Histone Deacetylase 3 and 4 Complex Stimulates the Transcriptional Activity of the Mineralocorticoid Receptor

Abstract

Histone deacetylases (HDACs) act as corepressors in gene transcription by altering the acetylation of histones, resulting in epigenetic gene silencing. We previously reported that HDAC3 acts as a coactivator of the mineralocorticoid receptor (MR). Although HDAC3 forms complexes with class II HDACs, their potential role in the transcriptional activity of MR is unclear. We hypothesized that HDAC4 of the class II family stimulates the transcriptional activity of MR. The expression of MR target genes was measured by quantitative real-time PCR. MR and RNA polymerase II recruitment to promoters of MR target genes was analyzed by chromatin immunoprecipitation. The association of MR with HDACs was investigated by co-immunoprecipitation. MR acetylation was determined with an anti-acetyl-lysine antibody after immunoprecipitation with an anti-MR antibody. Among the class II HDACs, HDAC4 interacted with both MR and HDAC3 after aldosterone stimulation. The nuclear translocation of HDAC4 was mediated by protein kinase A (PKA) and protein phosphatases (PP). The transcriptional activity of MR was significantly decreased by inhibitors of PKA (H89), PP1/2 (calyculin A), class I HDACs (MS-275), but not class II HDACs (MC1568). MR acetylation was increased by H89, calyculin A, and MS-275, but not by MC1568. Interaction between MR and HDAC3 was significantly decreased by H89, calyculin A, and HDAC4 siRNA. A non-genomic effect of MR via PKA and PP1/2 induced nuclear translocation of HDAC4 to facilitate the interaction between MR and HDAC3. Thus, we have uncovered a crucial role for a class II HDAC in the activation of MR-dependent transcription.

Emerging Roles of the Mineralocorticoid Receptor in Pathology: Toward New Paradigms in Clinical Pharmacology

“…In utero exposure to di-(2-ethylhexyl) phtalate leads to loss of methylation of MR gene promotor and reduced MR mRNA expression in testes (Martinez-Arguelles et al, 2009). Histone deacetylase 3 and 4 complexes have been reported to regulate MR transcriptional activity in cultured cells (Lee et al, 2015). Epigenetic mechanism may regulate MR expression via expression of microRNAs (miRNAs/miRs) and short regulatory RNAs.…”

Aberrant Expression of Histone Deacetylases 4 in Cognitive Disorders: Molecular Mechanisms and a Potential Target

“…First, HDAC4 interacts with multiple transcriptional factors [e.g., myocyte enhancer 2 (MEF2), runt related transcription factor 2 (Runx2), serum response factor (SRF), heterochromatin protein 1(HP1), nuclear factor kappa B (NF-κB)] regulating gene transcription (Sando et al, 2012; Ronan et al, 2013). Although HDAC4 per se lacks deacetylase activity, it may be involved in histone deacetylation-mediated transcriptional regulation via interacting with HDAC3, another member of the HDAC family with deacetylase activity (Grozinger et al, 1999; Lee et al, 2015). For example, Lee et al (2015) showed that HDAC4 is crucial for HDAC3-mediated deacetylation of mineralocorticoid receptor, which could be inhibited by class I HDAC inhibitor but not class II HDAC inhibitor, indicating that HDAC4 is implicated in protein deacetylation via the deacetylase activity of HDAC3.…”

“…Although HDAC4 per se lacks deacetylase activity, it may be involved in histone deacetylation-mediated transcriptional regulation via interacting with HDAC3, another member of the HDAC family with deacetylase activity (Grozinger et al, 1999; Lee et al, 2015). For example, Lee et al (2015) showed that HDAC4 is crucial for HDAC3-mediated deacetylation of mineralocorticoid receptor, which could be inhibited by class I HDAC inhibitor but not class II HDAC inhibitor, indicating that HDAC4 is implicated in protein deacetylation via the deacetylase activity of HDAC3. Moreover, the deacetylase activity of HDAC4 needs to be further investigated by multiple approaches as it is not convincing by the in vitro assay from one study (Lahm et al, 2007).…”

“…regulating the transcription of genes involved in synaptogenesis, synaptic plasticity and neurodevelopment, such as activity regulated cytoskeleton associated protein ( Arc ) and protocadherin ( Pcdh10 ) ( Figure 1 ) (Grozinger et al, 1999; Sando et al, 2012; Ronan et al, 2013; Rashid et al, 2014; Lee et al, 2015; Sharma et al, 2015; Krishna et al, 2016; Nott et al, 2016). First, nuclear HDAC4 represses the expression of constituents of synapses leading to the impairment of synaptic architecture and strength in mice (Sando et al, 2012).…”

30 YEARS OF THE MINERALOCORTICOID RECEPTOR: Coregulators as mediators of mineralocorticoid receptor signalling diversity

“…Lee and coworkers (Lee et al 2015) have reported that the class II HDAC, HDAC4 mediates an interaction between HDAC3 and the MR, which coactivates aldosterone-induced, MR-mediated transactivation. Obradovic and coworkers (Obradovic et al 2004) sought to address the role of coregulators in conferring MR vs GR specificity in neurons where both receptors are responding to the same ligand, cortisol.…”