Abstract:Background: Class IIa histone deacetylases (HDACs) repress transcription through association with the SMRT/NCOR co-repressor complex.Results: A repeated peptide motif mediates recruitment of class IIa HDACs to the co-repressor proteins interacting adjacent to the active site.Conclusion: Class IIa HDACs are recruited to co-repressors by a simple repeated peptide motif.Significance: First insights into the assembly of Class IIa HDACs with repression complexes.
“…8c). These data confirm a role of the HDAC7 surface zinc binding site in SMRT binding, as also observed in HDAC4 7, 49, 58 .Figure 8Test of SMRT(1255–1452) binding to the C535A/H541A mutant of HDAC7. ( a ) Intensities of resonance signals of SMRT(1255–1452) residues in 15 N- 1 H HSQC NMR spectra with added 3.6-fold molar excess of the HDAC7 (C535A/H541A) mutant, normalized to corresponding intensities in the HSQC spectrum of free SMRT(1255–1452).…”
The 2525 amino acid SMRT corepressor is an intrinsically disordered hub protein responsible for binding and coordinating the activities of multiple transcription factors and chromatin modifying enzymes. Here we have studied its interaction with HDAC7, a class IIa deacetylase that interacts with the corepressor complex together with the highly active class I deacetylase HDAC3. The binding site of class IIa deacetylases was previously mapped to an approximate 500 amino acid region of SMRT, with recent implication of short glycine-serine-isoleucine (GSI) containing motifs. In order to characterize the interaction in detail, we applied a random library screening approach within this region and obtained a range of stable, soluble SMRT fragments. In agreement with an absence of predicted structural domains, these were characterized as intrinsically disordered by NMR spectroscopy. We identified one of them, comprising residues 1255–1452, as interacting with HDAC7 with micromolar affinity. The binding site was mapped in detail by NMR and confirmed by truncation and alanine mutagenesis. Complementing this with mutational analysis of HDAC7, we show that HDAC7, via its surface zinc ion binding site, binds to a 28 residue stretch in SMRT comprising a GSI motif followed by an alpha helix.
“…8c). These data confirm a role of the HDAC7 surface zinc binding site in SMRT binding, as also observed in HDAC4 7, 49, 58 .Figure 8Test of SMRT(1255–1452) binding to the C535A/H541A mutant of HDAC7. ( a ) Intensities of resonance signals of SMRT(1255–1452) residues in 15 N- 1 H HSQC NMR spectra with added 3.6-fold molar excess of the HDAC7 (C535A/H541A) mutant, normalized to corresponding intensities in the HSQC spectrum of free SMRT(1255–1452).…”
The 2525 amino acid SMRT corepressor is an intrinsically disordered hub protein responsible for binding and coordinating the activities of multiple transcription factors and chromatin modifying enzymes. Here we have studied its interaction with HDAC7, a class IIa deacetylase that interacts with the corepressor complex together with the highly active class I deacetylase HDAC3. The binding site of class IIa deacetylases was previously mapped to an approximate 500 amino acid region of SMRT, with recent implication of short glycine-serine-isoleucine (GSI) containing motifs. In order to characterize the interaction in detail, we applied a random library screening approach within this region and obtained a range of stable, soluble SMRT fragments. In agreement with an absence of predicted structural domains, these were characterized as intrinsically disordered by NMR spectroscopy. We identified one of them, comprising residues 1255–1452, as interacting with HDAC7 with micromolar affinity. The binding site was mapped in detail by NMR and confirmed by truncation and alanine mutagenesis. Complementing this with mutational analysis of HDAC7, we show that HDAC7, via its surface zinc ion binding site, binds to a 28 residue stretch in SMRT comprising a GSI motif followed by an alpha helix.
“…Most HDAC inhibitors lack isoform selectivity and generally consist of a chelating moiety that interacts with the active-site zinc atom, a narrow linker region that spans the catalytic groove and a capping group (Sternson et al, 2001). It has emerged that some HDAC inhibitors can disrupt the class IIa HDAC corepressor complex by changing the conformation of the class IIa HDAC active site, which mediates physical association with N-Cor/SMRT (Hudson et al, 2015;Lahm et al, 2007). Therefore, HDAC inhibitors that were thought to only inhibit class I HDAC catalytic activity may have efficacy against class IIa HDAC transcriptional repression.…”
Drugs that recapitulate aspects of the exercise adaptive response have the potential to provide better treatment for diseases associated with physical inactivity. We previously observed reduced skeletal muscle class IIa HDAC (histone deacetylase) transcriptional repressive activity during exercise. Here, we find that exercise-like adaptations are induced by skeletal muscle expression of class IIa HDAC mutants that cannot form a corepressor complex. Adaptations include increased metabolic gene expression, mitochondrial capacity, and lipid oxidation. An existing HDAC inhibitor, Scriptaid, had similar phenotypic effects through disruption of the class IIa HDAC corepressor complex. Acute Scriptaid administration to mice increased the expression of metabolic genes, which required an intact class IIa HDAC corepressor complex. Chronic Scriptaid administration increased exercise capacity, whole-body energy expenditure and lipid oxidation, and reduced fasting blood lipids and glucose. Therefore, compounds that disrupt class IIa HDAC function could be used to enhance metabolic health in chronic diseases driven by physical inactivity.
“…A number of other studies using various HDAC inhibitors have reported similar enhancements in various aspects of muscle and whole-body metabolism, including insulin sensitivity (Tan et al 2015) and enhanced oxidative capacity (Galmozzi et al 2013). The exact mechanism of action of some of these broad-spectrum HDAC inhibitors remains to be determined, but could include inhibition of HDAC3, the class I HDAC that provides deacetylase activity to the class IIa HDAC corepressor complex (Fischle et al 2002;Hudson et al 2015). Systemic administration of these inhibitors could have compound-specific effects in tissues other than skeletal muscle.…”
Section: Epigenetic Therapies To Induce Exercise Adaptationsmentioning
An acute bout of exercise is sufficient to induce changes in skeletal muscle gene expression that are ultimately responsible for the adaptive responses to exercise. Although much research has described the intracellular signaling responses to exercise that are linked to transcriptional regulation, the epigenetic mechanisms involved are only just emerging. This review will provide an overview of epigenetic mechanisms and what is known in the context of exercise. Additionally, we will explore potential interactions between metabolism during exercise and epigenetic regulation, which serves as a framework for potential areas for future research. Finally, we will consider emerging opportunities to pharmacologically manipulate epigenetic regulators and mechanisms to induce aspects of the skeletal muscle exercise adaptive response for therapeutic intervention in various disease states.
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