MEG3 Upregulation in Myotonic Dystrophy and Its Correction by Antisense Conjugates Targeting Disease-Causing Mutations [mRNA-seq]
MEG3 upregulation has been confirmed to independently promote apoptosis in cancer, cardiovascular disease, and Alzheimer's Disease. In this study, we unveiled that MEG3 is highly upregulated in Myotonic Dystrophy 1 (DM1) human muscle cells when compared with wild type cells. It is also increased in the muscle of DM1 mouse models, 15-fold in HSA-LR, and 6-fold in LC15. We also observed an increase of MEG3 in SMA mice (5-fold) indicating that MEG3 levels could play a role in the neuromuscular pathology leading to cell loss. Additionally in DM1, RNA sequencing revealed transcript retention of miRNAs and LncRNAs in the nucleus versus the cytoplasm, a phenomenon not observed with mRNAs. This nuclear retention could exacerbate pathological mechanisms involving non-coding RNA, such as MEG3-led apoptosis. In DM1 mice (HSA-LR), the correction of DM1 pathology with a peptide antisense oligonucleotide conjugate targeting the repeat expansion, a family of compounds currently being tested in a DM1 clinical trial, was able to also reduce the levels of MEG3. When direct interventions for the root cause of a disease are unavailable, the downregulation of MEG3 and its effect on apoptosis may serve as an alternative therapeutic approach, notably in conditions that arise from complex interactions of genetic and environmental factors. Overall design: To detect misregulated lncRNAs in sub-cellular compartments from healthy and DM1 affected human myotubes, we used PARIS kit to fraction human myotubes into nucleus and cytoplasm fractions. Then RNA-Seq was performed and expression levels of lncRNAs were determined.