Abstract
Circular RNAs (circRNAs) constitute a recently re-discovered class of non-coding RNAs functioning as sponges for miRNAs and proteins, affecting RNA splicing and regulating transcription. CircRNAs are generated by “back-splicing”, which is the linking covalently of 3′- and 5′-ends of exons. Thus, circRNA levels might be deregulated in conditions associated with altered RNA-splicing. Significantly, growing evidence indicates their role in human diseases. Specifically, myotonic dystrophy type 1 (DM1) is a multisystemic disorder caused by expanded CTG repeats in the DMPK gene which results in abnormal mRNA-splicing. In this investigation, circRNAs expressed in DM1 skeletal muscles were identified by analyzing RNA-sequencing data-sets followed by qPCR validation. In muscle biopsies, out of nine tested, four transcripts showed an increased circular fraction: CDYL, HIPK3, RTN4_03, and ZNF609. Their circular fraction values correlated with skeletal muscle strength and with splicing biomarkers of disease severity, and displayed higher values in more severely affected patients. Moreover, Receiver-Operating-Characteristics curves of these four circRNAs discriminated DM1 patients from controls. The identified circRNAs were also detectable in peripheral-blood-mononuclear-cells (PBMCs) and the plasma of DM1 patients, but they were not regulated significantly. Finally, increased circular fractions of RTN4_03 and ZNF609 were also observed in differentiated myogenic cell lines derived from DM1 patients. In conclusion, this pilot study identified circRNA dysregulation in DM1 patients.
Highlights
Myotonic dystrophy type 1 (DM1), known as Steinert disease (OMIM #160900), is an autosomal dominant multi-systemic disorder with a spectrum of clinical manifestations that includes myotonia, reduced muscle strength, cardiac arrhythmia, insulin resistance, cataracts, hypogonadism, and, in the most severe forms, cognitive defects [1,2,3,4]
A major patho-mechanism underpinning DM1 is the generation of toxic RNAs containing expanded CUG triplets that accumulate as distinctive nuclear foci and dysregulate the activity of RNA processing factors, including MBNL1 and CELF1 as well as Staufen1 and DDX5 [6,7,8,9,10,11,12]
Published RNA sequencing (RNAseq) data of ribo-depleted libraries derived from five controls and 25 DM1 tibialis anterior biopsies [37,38] were investigated for circRNA expression
Summary
Myotonic dystrophy type 1 (DM1), known as Steinert disease (OMIM #160900), is an autosomal dominant multi-systemic disorder with a spectrum of clinical manifestations that includes myotonia, reduced muscle strength, cardiac arrhythmia, insulin resistance, cataracts, hypogonadism, and, in the most severe forms, cognitive defects [1,2,3,4]. A major patho-mechanism underpinning DM1 is the generation of toxic RNAs containing expanded CUG triplets that accumulate as distinctive nuclear foci and dysregulate the activity of RNA processing factors, including MBNL1 and CELF1 as well as Staufen and DDX5 [6,7,8,9,10,11,12]. Expanded CUG repeats have been demonstrated to be toxic in several cell types and animal models [13,14,15], disrupting pre-mRNA alternative splicing [16]. RNA splicing alterations result in the re-emergence of developmentally immature alternative splicing and polyadenylation patterns in adult muscles, as well as in alterations of the localization and turnover of specific transcripts [7,16,17,18,19]
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