Small Molecule Screening Identifies HSP90 as a Modifier of RNA Foci in Myotonic Dystrophy Type 1
Year: 2024
Type: article
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.
Source: Molecular and Cellular Biology
Authors: Sara J. Johnson, Hannah L. Johnson, Reid T. Powell, Clifford Stephan, Fabio Stossi, Thomas A. Cooper
Institutions: Baylor College of Medicine, Texas A&M University
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
Awards: G1147702603, G1738995106, G274084553, G3152434804, Verbundprojekt: Netzwerk Mitochondriale Erkrankungen (mitoNET), TP CU, C1, D2: Koordination, Register, Biobank Muskelgewebe, The Combinatorial Drug Discovery Program (CDDP), G4819929959, G4871197301, Netzwerk für Seltene Erkrankungen: Muskeldystrophien (MD-NET), ACQUISITION OF THE YOKOGAWA CV8000 HIGH THROUGHPUT SPINNING DISK MICROSCOPE AND ROBOTICS, GCC Center for Advanced Microscopy and Image Informatics, The Combinatorial Drug Discovery Program (CDDP), Transcriptome processing networks in skeletal muscle: mechanisms and functions, G7837447426, G8413015676, G9000013585, G9000240210, Baylor College of Medicine Cancer Center - Cancer Center Support Grant
OpenAlex ID: W4403495370