Apabetalone, a Clinical-Stage, Selective BET Inhibitor, Opposes DUX4 Target Gene Expression in Primary Human FSHD Muscle Cells.
Christopher D SarsonsDean GilhamLaura M TsujikawaSylwia WasiakLi FuBrooke D RakaiStephanie C StotzAgostina CarestiaMichael SweeneyEwelina KulikowskiPublished in: Biomedicines (2023)
Facioscapulohumeral dystrophy (FSHD) is a muscle disease caused by inappropriate expression of the double homeobox 4 (DUX4) gene in skeletal muscle, and its downstream activation of pro-apoptotic transcriptional programs. Inhibitors of DUX4 expression have the potential to treat FSHD. Apabetalone is a clinical-stage bromodomain and extra-terminal (BET) inhibitor, selective for the second bromodomain on BET proteins. Using primary human skeletal muscle cells from FSHD type 1 patients, we evaluated apabetalone for its ability to counter DUX4's deleterious effects and compared it with the pan-BET inhibitor JQ1, and the p38 MAPK inhibitor-and DUX4 transcriptional repressor-losmapimod. We applied RNA-sequencing and bioinformatic analysis to detect treatment-associated impacts on the transcriptome of these cells. Apabetalone inhibited the expression of DUX4 downstream markers, reversing hallmarks of FSHD gene expression in differentiated muscle cells. JQ1, but not apabetalone, was found to induce apoptosis. While both BET inhibitors modestly impacted differentiation marker expression, they did not affect myotube fusion. Losmapimod also reduced expression of DUX4 target genes but differed in its impact on FSHD-associated pathways. These findings demonstrate that apabetalone inhibits DUX4 target gene expression and reverses transcriptional programs that contribute to FSHD pathology, making this drug a promising candidate therapeutic for FSHD.
Keyphrases
- gene expression
- skeletal muscle
- poor prognosis
- cell cycle arrest
- induced apoptosis
- dna methylation
- cell death
- endothelial cells
- oxidative stress
- endoplasmic reticulum stress
- genome wide
- end stage renal disease
- transcription factor
- binding protein
- chronic kidney disease
- signaling pathway
- insulin resistance
- public health
- emergency department
- ejection fraction
- single cell
- heat shock
- long non coding rna
- risk assessment
- induced pluripotent stem cells
- peritoneal dialysis
- data analysis
- human health
- electronic health record
- bioinformatics analysis
- patient reported outcomes
- adverse drug