Perfilado transcriptómico de las interacciones de ARN en un modelo murino de Distrofia miotónica tipo 1 (DM1).

Abstract

Myotonic dystrophy type 1 (DM1) is an autosomal dominant neuromuscular disease caused by the expansion of the CTG triplet in the DMPK gene, which leads to the accumulation of abnormal transcripts and the sequestration of splicing regulatory proteins, causing gene dysregulation and multisystemic manifestations. Different investigations have pointed out the participation of microRNAs in the progression of the disease, especially hsa-miR-23b-3p, whose activity decreases the expression of MBNL1 and increases the pathological phenotype. For this reason, the present study aimed to identify the transcriptomic effects of treatment with ASOs by analyzing gene expression data. For this purpose, transcriptomic data of miRNA targets originated from a murine model of DM1, distributed in three experimental conditions: ASO- treated patient, untreated patient (PBS) and healthy control (FVB), were analyzed using the R open-source software. Differential expression analyses of ASO target genes revealed that the PBS vs FVB comparison showed a predominance of overexpressed genes linked to DM1 progression, whereas ASO vs PBS and ASO vs FVB only had underexpressed genes. In addition, genes involved in key cellular processes for muscle maintenance such as energy metabolism, cytoskeleton organization and muscle contraction were identified. In addition, genes involved in key cellular processes for muscle maintenance such as energy metabolism, cytoskeleton organization and muscle contraction were identified. The treatment increased the expression level of MBNL1 which modified the fetal splicing pattern by altering the expression of its targets. In conclusion, this research contributed with the identification of the recovery of transcriptomic alterations in MBNL1 targets directly related to DM1 and opens the door to future research in order to complement this study with alternative splicing and isoform analyses, which will allow to deepen the knowledge about how these genes participate in DM1 and the effect of ASOs treatment.