Local Non-Coding Regulatory Elements in Muscular Dystrophies

Abstract

Muscular dystrophies are a class of diseases characterized by muscular weakness, breakdown, and heavily impaired function and quality of life. Numerous types of muscular dystrophies have been identified, with different causative genes and dystrophic mechanisms. While the majority of studies emphasize the protein product encoded by each gene, a growing body of research has identified non-coding elements as key regulators of muscular dystrophy. In this review, we summarize the common noncoding mechanisms known to regulate multiple forms of muscular dystrophies. We also highlight individual studies exploring local, disease-specific noncoding elements to each disease. Together, this provides a comprehensive overview of the major role of non-coding regulation in muscular dystrophies.

Keywords: CMD; DM; DMD; FSHD; LGMD; OPMD; epigenetics; lncRNA; miRNA; ncRNA.

Figure 1

A depiction of whether commonly dysregulated miRNAs are dysregulated in each form of muscular dystrophy, and the tissue used for assessment. Orange boxes represent upregulation in that disease, blue boxes represent downregulation, and grey boxes represent normal expression. Pink boxes represent that to the best of the authors knowledge, no studies have explored this miRNA-disease combination. All subtypes of LGMDs were included in the LGMD column, as most pertinent studies did not separate by subtype.

Figure 2

Schematic representation of chromatin and methylation profile in healthy and DM1 affected muscle cells. Black arrows indicate transcription start site of each gene or antisense transcript. Red arrows indicate decrease in gene expression and green arrows increase in gene expression. In healthy condition DMPK gene remains unmethylated with the exception exon 4 and surrounding introns. In addition, unmethylated CTCF binding sites upstream (CTCF1) and downstream (CTCF2) the CTG repeats allows CTCF binding. SIX5 and DWMD promoter regions are characterized by open chromatin status. DWMD 3′ end as enhancer of DMPK driving increase expression in muscle cells. DM1 antisense transcripts (DM1-AS) is in low levels in WT cells. However, in DM1, hypermethylation of CTCF sites and upstream regions prevents CTCF to bind, driving downstream effects that are still debated. In addition, hypermethylation results in a reduction in expression of SIX5 (homeodomain transcription factor) contributing to the pathogenesis of DM1. Moreover, histone tail modifications changes to inactive marks that close chromatin. DM1 antisense transcripts (DM1-AS) carrying expanded CTG repeats increase in DM1 hypothesized to be involved in the pathogenesis of DM1. Finally, DMPK transcripts function as a “magnet” for splicing factors (MBNL) and miRNAs with CAG repeats (miR-16 and miR-107) in their seed sequences, preventing miRNA’s normal function.