Research project

Circular RNA role in Myotonic Dystrophy type 1 (DSB.AD006.297)

Thematic area

Biomedical sciences

Project area

Biologia Molecolare/Cellulare (DSB.AD006)

Structure responsible for the research project

Istituto di Biochimica e Biologia Cellulare (IBBC)

Project manager

GERMANA FALCONE
Phone number: 06 90091323
Email: germana.falcone@cnr.it

Abstract

Myotonic dystrophy type 1 (DM1) is a neuromuscular disorder caused by an unstable (CTG)n repeat in the DM protein kinase (DMPK) gene. Characteristic DM1 molecular features have been associated with a toxic RNA gain of function of the CUG expansions. Expanded CUG-repeats sequester nuclear proteins and accumulate into distinctive foci within cell nuclei. They have been demonstrated to be toxic per se, disrupting gene transcription and pre-mRNA alternative splicing. Splicing events do not always produce a linear transcript. Circular RNAs (circRNAs) are emerging as key new members of the gene regulatory milieu, which are produced by back-splicing events within genes. Many circRNAs have been found to be important regulators of cellular physiology and pathology by a variety of mechanisms, and perturbations of circRNA expression have been recently reported in association with disease, including DM1. In this project the following aims will be pursued:1. Identify circRNAs dysregulated in muscle biopsies of DM1 patients. 2. Assess the potential of circRNAs as DM1 biomarkers. 3. Functionally validate the differentially expressed circRNAs in DM1 in vitro models.

Goals

Given that alternative splicing is altered severely in DM1, we hypothesized that circRNA regulation is also affected. Accordingly, analysis of publicly available gene-expression datasets indicate a pervasive dysregulation of circRNA levels and we identified a subset of circRNAs that are significantly increased in muscle biopsies of DM1 patients. However, little is known on the role of circRNA in DM1, and research is urgently required to understand their function and potential use as biomarkers. To this purpose, the following aims will be pursued:
1. Identify circRNAs dysregulated in muscle biopsies of DM1 patients. DM1-circRNAs candidates identified by the analysis of public DM1 RNA-seq datasets and by our previous studies will be extensively validated and characterized molecularly;
2. Assess the potential of circRNAs as DM1 biomarkers.
3. Functionally validate the differentially expressed circRNAs in DM1 in vitro models. Multiple myogenic cell lines and primary myoblasts derived from DM1 patients will be used for functional validation.

Start date of activity

26/08/2020

Keywords

myotonic dystrophy, circular RNAs, splicing regulation

Last update: 29/03/2024