scholarly journals An Overview of Circular RNAs and Their Implications in Myotonic Dystrophy

2019 ◽  
Vol 20 (18) ◽  
pp. 4385 ◽  
Author(s):  
Karol Czubak ◽  
Saam Sedehizadeh ◽  
Piotr Kozlowski ◽  
Marzena Wojciechowska
Keyword(s):  
Myotonic Dystrophy ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Current Knowledge ◽  
Circular Rnas ◽  
Contributing Factors ◽  
Aberrant Expression ◽  
New Members ◽  
Human Disorders

Circular RNAs (circRNAs) are a class of single-stranded covalently closed RNA rings. Biogenesis of circRNAs, which may occur co-transcriptionally and post-transcriptionally via a back-splicing mechanism, requires the presence of complementary and/or inverted repeat sequences in introns flanking back-spliced exons and is facilitated by RNA-binding proteins. CircRNAs are abundant across eukaryotes; however, their biological functions remain largely speculative. Recently, they have been emerging as new members of a gene regulatory network and contributing factors in various human diseases including cancer, neurological, muscular and cardiovascular disorders. In this review, we present an overview of the current knowledge about circRNAs biogenesis and their aberrant expression in various human disorders. In particular, we focus on the latest discovery of circRNAs global upregulation in myotonic dystrophy type 1 (DM1) skeletal muscles and the role these prospective biomarkers might have for prognosis and therapeutic response in DM1.

scholarly journals High-throughput kinome-RNAi screen identifies protein kinase R activator (PACT) as a novel genetic modifier of CUG foci integrity in myotonic dystrophy type 1 (DM1)

PLoS ONE ◽  
2021 ◽  
Vol 16 (9) ◽  
pp. e0256276
Author(s):  
Nafisa Neault ◽  
Sean O’Reilly ◽  
Aiman Tariq Baig ◽  
Julio Plaza-Diaz ◽  
Mehrdad Azimi ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Myotonic Dystrophy ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Genetic Modifier ◽  
Myotonic Dystrophy Type 1 ◽  
Myotonic Dystrophy Type ◽  
Aberrant Expression ◽  
Significant Correction

Myotonic Dystrophy Type 1 (DM1) is the most common form of adult muscular dystrophy (~1:8000). In DM1, expansion of CTG trinucleotide repeats in the 3’ untranslated region of the dystrophia myotonica protein kinase (DMPK) gene results in DMPK mRNA hairpin structures which aggregate as insoluble ribonuclear foci and sequester several RNA-binding proteins. The resulting sequestration and misregulation of important splicing factors, such as muscleblind-like 1 (MBNL1), causes the aberrant expression of fetal transcripts for several genes that contribute to the disease phenotype. Previous work has shown that antisense oligonucleotide-mediated disaggregation of the intranuclear foci has the potential to reverse downstream anomalies. To explore whether the nuclear foci are, to some extent, controlled by cell signalling pathways, we have performed a screen using a small interfering RNA (siRNA) library targeting 518 protein kinases to look at kinomic modulation of foci integrity. RNA foci were visualized by in situ hybridization of a fluorescent-tagged (CAG)10 probe directed towards the expanded DMPK mRNA and the cross-sectional area and number of foci per nuclei were recorded. From our screen, we have identified PACT (protein kinase R (PKR) activator) as a novel modulator of foci integrity and have shown that PACT knockdown can both increase MBNL1 protein levels; however, these changes are not suffcient for significant correction of downstream spliceopathies.

scholarly journals Brain Pathogenesis and Potential Therapeutic Strategies in Myotonic Dystrophy Type 1

2021 ◽  
Vol 13 ◽  
Author(s):  
Jie Liu ◽  
Zhen-Ni Guo ◽  
Xiu-Li Yan ◽  
Yi Yang ◽  
Shuo Huang
Keyword(s):  
Myotonic Dystrophy ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Brain Diseases ◽  
Myotonic Dystrophy Type 1 ◽  
Myotonic Dystrophy Type ◽  
Multiple Systems ◽  
Intervention Measures ◽  
Therapeutic Tools

Myotonic dystrophy type 1 (DM1) is the most common muscular dystrophy that affects multiple systems including the muscle and heart. The mutant CTG expansion at the 3′-UTR of the DMPK gene causes the expression of toxic RNA that aggregate as nuclear foci. The foci then interfere with RNA-binding proteins, affecting hundreds of mis-spliced effector genes, leading to aberrant alternative splicing and loss of effector gene product functions, ultimately resulting in systemic disorders. In recent years, increasing clinical, imaging, and pathological evidence have indicated that DM1, though to a lesser extent, could also be recognized as true brain diseases, with more and more researchers dedicating to develop novel therapeutic tools dealing with it. In this review, we summarize the current advances in the pathogenesis and pathology of central nervous system (CNS) deficits in DM1, intervention measures currently being investigated are also highlighted, aiming to promote novel and cutting-edge therapeutic investigations.

Abstract P104: Reactivation of Embryonic Gene Program due to CUG Repeat RNA Expression in Myotonic Dystrophy

2011 ◽  
Vol 109 (suppl_1) ◽  
Author(s):  
Auinash Kalsotra ◽  
Ravi Singh ◽  
Chad Creighton ◽  
Thomas Cooper
Keyword(s):  
Gene Expression ◽  
Myotonic Dystrophy ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Expression Patterns ◽  
Causative Mutation ◽  
Inherited Disease ◽  
Aberrant Expression ◽  
Organ Systems ◽  
General Response

Myotonic dystrophy type 1 (DM1) is a dominantly inherited disease that affects multiple organ systems. Cardiac involvement, which is characterized by conduction defects and arrhythmias, is the second leading cause of death in DM1 patients. The causative mutation is a CTG expansion in the 3' untranslated region of DMPK gene resulting in aberrant expression of CUG repeat RNA that accumulates into nuclear foci and causes misregulation in alternative splicing. Here we show that heart-specific and inducible expression of CUG repeat RNA in a DM1 mouse model results in global reactivation of embryonic gene expression program in adult heart that is distinct from a general hypertrophic stress response. Using q-PCR TaqMan arrays, we identified 54 miRNAs that were differentially expressed in DM1 mouse hearts one week following induction of CUG repeat RNA. Interestingly, 83% (45/54) of them exhibited a developmental shift in expression towards the embryonic pattern. Because over 90% (41/45) of them were down regulated within 72 hr after induction of repeat RNA and only 2/22 examined decreased in two unrelated mouse models of heart disease, we conclude their reduced expression is specific to DM1 and not simply a general response to cardiac injury. Microarray studies revealed a developmental switch not only in the miRNA expression patterns but also a pervasive shift in mRNA steady state levels of a number of genes to embryonic stage. Intriguingly, we found that loss of MBNL1 or gain of CELF1 activity, two major RNA binding proteins disrupted in DM1, are not driving the miRNA misregulation since their expression is indistinguishable between wild type, MBNL1 knock out and CELF1 over expressing mice. Moreover, comparable decrease in ten out of ten primary miRNA transcripts examined suggests loss of expression is not due to a processing defect. Instead, we discovered that adult-to-embryonic shift in expression of select micro- and messenger RNAs in DM1 heart occurs due to specific inactivation of a Mef2 transcriptional program. We are currently determining causal contributions of this Mef2-miRNA circuitry in the developmental reprogramming of gene expression in DM1 as well as its direct role in cardiac manifestations of this disease.

scholarly journals Increased Muscleblind levels by chloroquine treatment improve myotonic dystrophy type 1 phenotypes in in vitro and in vivo models

2019 ◽  
Vol 116 (50) ◽  
pp. 25203-25213 ◽  
Author(s):  
Ariadna Bargiela ◽  
Maria Sabater-Arcis ◽  
Jorge Espinosa-Espinosa ◽  
Miren Zulaica ◽  
Adolfo Lopez de Munain ◽  
...  
Keyword(s):  
Myotonic Dystrophy ◽  
Rna Binding ◽  
Trinucleotide Repeat ◽  
Rna Binding Proteins ◽  
Myotonic Dystrophy Type 1 ◽  
Myotonic Dystrophy Type ◽  
Muscle Area ◽  
In Vivo Models

Myotonic dystrophy type 1 (DM1) is a life-threatening and chronically debilitating neuromuscular disease caused by the expansion of a CTG trinucleotide repeat in the 3′ UTR of the DMPK gene. The mutant RNA forms insoluble structures capable of sequestering RNA binding proteins of the Muscleblind-like (MBNL) family, which ultimately leads to phenotypes. In this work, we demonstrate that treatment with the antiautophagic drug chloroquine was sufficient to up-regulate MBNL1 and 2 proteins in Drosophila and mouse (HSALR) models and patient-derived myoblasts. Extra Muscleblind was functional at the molecular level and improved splicing events regulated by MBNLs in all disease models. In vivo, chloroquine restored locomotion, rescued average cross-sectional muscle area, and extended median survival in DM1 flies. In HSALR mice, the drug restored muscular strength and histopathology signs and reduced the grade of myotonia. Taken together, these results offer a means to replenish critically low MBNL levels in DM1.

scholarly journals circRNAs Signature as Potential Diagnostic and Prognostic Biomarker for Diabetes Mellitus and Related Cardiovascular Complications

Cells ◽  
2020 ◽  
Vol 9 (3) ◽  
pp. 659 ◽  
Author(s):  
Mohamed Zaiou
Keyword(s):  
Diabetes Mellitus ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Current Knowledge ◽  
Vascular Complications ◽  
Cardiovascular Complications ◽  
Future Research ◽  
Circular Rnas ◽  
Obesity Hypertension ◽  
Based Medicine

Circular RNAs (circRNAs) belong to the ever-growing class of naturally occurring noncoding RNAs (ncRNAs) molecules. Unlike linear RNA, circRNAs are covalently closed transcripts mostly generated from precursor-mRNA by a non-canonical event called back-splicing. They are highly stable, evolutionarily conserved, and widely distributed in eukaryotes. Some circRNAs are believed to fulfill a variety of functions inside the cell mainly by acting as microRNAs (miRNAs) or RNA-binding proteins (RBPs) sponges. Furthermore, mounting evidence suggests that the misregulation of circRNAs is among the first alterations in various metabolic disorders including obesity, hypertension, and cardiovascular diseases. More recent research has revealed that circRNAs also play a substantial role in the pathogenesis of diabetes mellitus (DM) and related vascular complications. These findings have added a new layer of complexity to our understanding of DM and underscored the need to reexamine the molecular pathways that lead to this disorder in the context of epigenetics and circRNA regulatory mechanisms. Here, I review current knowledge about circRNAs dysregulation in diabetes and describe their potential role as innovative biomarkers to predict diabetes-related cardiovascular (CV) events. Finally, I discuss some of the actual limitations to the promise of these RNA transcripts as emerging therapeutics and provide recommendations for future research on circRNA-based medicine.

scholarly journals A comprehensive atlas of fetal splicing patterns in the brain of adult myotonic dystrophy type 1 patients

2021 ◽  
Author(s):  
Max J. F. Degener ◽  
Remco T.P. van Cruchten ◽  
Brittney A. Otero ◽  
Eric T. Wang ◽  
Derick G. Wansink ◽  
...  
Keyword(s):  
Myotonic Dystrophy ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Myotonic Dystrophy Type 1 ◽  
Myotonic Dystrophy Type ◽  
Healthy Individuals ◽  
Developmentally Regulated ◽  
The Central Nervous System ◽  
Splicing Patterns

ABSTRACTIn patients with myotonic dystrophy type 1 (DM1), dysregulation of RNA-binding proteins like MBNL and CELF1 leads to alternative splicing of exons and is thought to induce a return to fetal splicing patterns in adult tissues, including the central nervous system (CNS). To comprehensively evaluate this, we created an atlas of developmentally regulated splicing patterns in the frontal cortex of healthy individuals and DM1 patients by combining RNA-seq data from BrainSpan, GTEx and DM1 patients. Thirty four splice events displayed an inclusion pattern in DM1 patients that is typical for the fetal situation in healthy individuals. The regulation of DM1-relevant splicing patterns could partly be explained by changes in mRNA expression of the splice regulators MBNL1, MBNL2 and CELF1. On the contrary, interindividual differences in splicing patterns between healthy adults could not be explained by differential expression of these splice regulators. Our findings lend transcriptome-wide evidence to the previously noted shift to fetal splicing patterns in the adult DM1 brain as a consequence of an imbalance in antagonistic MBNL and CELF1 activities. Our atlas serves as a solid foundation for further study and understanding of the cognitive phenotype in patients.

scholarly journals Staufen1 impairs stress granule formation in skeletal muscle cells from myotonic dystrophy type 1 patients

2016 ◽  
Vol 27 (11) ◽  
pp. 1728-1739 ◽  
Author(s):  
Aymeric Ravel-Chapuis ◽  
Amanda Klein Gunnewiek ◽  
Guy Bélanger ◽  
Tara E. Crawford Parks ◽  
Jocelyn Côté ◽  
...  
Keyword(s):  
Myotonic Dystrophy ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Muscle Cells ◽  
Cellular Stress Response ◽  
Granule Formation ◽  
A Cell ◽  
Cell Type Specific ◽  
Cug Repeats

Myotonic dystrophy (DM1) is caused by an expansion of CUG repeats (CUGexp) in the DMPK mRNA 3′UTR. CUGexp-containing mRNAs become toxic to cells by misregulating RNA-binding proteins. Here we investigated the consequence of this RNA toxicity on the cellular stress response. We report that cell stress efficiently triggers formation of stress granules (SGs) in proliferating, quiescent, and differentiated muscle cells, as shown by the appearance of distinct cytoplasmic TIA-1– and DDX3-containing foci. We show that Staufen1 is also dynamically recruited into these granules. Moreover, we discovered that DM1 myoblasts fail to properly form SGs in response to arsenite. This blockage was not observed in DM1 fibroblasts, demonstrating a cell type–specific defect. DM1 myoblasts display increased expression and sequestration of toxic CUGexp mRNAs compared with fibroblasts. Of importance, down-regulation of Staufen1 in DM1 myoblasts rescues SG formation. Together our data show that Staufen1 participates in the inhibition of SG formation in DM1 myoblasts. These results reveal that DM1 muscle cells fail to properly respond to stress, thereby likely contributing to the complex pathogenesis of DM1.

scholarly journals Functional Roles and Biological Mechanisms of Circular RNAs and Their Encoded Peptides in Glioma: A Narrative Review

2021 ◽  
Vol 8 (4) ◽  
pp. 157-167
Author(s):  
Seyedeh Zahra Bakhti ◽  
Sana Dadashi ◽  
Anahita Dah Pahlevan ◽  
Fatemeh Kafshresan
Keyword(s):  
Rna Binding ◽  
Rna Binding Proteins ◽  
Current Knowledge ◽  
Expression Patterns ◽  
Circular Rnas ◽  
Specific Expression ◽  
Diagnostic Biomarkers ◽  
Functional Roles ◽  
Non Coding Rnas ◽  
Mirna Sponges

Circular RNAs (circRNAs) are a complicated class of non-coding RNAs that have a covalently closed loop structure and are very stable and cautious. Multiple biological processes of malignancy, including tumorigenesis, development, invasion, metastasis, apoptosis, and vascularization, are disrupted by an increased number of circRNAs. Recent research has showed that circRNAs, functioning as microRNA (miRNA) sponges or protein scaffolds, interacting with RNA-binding proteins (RBPs), and autophagy regulators, affect the transcription and splicing regulation. Many circRNAs have tissue-specific expression patterns and are heavily conserved. CircRNA levels in neurons are dynamically modulated. Growing evidence suggests that circRNAs are highly abundant in neural tissues, perhaps owing to the proliferation of particular genes that promote circularization, implying that circRNA dysregulation is linked to nervous system disorders including glioma. The most widespread and deadly primary malignant brain tumor is glioma. CircRNA has a close connection to glioma, according to reported research. Here, the current knowledge about the properties of circRNAs is introduced and the biological and molecular functions of circRNAs are described. Then, the clinical association of circRNAs with glioma/glioblastoma and their level of expression and their regulatory mechanisms in tumorigenesis are discussed. Moreover, the potential of circRNAs as diagnostic biomarkers and predictors of brain cancer risk and possible therapeutic targets in medicine is examined.

scholarly journals RNA-Binding Proteins in Pulmonary Hypertension

2020 ◽  
Vol 21 (11) ◽  
pp. 3757 ◽  
Author(s):  
Hui Zhang ◽  
R. Dale Brown ◽  
Kurt R. Stenmark ◽  
Cheng-Jun Hu
Keyword(s):  
Gene Expression ◽  
Pulmonary Hypertension ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Current Knowledge ◽  
Critical Role ◽  
Apoptosis Resistance ◽  
Aberrant Expression ◽  
Expression Of Genes

Pulmonary hypertension (PH) is a life-threatening disease characterized by significant vascular remodeling and aberrant expression of genes involved in inflammation, apoptosis resistance, proliferation, and metabolism. Effective therapeutic strategies are limited, as mechanisms underlying PH pathophysiology, especially abnormal expression of genes, remain unclear. Most PH studies on gene expression have focused on gene transcription. However, post-transcriptional alterations have been shown to play a critical role in inflammation and metabolic changes in diseases such as cancer and systemic cardiovascular diseases. In these diseases, RNA-binding proteins (RBPs) have been recognized as important regulators of aberrant gene expression via post-transcriptional regulation; however, their role in PH is less clear. Identifying RBPs in PH is of great importance to better understand PH pathophysiology and to identify new targets for PH treatment. In this manuscript, we review the current knowledge on the role of dysregulated RBPs in abnormal mRNA gene expression as well as aberrant non-coding RNA processing and expression (e.g., miRNAs) in PH.

scholarly journals Identification of Novel RNA Binding Proteins Influencing Circular RNA Expression in Hepatocellular Carcinoma

2021 ◽  
Vol 22 (14) ◽  
pp. 7477
Author(s):  
Rok Razpotnik ◽  
Petra Nassib ◽  
Tanja Kunej ◽  
Damjana Rozman ◽  
Tadeja Režen
Keyword(s):  
Hepatocellular Carcinoma ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Regulatory Protein ◽  
Circular Rna ◽  
Differentially Expressed ◽  
Circular Rnas ◽  
Bioinformatics Analyses ◽  
Published Evidence

Circular RNAs (circRNAs) are increasingly recognized as having a role in cancer development. Their expression is modified in numerous cancers, including hepatocellular carcinoma (HCC); however, little is known about the mechanisms of their regulation. The aim of this study was to identify regulators of circRNAome expression in HCC. Using publicly available datasets, we identified RNA binding proteins (RBPs) with enriched motifs around the splice sites of differentially expressed circRNAs in HCC. We confirmed the binding of some of the candidate RBPs using ChIP-seq and eCLIP datasets in the ENCODE database. Several of the identified RBPs were found to be differentially expressed in HCC and/or correlated with the overall survival of HCC patients. According to our bioinformatics analyses and published evidence, we propose that NONO, PCPB2, PCPB1, ESRP2, and HNRNPK are candidate regulators of circRNA expression in HCC. We confirmed that the knocking down the epithelial splicing regulatory protein 2 (ESRP2), known to be involved in the maintenance of the adult liver phenotype, significantly changed the expression of candidate circRNAs in a model HCC cell line. By understanding the systemic changes in transcriptome splicing, we can identify new proteins involved in the molecular pathways leading to HCC development and progression.

Sign in / Sign up

Export Citation Format

Share Document