HDAC3 (histone deacetylase 3; HGNC:4854, NCBI Gene ID 8841) is a human locus mapped to chromosome band 5q31.3 that encodes zn2+-dependent Class I histone deacetylase 3 (428 aa; 49 kDa; EC 3.5.1.98). HDAC3 acts in obligate catalytic subunit of the NCoR1/SMRT (NCOR2) complex activated by InsP4; mediates Rev-erb-alpha circadian hepatic lipogenesis repression & MECP2/THRA/THRB silencing, together with HDAC1 (Class I Paralog Gene), HDAC4 (Class IIa Scaffold That Recruits NCoR-HDAC3), and THRA (Thyroid Hormone Receptor Alpha Recruits NCoR-HDAC3). Encodes Class I histone deacetylase 3, the sole catalytic engine of the NCoR1 and SMRT nuclear receptor corepressor complexes governing circadian lipid metabolism.
Approved Symbol
HDAC3
Chromosomal Locus
5q31.3
Encoded Product
Zn2+-dependent Class I histone deacetylase 3 (428 aa; 49 kDa; EC 3.5.1.98)
Primary Pathway
Obligate catalytic subunit of the NCoR1/SMRT (NCOR2) complex activated by InsP4; mediates Rev-erb-alpha circadian hepatic lipogenesis repression & MECP2/THRA/THRB silencing
Clinical / Therapeutic Role
Controls rhythmic hepatic lipid metabolism, brown fat UCP1 thermogenesis & long-term memory gating; target of RGFP966
Gene Structure & Expression
Genomic Organization & Cytogenetic Locus: 15-exon gene on chromosome 5q31.3 encoding a 428-amino-acid Class I deacetylase with a distinct C-terminal tail that does not join Sin3 or NuRD complexes, instead binding exclusively to the Deacetylase Activation Domain (DAD) of Nuclear Receptor Corepressor 1 (NCOR1) and Silencing Mediator for Retinoid and Thyroid receptors (SMRT / NCOR2).
Cellular & Tissue Expression Profile: Ubiquitously expressed in both the nucleus and cytoplasm of hepatic hepatocytes, brown and white adipocytes, cardiac and skeletal myocytes, macrophages, and central nervous system neurons.
Molecular Function & Pathways
Biochemical & Physiological Mechanism: Remains catalytically inactive as a free monomer until its interface with the DAD domain of NCoR1 or SMRT is glued together by a single molecule of D-myo-inositol-1,4,5,6-tetrakisphosphate (InsP4) acting as an intermolecular cofactor; in the liver, the circadian nuclear receptor Rev-erb-alpha (NR1D1) recruits NCoR1-HDAC3 every day during the light/fasting phase to deacetylate H3K9ac/H3K27ac at >10,000 genomic loci and repress de novo lipogenesis, whereas at night Rev-erb-alpha drops and HDAC3 departs to permit feeding-induced lipid synthesis; NCoR1-HDAC3 is also recruited by unliganded thyroid hormone receptors (THRA/THRB) and by neuronal MECP2.
Clinical & Therapeutic Significance
Human Genetic Variants & Disease Phenotypes: Hepatocyte-specific deletion of Hdac3 causes massive circadian derepression of lipid synthesis and severe hepatosteatosis ("fatty liver") paradoxically accompanied by heightened insulin sensitivity (because carbon is shunted into safe lipid droplets away from gluconeogenesis), whereas selective deletion or inhibition of HDAC3 in brown adipocytes derepresses UCP1 enhancers to confer profound cold tolerance, and focal HDAC3 deletion in dorsal hippocampus converts subthreshold learning events into persistent long-term memories.
Therapeutic & Clinical Pharmacology: Selective benzamide HDAC3 inhibitors (such as RGFP966) are extensively investigated to enhance extinction of fear/addiction memories, promote remyelination, and reactivate latent HIV-1 reservoirs or silenced FXN (frataxin) alleles in Friedreich ataxia.