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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.

skeletal muscle

BET bromodomain inhibitors and agonists of the beta-2 adrenergic receptor identified in screens for compounds that inhibit DUX4 expression in FSHD muscle cells