Apabetalone, a Clinical-Stage, Selective BET Inhibitor, Opposes DUX4 Target Gene Expression in Primary Human FSHD Muscle Cells
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 <i>DUX4</i> expression have the potential to treat F...
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| Format: | Article |
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MDPI AG
2023-09-01
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| Series: | Biomedicines |
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| Online Access: | https://www.mdpi.com/2227-9059/11/10/2683 |
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| author | Christopher D. Sarsons Dean Gilham Laura M. Tsujikawa Sylwia Wasiak Li Fu Brooke D. Rakai Stephanie C. Stotz Agostina Carestia Michael Sweeney Ewelina Kulikowski |
| author_facet | Christopher D. Sarsons Dean Gilham Laura M. Tsujikawa Sylwia Wasiak Li Fu Brooke D. Rakai Stephanie C. Stotz Agostina Carestia Michael Sweeney Ewelina Kulikowski |
| author_sort | Christopher D. Sarsons |
| collection | DOAJ |
| description | 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 <i>DUX4</i> 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. |
| first_indexed | 2024-03-10T21:25:22Z |
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| id | doaj.art-51286032f8f3442ebfcdb580ce159e02 |
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| language | English |
| last_indexed | 2024-03-10T21:25:22Z |
| publishDate | 2023-09-01 |
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| series | Biomedicines |
| spelling | doaj.art-51286032f8f3442ebfcdb580ce159e022023-11-19T15:45:36ZengMDPI AGBiomedicines2227-90592023-09-011110268310.3390/biomedicines11102683Apabetalone, a Clinical-Stage, Selective BET Inhibitor, Opposes DUX4 Target Gene Expression in Primary Human FSHD Muscle CellsChristopher D. Sarsons0Dean Gilham1Laura M. Tsujikawa2Sylwia Wasiak3Li Fu4Brooke D. Rakai5Stephanie C. Stotz6Agostina Carestia7Michael Sweeney8Ewelina Kulikowski9Resverlogix Corp., 300, 4820 Richard Road SW, Calgary, AB T3E 6L1, CanadaResverlogix Corp., 300, 4820 Richard Road SW, Calgary, AB T3E 6L1, CanadaResverlogix Corp., 300, 4820 Richard Road SW, Calgary, AB T3E 6L1, CanadaResverlogix Corp., 300, 4820 Richard Road SW, Calgary, AB T3E 6L1, CanadaResverlogix Corp., 300, 4820 Richard Road SW, Calgary, AB T3E 6L1, CanadaResverlogix Corp., 300, 4820 Richard Road SW, Calgary, AB T3E 6L1, CanadaResverlogix Corp., 300, 4820 Richard Road SW, Calgary, AB T3E 6L1, CanadaResverlogix Corp., 300, 4820 Richard Road SW, Calgary, AB T3E 6L1, CanadaResverlogix Corp., 535 Mission St., 14th Floor, San Francisco, CA 94105, USAResverlogix Corp., 300, 4820 Richard Road SW, Calgary, AB T3E 6L1, CanadaFacioscapulohumeral 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 <i>DUX4</i> 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.https://www.mdpi.com/2227-9059/11/10/2683facioscapulohumeral muscular dystrophyFSHDDUX4bromodomain and extra-terminal domainBET inhibitortranscriptome |
| spellingShingle | Christopher D. Sarsons Dean Gilham Laura M. Tsujikawa Sylwia Wasiak Li Fu Brooke D. Rakai Stephanie C. Stotz Agostina Carestia Michael Sweeney Ewelina Kulikowski Apabetalone, a Clinical-Stage, Selective BET Inhibitor, Opposes DUX4 Target Gene Expression in Primary Human FSHD Muscle Cells Biomedicines facioscapulohumeral muscular dystrophy FSHD DUX4 bromodomain and extra-terminal domain BET inhibitor transcriptome |
| title | Apabetalone, a Clinical-Stage, Selective BET Inhibitor, Opposes DUX4 Target Gene Expression in Primary Human FSHD Muscle Cells |
| title_full | Apabetalone, a Clinical-Stage, Selective BET Inhibitor, Opposes DUX4 Target Gene Expression in Primary Human FSHD Muscle Cells |
| title_fullStr | Apabetalone, a Clinical-Stage, Selective BET Inhibitor, Opposes DUX4 Target Gene Expression in Primary Human FSHD Muscle Cells |
| title_full_unstemmed | Apabetalone, a Clinical-Stage, Selective BET Inhibitor, Opposes DUX4 Target Gene Expression in Primary Human FSHD Muscle Cells |
| title_short | Apabetalone, a Clinical-Stage, Selective BET Inhibitor, Opposes DUX4 Target Gene Expression in Primary Human FSHD Muscle Cells |
| title_sort | apabetalone a clinical stage selective bet inhibitor opposes dux4 target gene expression in primary human fshd muscle cells |
| topic | facioscapulohumeral muscular dystrophy FSHD DUX4 bromodomain and extra-terminal domain BET inhibitor transcriptome |
| url | https://www.mdpi.com/2227-9059/11/10/2683 |
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