BET bromodomain inhibitors and agonists of the beta-2 adrenergic receptor identified in screens for compounds that inhibit DUX4 expression in FSHD muscle cells
Abstract Background Facioscapulohumeral dystrophy (FSHD) is a progressive muscle disease caused by mutations that lead to epigenetic derepression and inappropriate transcription of the double homeobox 4 (DUX4) gene in skeletal muscle. Drugs that enhance the repression of DUX4 and prevent its express...
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doaj-851f6001f8d54b48828ccacb12eb61942020-11-24T21:47:58ZengBMCSkeletal Muscle2044-50402017-09-017111810.1186/s13395-017-0134-xBET bromodomain inhibitors and agonists of the beta-2 adrenergic receptor identified in screens for compounds that inhibit DUX4 expression in FSHD muscle cellsAmy E. Campbell0Jonathan Oliva1Matthew P. Yates2Jun Wen Zhong3Sean C. Shadle4Lauren Snider5Nikita Singh6Shannon Tai7Yosuke Hiramuki8Rabi Tawil9Silvère M. van der Maarel10Stephen J. Tapscott11Francis M. Sverdrup12Human Biology Division, Fred Hutchinson Cancer Research CenterEdward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis UniversityEdward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis UniversityHuman Biology Division, Fred Hutchinson Cancer Research CenterHuman Biology Division, Fred Hutchinson Cancer Research CenterHuman Biology Division, Fred Hutchinson Cancer Research CenterEdward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis UniversityEdward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis UniversityHuman Biology Division, Fred Hutchinson Cancer Research CenterDepartment of Neurology, University of Rochester Medical CenterDepartment of Human Genetics, Leiden University Medical CenterHuman Biology Division, Fred Hutchinson Cancer Research CenterEdward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis UniversityAbstract Background Facioscapulohumeral dystrophy (FSHD) is a progressive muscle disease caused by mutations that lead to epigenetic derepression and inappropriate transcription of the double homeobox 4 (DUX4) gene in skeletal muscle. Drugs that enhance the repression of DUX4 and prevent its expression in skeletal muscle cells therefore represent candidate therapies for FSHD. Methods We screened an aggregated chemical library enriched for compounds with epigenetic activities and the Pharmakon 1600 library composed of compounds that have reached clinical testing to identify molecules that decrease DUX4 expression as monitored by the levels of DUX4 target genes in FSHD patient-derived skeletal muscle cell cultures. Results Our screens identified several classes of molecules that include inhibitors of the bromodomain and extra-terminal (BET) family of proteins and agonists of the beta-2 adrenergic receptor. Further studies showed that compounds from these two classes suppress the expression of DUX4 messenger RNA (mRNA) by blocking the activity of bromodomain-containing protein 4 (BRD4) or by increasing cyclic adenosine monophosphate (cAMP) levels, respectively. Conclusions These data uncover pathways involved in the regulation of DUX4 expression in somatic cells, provide potential candidate classes of compounds for FSHD therapeutic development, and create an important opportunity for mechanistic studies that may uncover additional therapeutic targets.http://link.springer.com/article/10.1186/s13395-017-0134-xFacioscapulohumeral muscular dystrophyFSHDDUX4BromodomainAdrenergicHigh-throughput screening |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Amy E. Campbell Jonathan Oliva Matthew P. Yates Jun Wen Zhong Sean C. Shadle Lauren Snider Nikita Singh Shannon Tai Yosuke Hiramuki Rabi Tawil Silvère M. van der Maarel Stephen J. Tapscott Francis M. Sverdrup |
spellingShingle |
Amy E. Campbell Jonathan Oliva Matthew P. Yates Jun Wen Zhong Sean C. Shadle Lauren Snider Nikita Singh Shannon Tai Yosuke Hiramuki Rabi Tawil Silvère M. van der Maarel Stephen J. Tapscott Francis M. Sverdrup BET bromodomain inhibitors and agonists of the beta-2 adrenergic receptor identified in screens for compounds that inhibit DUX4 expression in FSHD muscle cells Skeletal Muscle Facioscapulohumeral muscular dystrophy FSHD DUX4 Bromodomain Adrenergic High-throughput screening |
author_facet |
Amy E. Campbell Jonathan Oliva Matthew P. Yates Jun Wen Zhong Sean C. Shadle Lauren Snider Nikita Singh Shannon Tai Yosuke Hiramuki Rabi Tawil Silvère M. van der Maarel Stephen J. Tapscott Francis M. Sverdrup |
author_sort |
Amy E. Campbell |
title |
BET bromodomain inhibitors and agonists of the beta-2 adrenergic receptor identified in screens for compounds that inhibit DUX4 expression in FSHD muscle cells |
title_short |
BET bromodomain inhibitors and agonists of the beta-2 adrenergic receptor identified in screens for compounds that inhibit DUX4 expression in FSHD muscle cells |
title_full |
BET bromodomain inhibitors and agonists of the beta-2 adrenergic receptor identified in screens for compounds that inhibit DUX4 expression in FSHD muscle cells |
title_fullStr |
BET bromodomain inhibitors and agonists of the beta-2 adrenergic receptor identified in screens for compounds that inhibit DUX4 expression in FSHD muscle cells |
title_full_unstemmed |
BET bromodomain inhibitors and agonists of the beta-2 adrenergic receptor identified in screens for compounds that inhibit DUX4 expression in FSHD muscle cells |
title_sort |
bet bromodomain inhibitors and agonists of the beta-2 adrenergic receptor identified in screens for compounds that inhibit dux4 expression in fshd muscle cells |
publisher |
BMC |
series |
Skeletal Muscle |
issn |
2044-5040 |
publishDate |
2017-09-01 |
description |
Abstract Background Facioscapulohumeral dystrophy (FSHD) is a progressive muscle disease caused by mutations that lead to epigenetic derepression and inappropriate transcription of the double homeobox 4 (DUX4) gene in skeletal muscle. Drugs that enhance the repression of DUX4 and prevent its expression in skeletal muscle cells therefore represent candidate therapies for FSHD. Methods We screened an aggregated chemical library enriched for compounds with epigenetic activities and the Pharmakon 1600 library composed of compounds that have reached clinical testing to identify molecules that decrease DUX4 expression as monitored by the levels of DUX4 target genes in FSHD patient-derived skeletal muscle cell cultures. Results Our screens identified several classes of molecules that include inhibitors of the bromodomain and extra-terminal (BET) family of proteins and agonists of the beta-2 adrenergic receptor. Further studies showed that compounds from these two classes suppress the expression of DUX4 messenger RNA (mRNA) by blocking the activity of bromodomain-containing protein 4 (BRD4) or by increasing cyclic adenosine monophosphate (cAMP) levels, respectively. Conclusions These data uncover pathways involved in the regulation of DUX4 expression in somatic cells, provide potential candidate classes of compounds for FSHD therapeutic development, and create an important opportunity for mechanistic studies that may uncover additional therapeutic targets. |
topic |
Facioscapulohumeral muscular dystrophy FSHD DUX4 Bromodomain Adrenergic High-throughput screening |
url |
http://link.springer.com/article/10.1186/s13395-017-0134-x |
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