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Fig. 7 | Skeletal Muscle

Fig. 7

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

Fig. 7

Model of DUX4 regulation by BET proteins and beta-2 adrenergic signaling. BRD4 binds acetylated lysines at the D4Z4 array and recruits complexes such as P-TEFb and Mediator to facilitate transcriptional activation by RNA polymerase II. This is counteracted by the activity of HDAC1/2, which deacetylate lysines to inhibit gene induction. BRD4 binding to acetylated lysines may also shield these residues from HDAC1/2 activity. BETi prevent the binding of BRD4 to acetylated lysines and therefore block DUX4 expression while allowing HDAC1/2 access to the exposed acetyl groups. Beta-2 agonist binding to the beta-2 adrenergic receptor results in Gs G protein-mediated activation of adenylyl cyclase, which catalyzes the formation of cAMP. Downstream effectors of cAMP include PKA-dependent and PKA-independent pathways. The inhibitory effect of beta-2 agonists on DUX4 expression appears to be mostly mediated through PKA-independent pathways, possibly including the speculative one outlined here which is imagined to act through signaling molecules such as phosphatases (PPtases) and mitogen-activated protein kinases (MAPKs) to influence chromatin modifiers like lysine methyltransferases (KMTases) to impact transcription of the DUX4 gene

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