Journal Article Ppublish
PubMed: 39415708 DOI: 10.1080/10985549.2024.2408025
Small Molecule Screening Identifies HSP90 as a Modifier of RNA Foci in Myotonic Dystrophy Type 1.
Mol Cell Biol 45(6):225-237
Authors: Sara J Johnson, Hannah L Johnson, Reid T Powell, Clifford Stephan, Fabio Stossi, Thomas A Cooper
Affiliations
- Department of Pathology & Immunology, Baylor College of Medicine, Houston, Texas, USA. Department of Molecular & Cellular Biology, Baylor College of Medicine, Houston, Texas, USA.
- Department of Molecular & Cellular Biology, Baylor College of Medicine, Houston, Texas, USA.
- Department of Translational Medical Science, Institute of Biosciences and Technology, Texas A&M University, Houston, Texas, USA.
- Department of Pathology & Immunology, Baylor College of Medicine, Houston, Texas, USA.
- Department of Molecular Physiology & Biophysics, Baylor College of Medicine, Houston, Texas, USA.
Abstract
Myotonic dystrophy type 1 (DM1) is a multisystemic disorder caused by a CTG triplet repeat expansion within the 3' untranslated region of the DMPK gene. Expression of the expanded allele generates RNA containing long tracts of CUG repeats (CUGexp RNA) that form hairpin structures and accumulate in nuclear RNA foci; however, the factors that control DMPK expression and the formation of CUGexp RNA foci remain largely unknown. We performed an unbiased small molecule screen in an immortalized human DM1 skeletal muscle myoblast cell line and identified HSP90 as a modifier of endogenous RNA foci. Small molecule inhibition of HSP90 leads to enhancement of RNA foci and upregulation of DMPK mRNA levels. Knockdown and overexpression of HSP90 in undifferentiated DM1 myoblasts validated the impact of HSP90 with upregulation and downregulation of DMPK mRNA, respectively. Furthermore, we identified p-STAT3 as a downstream mediator of HSP90 impacting levels of DMPK mRNA and RNA foci. Interestingly, differentiated cells exhibited an opposite effect of HSP90 inhibition displaying downregulation of DMPK mRNA through a mechanism independent of p-STAT3 involvement. This study has revealed a novel mediator for DMPK mRNA and foci regulation in DM1 cells with the potential to identify targets for future therapeutic intervention.
MeSH
Cells, Up-Regulation, Genes, Myotonic Dystrophy, Myoblasts, Cell Biology, Down-Regulation, Rna, Small Molecules