucleated myofibers. Besides proteins and miRNAs, long noncoding RNAs (lncRNAs) have been shown to participate in myogenic regulatory circuitries. Here, we characterize a murine chromatin‐associated muscle‐specific lncRNA, Charme, which contributes to the robustness of the myogenic program in vitro and in vivo. In myocytes, Charme depletion triggers the disassembly of a specific chromosomal domain and the downregulation of myogenic genes contained therein. Notably, several Charme‐sensitive genes are associated with human cardiomyopathies and Charme depletion in mice results in a peculiar cardiac remodeling phenotype with changes in size, structure, and shape of the heart. Moreover, the existence of an orthologous transcript in human, regulating the same subset of target genes, suggests an important and evolutionarily conserved function for Charme. Altogether, these data describe a new example of a chromatin‐associated lncRNA regulating the robustness of skeletal and cardiac myogenesis.

A high-content RNAi screen reveals multiple roles for long noncoding RNAs in cell division

“…However, exogenous lncRNA expression is not expected to rescue phenotypes associated with depletion of cis-acting chromatin-associated lncRNAs [42][43][44] . To assess a possible cis effect, we employed the CRISPR activation (CRISPRa) system 45 , which uses catalytically inactive dCas9 fused to transcriptional activator VP64, and guide 5 RNAs (gRNAs) targeting different regions of the linc00899 promoter.…”

Epigenetic silencing of LncRNA ANRIL enhances liver fibrosis and HSC activation through activating AMPK pathway

“…Epigenetic provides to a heritable modulation in gene expression that does not alter the DNA itself . Epigenetic influences generally refer to aberrant DNA methylation and non‐coding RNA (ncRNA) modifications . With regard to the latter, de novo DNA methylation activity catalysed by DNA methyltransferase 3A (DNMT3A) is methylated by addition of transfer methyl groups to the C‐5 position in the cytosine ring .…”

“…7,8 Epigenetic influences generally refer to aberrant DNA methylation and non-coding RNA (ncRNA) modifications. 9,10 With regard to the latter, de novo DNA methylation activity catalysed by DNA methyltransferase 3A (DNMT3A) is methylated by addition of transfer methyl groups to the C-5 position in the cytosine ring. 11,12 DNA methylation can establish a docking site for transcriptional repressors to permanent gene silencing.…”

Roles of lncRNAs and circRNAs in regulating skeletal muscle development

“…47 a classical eRNA that induces transcription of the adjacent MyoD RNA and also a trans-acting lncRNA that acts independently of MyoD. 53 The lncRNA Irm enhances myogenic differentiation by directly binding to MEF2D, which in turn promotes the assembly of the MyoD-MEF2D complex on the regulatory elements of target genes. 48 Some lncRNAs can bind to proteins to regulate muscle development and atrophy.…”

“…Charme inhibition mainly affects the ability of myogenic cells to fuse and proceed to the later stages of differentiation. 53 The lncRNA Irm enhances myogenic differentiation by directly binding to MEF2D, which in turn promotes the assembly of the MyoD-MEF2D complex on the regulatory elements of target genes. 54,55 Atrolnc-1 interacts with the A20 binding inhibitor of NF-κB-1, promoting the activation of NF-κB and resulting in an increase in MuRF-1 to promote muscle wasting.…”