Histone deacetylase 3 (HDAC3) and HDAC4 were reported to facilitate the NR3C2-mediated expression of target genes such as TSC22D3 (Lee HA et al. 2013, 2015). Aldosterone was found to induce the translocation of HDAC4 into the nucleus in HEK293 cells (Lee HA et al. 2015). Co-immunoprecipitation assay showed aldosterone-induced NR3C2 (MR) interaction with HDAC3 or HDAC4 in HEK293 cells expressing HA-tagged NR3C2 and Flag-tagged HDACs (Lee HA et al. 2013, 2015). Treatment with aldosterone also promoted an interaction between HDAC3 and HDAC4 (Lee HA et al. 2015). Further, knockdown of HDAC4 by siRNA resulted in the decreased interaction between NR3C2 and HDAC3 in the nucleus of aldosterone-treated HEK293 cells (Lee HA et al. 2015). In addition, knockdown of either HDAC3 or HDAC4 by corresponding siRNA resulted in increased acetylation of NR3C2, and attenuated expression of GILZ (TSC22D3) and SGK1 in aldosterone-treated HEK293 cells (Lee HA et al. 2013, 2015). Valproic acid (VPA) and other class I HDAC inhibitors attenuated recruitment of NR3C2 and RNA polymerase II (Pol II) on the TSC22D3 (GILZ) promoter induced by aldosterone in HEK293 cells (Lee HA et al. 2013). Thus, acetylation of NR3C2 (MR) reduced GRE binding affinity, Pol II recruitment, and expression of target genes, which regulate intracellular salt balance. Nuclear HDAC4 facilitated the interaction between NR3C2 and HDAC3 which catalyzed the deacetylation of NR3C2 in its hinge region in vitro thus enhancing the transcriptional activity of NR3C2 (Lee HA et al. 2013, 2015).