A Histone Deacetylase 4/Myogenin Positive Feedback Loop Coordinates Denervation-dependent Gene Induction and Suppression

Abstract

Muscle activity contributes to formation of the neuromuscular junction and affects muscle metabolism and contractile properties through regulated gene expression. However, the mechanisms coordinating these diverse activity-regulated processes remain poorly characterized. Recently, it was reported that histone deacetylase 4 (HDAC4) can mediate denervation-induced myogenin and nicotinic acetylcholine receptor gene expression. Here, we report that HDAC4 is not only necessary for denervation-dependent induction of genes involved in synaptogenesis (nicotinic acetylcholine receptor and muscle-specific receptor tyrosine kinase) but also for denervation-dependent suppression of genes involved in glycolysis (muscle-specific enolase and phosphofructokinase). In addition, HDAC4 differentially regulates genes involved in muscle fiber type specification by inducing myosin heavy chain IIA and suppressing myosin heavy chain IIB. Consistent with these regulated gene profiles, HDAC4 is enriched in fast oxidative fibers of innervated tibialis anterior muscle and HDAC4 knockdown enhances glycolysis in cultured myotubes. HDAC4 mediates gene induction indirectly by suppressing the expression of Dach2 and MITR that function as myogenin gene corepressors. In contrast, HDAC4 is directly recruited to myocyte enhancer factor 2 sites within target promoters to mediate gene suppression. Finally, we discovered an HDAC4/myogenin positive feedback loop that coordinates gene induction and repression underlying muscle phenotypic changes after muscle denervation.

Dach2-Hdac9 signaling regulates reinnervation of muscle endplates

“…Dach2 and Hdac9 are transcriptional corepressors that are highly expressed in innervated muscle and decrease following muscle denervation (Méjat et al, 2005;Tang et al, 2009). Using two models of nerve injury we show that Dach2 and Hdac9 reduce the rate of muscle reinnervation.…”

“…Previous studies have shown Dach2 and Hdac9 repress Myog expression and that Myog regulated the expression of genes that are associated with endplate formation, like those encoding nAChRs and Musk (Méjat et al, 2005;Macpherson et al, 2006;Tang et al, , 2009. Interestingly, miR206, a gene previously shown to participate in endplate reinnervation (Williams et al, 2009) is also regulated in a Dach2/Hdac9-dependent manner (Fig.…”

“…Although our observations on the effect of Myog and Gdf5 on muscle reinnervation were limited to soleus muscle, these proteins are induced after denervation of other skeletal muscles Tang et al, 2009;Sartori et al, 2013); however, the generality of their effect on muscle reinnervation remains to be tested.…”

“…Dach2 and Hdac9 are transcriptional co-repressors highly expressed in innervated muscle and suppressed following muscle denervation (Méjat et al, 2005;Tang et al, 2009). They mediate activity-dependent suppression of Myog, a muscle-specific transcription factor that is induced in denervated muscle (Buonanno et al, 1992) and an activator of genes encoding endplate-associated proteins, like nicotinic acetylcholine receptors (nAChRs) and Musk (Méjat et al, 2005;.…”

Unnerving atrophy

“…The potential for using HDAC inhibitors to treat ALS and other neuromuscular diseases is of great interest." 4,5 Hot for HDACs There are no disclosed class IIa-specific HDAC inhibitors in the clinic. Indeed, companies contacted by SciBX suggested the reason is not because they are hard to develop but rather that they have been a target class in search of an indication.…”