Deacetylase-Independent Function of HDAC3 in Transcription and Metabolism Requires Nuclear Receptor Corepressor

Abstract

Histone deacetylases (HDACs) are believed to regulate gene transcription by catalyzing deacetylation reactions. HDAC3 depletion in mouse liver upregulates lipogenic genes and results in severe hepatosteatosis. Here we show that pharmacologic HDAC inhibition in primary hepatocytes causes histone hyperacetylation but does not upregulate expression of HDAC3 target genes. Meanwhile, deacetylase-dead HDAC3 mutants can rescue hepatosteatosis and repress lipogenic genes expression in HDAC3-depleted mouse liver, demonstrating that histone acetylation is insufficient to activate gene transcription. Mutations abolishing interactions with the nuclear receptor corepressor (NCOR or SMRT) render HDAC3 nonfunctional in vivo. Additionally, liver-specific knockout of NCOR, but not SMRT, causes metabolic and transcriptomal alterations resembling those of mice without hepatic HDAC3, demonstrating that interaction with NCOR is essential for deacetylase-independent function of HDAC3. These findings highlight non-enzymatic roles of a major HDAC in transcriptional regulation in vivo and warrant reconsideration of the mechanism of action of HDAC inhibitors.

Antagonizing Peroxisome Proliferator–Activated Receptor α Activity Selectively Enhances Th1 Immunity in Male Mice

“…We observed that treatment with fenofibrate induced the corecruitment of PPARa and NCOR to the Ifng promoter as well as CNS-22 and CNS-34 sites, which are distal elements in the Ifng locus that are required for Th1 lineagespecific expression (2). The enhanced abundance of NCOR was also associated with reduced histone acetylation at these regulatory elements, which is consistent with the role of NCOR in tethering HDACs to gene control regions (32). Furthermore, our finding that knockdown of NCOR abrogated the effects of fenofibrate in reducing H4-Ac and IFN-g production, proved that NCOR is required for the effect of PPARa on IFN-g expression.…”

“…It was found that the ligand agonist rosiglitazone promotes the sumoylation and recruitment of PPARg to the Inos promoter, where it stabilizes the presence of an NCOR-containing corepressor complex, rendering the gene refractory to LPS stimulation (15). NCOR mediates the repressive effects of PPARs and other nuclear receptors by recruiting HDACs to gene-regulatory regions (32). Given that PPARa is also reported to be sumoylated upon ligand treatment (33), we hypothesized that PPARa may operate by a similar mechanism to repress Ifng.…”

Context and Auditory Fear are Differentially Regulated by HDAC3 Activity in the Lateral and Basal Subnuclei of the Amygdala

“…To test whether HDAC3 activity negatively regulates fear memory formation, we developed a dominant-negative point mutant virus (AAV2.1-HDAC3 (Y298H)-v5) to selectively disrupt HDAC3 activity. Substituting a histidine in place of the tyrosine abolishes the enzymatic activity of HDAC3 without affecting proteinprotein interactions (Lahm et al, 2007;Sun et al, 2013). To confirm that HDAC3(Y298H) mutation effectively blocks HDAC3-mediated deacetylation, we performed an in vitro HDAC3 deacetylase activity assay using purified HDAC3 (Y298H)-v5 or wild-type HDAC3-v5 protein.…”

“…To date, no study has tested whether the deacetylase activity of HDAC3 is specifically necessary for its ability to regulate memory formation. This is a key question, considering that HDAC3-mediated gene repression in other tissues does not necessarily require the enzymatic activity of HDAC3 (Sun et al, 2013). Further, another HDAC, HDAC4, can modulate memory independent of its deacetylase domain (Lahm et al, 2007;Sando et al, 2012).…”

Role of histone deacetylase 9 in regulating adipogenic differentiation and high fat diet-induced metabolic disease

“…These findings are consistent with a growing body of data implicating deacetylase-independent actions of many HDAC family members. 14 We subsequently determined that HDAC9 is a nutrient sensitive gene whose expression is upregulated in adipocytes from chronically high fat fed, obese mice. 10 Under these conditions, HDAC9 levels fail to decline in preadipocytes during in vitro adipogenic differentiation, suggesting that the regulatory mechanism controlling HDAC9 expression is disrupted in diet-induced obesity.…”