Abstract
Nuclear hormone receptors (NRs) regulate transcription of the target genes in a ligand-dependent manner in either a positive or negative direction, depending on the case. Deacetylation of histone tails is associated with transcriptional repression. A nuclear receptor corepressor (N-CoR) and a silencing mediator for retinoid and thyroid hormone receptors (SMRT) are the main corepressors responsible for gene suppression mediated by NRs. Among numerous histone deacetylases (HDACs), HDAC3 is the core component of the N-CoR/SMRT complex, and plays a central role in NR-dependent repression. Here, the roles of HDAC3 in ligand-independent repression, gene repression by orphan NRs, NRs antagonist action, ligand-induced repression, and the activation of a transcriptional coactivator are reviewed. In addition, some perspectives regarding the non-canonical mechanisms of HDAC3 action are discussed.
Highlights
The endocrine system is one of the major mechanisms that contributes to cell-specific functions and homeostasis
The promyelocytic leukemia (PML)-RAR alpha (RARA) protein is associated with nuclear receptor corepressor (N-CoR)/SMRT complex like unliganded retinoic acid receptor (RAR), and HDAC3 is involved in the gene repression as the main histone deacetylases (HDACs) [103,104,105]
As the core HDAC component of the N-CoR/SMRT corepressor complex, HDAC3 is largely responsible for transcriptional repression mediated by nuclear hormone receptors (NRs) and other transcription factors
Summary
The endocrine system is one of the major mechanisms that contributes to cell-specific functions and homeostasis. Whereas many peptide hormones bind to membrane-associated receptors, the receptors for a group of small lipophilic hormones mainly regulate the transcription of target genes in the nuclei [2]. These receptors are termed nuclear hormone receptors (NRs). NRs bind to the regulatory region of the target genes, typically as dimers, and regulate transcription in a ligand-dependent manner [2]. The most highly conserved region is the DNAbinding domain, which contains two zinc finger motifs [7,8] This region is responsible for the binding of the receptor to the specific DNA sequences, called hormone response elements (HREs), on the target genes. Given the importance of histone deacetylation by HDAC3, this review will focus on what has been proven about the role of HDAC3 in the NR-dependent repression, rather than the roles of corepressors
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