Global increase in circRNA levels in myotonic dystrophy

Czubak, Karol; Taylor, Katarzyna; Piasecka, Agnieszka; Sobczak, Krzysztof; Kozlowska, Katarzyna; Philips, Anna; Sedehizadeh, Saam; Brook, David; Wojciechowska, Marzena; Kozłowski, Piotr

doi:10.1101/489070

Cited by 3 publications

(4 citation statements)

References 52 publications

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“…Thus, the levels of up to 20 cir-cRNAs were assessed in myoblasts and skeletal muscle from DM1 patients and healthy controls. Surprisingly, none of the circRNAs analysed were significantly decreased in either DM1 model (Czubak et al, 2019). These experiments actually showed a trend towards a global increase in circRNAs in DM1 skeletal muscle, which was confirmed by comparison with RNA sequencing data available on the DMseq database (Wang et al, 2019).…”

Section: (C) Circrnasupporting

confidence: 67%

“…These experiments actually showed a trend towards a global increase in circRNAs in DM1 skeletal muscle, which was confirmed by comparison with RNA sequencing data available on the DMseq database (Wang et al, 2019). This increase in global circRNA levels occurred in both the quadratus femoris and the tibialis anterior muscle of DM1 patients (Czubak et al, 2019).…”

Section: (C) Circrnasupporting

confidence: 64%

“…Interestingly, the circRNAs that are increased appear to be related to other aspects of DM1 myopathy. For example, gene ontology analysis showed an enrichment in 'aberrant splicing' and a specific circRNA, circZfp609, is upregulated in proliferating myoblasts, but downregulated during myogenesis (Czubak et al, 2019). Thus, these data reveal a new player in myoblast reprogramming and suggest a role for cir-cRNAs in missplicing and abnormal muscle differentiation.…”

Section: (C) Circrnamentioning

confidence: 84%

“…Recently, in 2019, circRNAs, which are more stable ncRNAs covalently linked at the 3 0 and 5 0 ends, were also linked with DM1 myopathy (Czubak et al, 2019). It was originally proposed that, as MBNL1 participates in the biogenesis of cir-cRNAs (bringing circRNA-flanking introns closer together and facilitating back-splicing), the levels of circRNAs would be downregulated in DM1, as a result of MBNL1 sequestration (Czubak et al, 2019). Thus, the levels of up to 20 cir-cRNAs were assessed in myoblasts and skeletal muscle from DM1 patients and healthy controls.…”

Section: (C) Circrnamentioning

confidence: 99%

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The hallmarks of myotonic dystrophy type 1 muscle dysfunction

et al. 2020

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Myotonic dystrophy type 1 (DM1) is the most prevalent form of muscular dystrophy in adults and yet there are currently no treatment options. Although this disease causes multisystemic symptoms, it is mainly characterised by myopathy or diseased muscles, which includes muscle weakness, atrophy, and myotonia, severely affecting the lives of patients worldwide. On a molecular level, DM1 is caused by an expansion of CTG repeats in the 3′ untranslated region (3′UTR) of the DM1 Protein Kinase (DMPK) gene which become pathogenic when transcribed into RNA forming ribonuclear foci comprised of auto complementary CUG hairpin structures that can bind proteins. This leads to the sequestration of the muscleblind‐like (MBNL) family of proteins, depleting them, and the abnormal stabilisation of CUGBP Elav‐like family member 1 (CELF1), enhancing it. Traditionally, DM1 research has focused on this RNA toxicity and how it alters MBNL and CELF1 functions as key splicing regulators. However, other proteins are affected by the toxic DMPK RNA and there is strong evidence that supports various signalling cascades playing an important role in DM1 pathogenesis. Specifically, the impairment of protein kinase B (AKT) signalling in DM1 increases autophagy, apoptosis, and ubiquitin–proteasome activity, which may also be affected in DM1 by AMP‐activated protein kinase (AMPK) downregulation. AKT also regulates CELF1 directly, by affecting its subcellular localisation, and indirectly as it inhibits glycogen synthase kinase 3 beta (GSK3β), which stabilises the repressive form of CELF1 in DM1. Another kinase that contributes to CELF1 mis‐regulation, in this case by hyperphosphorylation, is protein kinase C (PKC). Additionally, it has been demonstrated that fibroblast growth factor‐inducible 14 (Fn14) is induced in DM1 and is associated with downstream signalling through the nuclear factor κB (NFκB) pathways, associating inflammation with this disease. Furthermore, MBNL1 and CELF1 play a role in cytoplasmic processes involved in DM1 myopathy, altering proteostasis and sarcomere structure. Finally, there are many other elements that could contribute to the muscular phenotype in DM1 such as alterations to satellite cells, non‐coding RNA metabolism, calcium dysregulation, and repeat‐associated non‐ATG (RAN) translation. This review aims to organise the currently dispersed knowledge on the different pathways affected in DM1 and discusses the unexplored connections that could potentially help in providing new therapeutic targets in DM1 research.

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Section: (C) Circrnasupporting

confidence: 67%

Section: (C) Circrnasupporting

confidence: 64%

Section: (C) Circrnamentioning

confidence: 84%

Section: (C) Circrnamentioning

confidence: 99%

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The hallmarks of myotonic dystrophy type 1 muscle dysfunction

et al. 2020

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Circular RNA differential expression in blood cell populations and exploration of circRNA deregulation in pediatric acute lymphoblastic leukemia

Gaffo

Boldrin

Molin

et al. 2019

Sci Rep

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Circular RNAs (circRNAs) are abundantly expressed in the haematopoietic compartment, but knowledge on their diversity among blood cell types is still limited. Nevertheless, emerging data indicate an array of circRNA functions exerted through interactions with other RNAs and proteins, by translation into peptides, and circRNA involvement as regulatory molecules in many biological processes and cancer mechanisms. Interestingly, the role of specific circRNAs in leukemogenesis has been disclosed by a few studies, mostly in acute myeloid leukemia. In this study, circRNA expression in B-cells, T-cells and monocytes of healthy subjects is described, including putative new circRNA genes. Expression comparison considered 6,228 circRNAs and highlighted cell population-specific expression and exon usage patterns. Differential expression has been confirmed by qRT-PCR for circRNAs specific of B-cells (circPAX5, circAFF3, circIL4R, and circSETBP1) or T-cells (circIKZF1, circTNIK, circTXK, and circFBXW7), and for circRNAs from intronic (circBCL2) and intergenic regions that were overexpressed in lymphocytes. Starting from this resource of circRNA expression in mature blood cell populations, targeted examination identified striking and generalized upregulated expression of circPAX5, circPVT1 and circHIPK3 in pediatric B-precursor acute lymphoblastic leukemia, and disclosed circRNAs with variable expression across cytogenetic subtypes.

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Global Increase in Circular RNA Levels in Myotonic Dystrophy

et al. 2019

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Splicing aberrations induced as a consequence of the sequestration of muscleblind-like splicing factors on the dystrophia myotonica protein kinase transcript, which contains expanded CUG repeats, present a major pathomechanism of myotonic dystrophy type 1 (DM1). As muscleblind-like factors may also be important factors involved in the biogenesis of circular RNAs (circRNAs), we hypothesized that the level of circRNAs would be decreased in DM1. To test this hypothesis, we selected 20 well-validated circRNAs and analyzed their levels in several experimental systems (e.g., cell lines, DM muscle tissues, and a mouse model of DM1) using droplet digital PCR assays. We also explored the global level of circRNAs using two RNA-Seq datasets of DM1 muscle samples. Contrary to our original hypothesis, our results consistently showed a global increase in circRNA levels in DM1, and we identified numerous circRNAs that were increased in DM1. We also identified many genes (including muscle-specific genes) giving rise to numerous (>10) circRNAs. Thus, this study is the first to show an increase in global circRNA levels in DM1. We also provided preliminary results showing the association of circRNA level with muscle weakness and alternative splicing changes that are biomarkers of DM1 severity.

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Global increase in circRNA levels in myotonic dystrophy

Cited by 3 publications

References 52 publications

The hallmarks of myotonic dystrophy type 1 muscle dysfunction

The hallmarks of myotonic dystrophy type 1 muscle dysfunction

Circular RNA differential expression in blood cell populations and exploration of circRNA deregulation in pediatric acute lymphoblastic leukemia

Global Increase in Circular RNA Levels in Myotonic Dystrophy

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