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

Area of Science:

• Genomics
• Molecular Biology
• Hepatology

Background:

• Myotonic dystrophy type 1 (DM1) results from expanded CTG repeats, impacting multiple organs.
• Muscleblind-like (MBNL) protein sequestration by CUG repeat RNAs is a key pathogenic event.
• Liver dysfunction and lipid abnormalities are common DM1 symptoms but are understudied.

Purpose of the Study:

• To investigate the molecular mechanisms underlying DM1-related liver abnormalities.
• To analyze transcriptome changes in DM1 patient livers and Mbnl-knockout mouse models.
• To identify specific genes and pathways affected by DM1 in the liver.

Main Methods:

• Transcriptome analysis using RNA-sequencing on postmortem DM1 patient livers and Mbnl-knockout mouse livers.
• Differential gene expression (DEG) analysis and aberrant splicing detection.
• Comparative analysis between Mbnl1- and Mbnl2-knockout mouse models.

Main Results:

• RNA-sequencing revealed significant DEGs and aberrant splicing in DM1 livers.
• MBNL1 deficiency partially explained transcriptomic changes observed in DM1 patients.
• Identified DEGs related to lipid metabolism and liver fibrosis; uncovered sex-specific pathway alterations.
• Aberrant splicing clusters included genes involved in lipid and glucose metabolism.
• Correlated splicing abnormalities with elevated serum gamma-glutamyl transferase levels.

Conclusions:

• DM1 significantly alters liver gene expression and splicing, impacting lipid metabolism and potentially causing fibrosis.
• MBNL1 plays a crucial role in mediating DM1-associated hepatic transcriptomic changes.
• These findings offer new molecular insights into DM1-related metabolic and hepatic complications.