Análisis comparativo del transcriptoma DM1 a nivel de poliadenilación alternativa e identificación de eventos de cambio de podio

Abstract

Myotonic dystrophy type 1 (DM1) is an autosomal dominant genetic disorder caused by the expansion of microsatellite repeats in the DMPK gene, characterized by a wide range of neuromuscular and multisystemic symptoms. A key mechanism in DM1 involves the sequestration of MBNL proteins by expanded CUG repeat RNA, which dysregulates alternative splicing and mRNA polyadenylation, contributing to the phenotypic diversity observed in the disease. This study utilized the bioinformatics tool tappAS to analyze alternative polyadenylation (APA) in 4,767 transcriptome sequences from DM1 patients and healthy subjects. A total of 304 genes with differential APA (DPA) were identified, 60 of which exhibited podium changes. These changes alter mRNA structure and potentially the function of the associated proteins. Specifically, genes involved in actin binding, actin filament binding, and muscle structural constitution, such as ASPH, KLHL3, LMOD3, MAP1A, MYH11, PDLIM3, and PPP1R9A, exhibited podium changes, suggesting alterations in cytoskeleton organization and myofibrillogenesis. Genes like OBSCN and TTN displayed DPA, which could impact sarcomere structure and function. Additionally, alterations in cell differentiation, mitochondrial function, and cell proliferation were observed in genes such as EIF3F, FBOX31, and OPA1. Regarding ion homeostasis and signal transduction, genes like CACNA1S and ASPH showed DPA, potentially compromising intracellular calcium regulation and growth factor signaling. Alterations in the regulation of sodium and calcium channels were also identified. In conclusion, the DPA events and podium changes detected reveal complex alterations in cellular and molecular processes in DM1, providing a comprehensive view of the pathogenic mechanisms and opening new avenues for therapeutic research.