Language
English
Publication Date
1-1-2025
Journal
Molecular Cell Biology
DOI
10.1080/10985549.2024.2408025
PMID
39415708
PMCID
PMC12317676
PubMedCentral® Posted Date
10-17-2023
PubMedCentral® Full Text Version
Author MSS
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.
Keywords
HSP90 Heat-Shock Proteins, Myotonic Dystrophy, Humans, Myotonin-Protein Kinase, Cell Line, RNA, Messenger, Myoblasts, Trinucleotide Repeat Expansion, STAT3 Transcription Factor, Small Molecule Libraries, Myotonic Dystrophy, RNA Foci, Small Molecule Screening, HSP90
Published Open-Access
yes
Recommended Citation
Johnson, Sara J; Johnson, Hannah L; Powell, Reid T; et al., "Small Molecule Screening Identifies HSP90 as a Modifier of RNA Foci in Myotonic Dystrophy Type 1" (2025). Faculty and Staff Publications. 4027.
https://digitalcommons.library.tmc.edu/baylor_docs/4027
Graphical Abstract