Transcriptome alterations underlying metabolic dysfunction and liver disease in myotonic dystrophy type 1 [mouse]

Myotonic dystrophy type 1 (DM1) is a multisystem disorder caused by toxic RNA transcribed from expanded CTG repeats in the DMPK gene, leading to sequestration of MBNL proteins. To investigate the role of MBNL1 and MBNL2 in DM1-related liver dysfunction, transcriptome analysis was performed on livers from Mbnl1 knockout (three females, two males), Mbnl2 knockout (two females, three males) and wild type (four females, four males) mice using bulk RNA sequencing (RNA-seq) on the MGI DNBSEQ-G400RS. Differential gene expression and alternative splicing analyses highlighted significant transcriptomic alterations, some of which overlapped with changes observed in DM1 patient livers. MBNL1 was found to contribute to transcriptomic changes related to lipid metabolism, liver fibrosis, and glucose homeostasis. Sex-specific differences in transcriptomic profiles were also detected, with distinct pathway alterations observed in male and female knockout mice. These results suggest that MBNL proteins play a critical role in maintaining liver function and provide a model for understanding DM1-related metabolic and hepatic abnormalities. Overall Design: RNA-seq analysis was performed on liver tissues collected from Mbnl1 knockout mice (n = 5), Mbnl2 knockout mice (n = 5), and wild-type controls (n = 8). Transcriptomic changes, including differential expression and splicing, were analyzed to identify the role of MBNL1 and MBNL2 in liver dysfunction.