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

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• The luciferase readout in this screen was designed to reflect the expression of DUX4, which in turn modulates the ZSCAN4 promoter. To determine whether BETi as a class block induction of DUX4, we measured DUX4 and DUX4 target gene mRNA levels after compound treatment in 54-2 FSHD1 and MB200 FSHD2 proliferating myoblast and differentiating myotube cell cultures using quantitative reverse transcription PCR (RT-qPCR). The BETi probe compound (+)-JQ1, the clinical candidate I-BET151, the Phase II clinical molecule I-BET762, and the Phase III clinical compound *RVX-208 prevented the activation of DUX4 and DUX4 target genes such as ZSCAN4 and tripartite motif containing 43 (TRIM43) under all conditions tested (Fig. 1b–c, Additional file 5: Figure S3). These results demonstrate that BETi block DUX4 expression in a manner independent of muscle differentiation in both FSHD1 and FSHD2 cells, suggesting that BETi act at a point in the transcriptional control of DUX4 common to both genetic defects

• Additional file 5: Figure S3. BETi block DUX4 target gene expression in FSHD myoblasts. (A) The expression level of ZSCAN4 mRNA after 72 h of treatment with the BETi (+)-JQ1, I-BET762, or I-BET151 in 54-2 FSHD1 myoblasts. (B) The BETi *RVX-208 inhibits ZSCAN4 and TRIM43 expression in FSHD2 MB200 myoblasts treated for 72 h with EC50s of 350 nM and 280 nM, respectively. Error bars indicate the standard deviation from the mean of three biological replicates. (PDF 53 kb)

(* My Bolding)

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