BET bromodomain inhibitors and agonists of the beta-2 adrenergic receptor identified in screens for compounds that inhibit DUX4 expression in FSHD muscle cells
| Autor: | Lauren Snider, Francis M. Sverdrup, Shannon Tai, Stephen J. Tapscott, Rabi Tawil, Matthew P. Yates, Jonathan Oliva, Nikita Singh, Jun Wen Zhong, Yosuke Hiramuki, Silvère M. van der Maarel, Sean C. Shadle, Amy E. Campbell |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
BRD4 lcsh:Diseases of the musculoskeletal system DUX4 Bromodomain Cell Cycle Proteins Biology Myoblasts Small Molecule Libraries 03 medical and health sciences 0302 clinical medicine Facioscapulohumeral muscular dystrophy medicine Cyclic AMP Myocyte Humans Orthopedics and Sports Medicine Epigenetics Molecular Biology Adrenergic beta-2 Receptor Agonists Cells Cultured Homeodomain Proteins FSHD Research High-throughput screening Skeletal muscle Nuclear Proteins Cell Biology medicine.disease Muscular Dystrophy Facioscapulohumeral 3. Good health High-Throughput Screening Assays 030104 developmental biology medicine.anatomical_structure Adrenergic Cancer research Beta-2 adrenergic receptor lcsh:RC925-935 030217 neurology & neurosurgery Transcription Factors |
| Zdroj: | Skeletal Muscle Skeletal Muscle, Vol 7, Iss 1, Pp 1-18 (2017) Skeletal Muscle, 7 |
| ISSN: | 2044-5040 |
| Popis: | 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. Electronic supplementary material The online version of this article (doi:10.1186/s13395-017-0134-x) contains supplementary material, which is available to authorized users. |
| Databáze: | OpenAIRE |
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