NR1D2

This gene encodes a member of the nuclear hormone receptor family, specifically the NR1 subfamily of receptors. The encoded protein functions as a transcriptional repressor and may play a role in circadian rhythms and carbohydrate and lipid metabolism. Alternatively spliced transcript variants have been described. [provided by RefSeq]

nuclear receptor subfamily 1, group D, member 2

Transcriptional repressor which coordinates circadian rhythm and metabolic pathways in a heme-dependent manner. Integral component of the complex transcription machinery that governs circadian rhythmicity and forms a critical negative limb of the circadian clock by directly repressing the expression of core clock components ARNTL/BMAL1 and CLOCK. Also regulates genes involved in metabolic functions, including lipid metabolism and the inflammatory response. Acts as a receptor for heme which stimulates its interaction with the NCOR1/HDAC3 corepressor complex, enhancing transcriptional repression. Recognizes two classes of DNA response elements within the promoter of its target genes and can bind to DNA as either monomers or homodimers, depending on the nature of the response element. Binds as a monomer to a response element composed of the consensus half-site motif 5'-[A/G]GGTCA-3' preceded by an A/T-rich 5' sequence (RevRE), or as a homodimer to a direct repeat of the core motif spaced by two nuclegotides (RevDR-2). Acts as a potent competitive repressor of ROR alpha (RORA) function and also negatively regulates the expression of NR1D1. Regulates lipid and energy homeostasis in the skeletal muscle via repression of genes involved in lipid metabolism and myogenesis including: CD36, FABP3, FABP4, UCP3, SCD1 and MSTN. Regulates hepatic lipid metabolism via the repression of APOC3. Represses gene expression at a distance in macrophages by inhibiting the transcription of enhancer-derived RNAs (eRNAs). In addition to its activity as a repressor, can also act as a transcriptional activator. Acts as a transcriptional activator of the sterol regulatory element-binding protein 1 (SREBF1) and the inflammatory mediator interleukin-6 (IL6) in the skeletal muscle (By similarity).
Plays a role in the regulation of circadian sleep/wake cycle; essential for maintaining wakefulness during the dark phase or active period (By similarity).
Key regulator of skeletal muscle mitochondrial function; negatively regulates the skeletal muscle expression of core clock genes and genes involved in mitochondrial biogenesis, fatty acid beta-oxidation and lipid metabolism (By similarity).
May play a role in the circadian control of neutrophilic inflammation in the lung (By similarity).

Cell differentiationManual Assertion Based On ExperimentIBA:GO_Central
Circadian behaviorISS:UniProtKB
Energy homeostasisISS:UniProtKB
Hormone-mediated signaling pathwayManual Assertion Based On ExperimentIBA:GO_Central
Lipid homeostasisISS:UniProtKB
Negative regulation of inflammatory responseIEA:Ensembl
Negative regulation of transcription by RNA polymerase IIManual Assertion Based On ExperimentIBA:GO_Central
Negative regulation of transcription, DNA-templatedManual Assertion Based On ExperimentIDA:UniProtKB
Positive regulation of transcription by RNA polymerase IIManual Assertion Based On ExperimentIBA:GO_Central
Positive regulation of transcription, DNA-templatedISS:UniProtKB
Regulation of circadian rhythmISS:UniProtKB
Regulation of inflammatory responseISS:UniProtKB
Regulation of lipid metabolic processISS:UniProtKB
Regulation of skeletal muscle cell differentiationISS:UniProtKB
Regulation of transcription, DNA-templatedManual Assertion Based On ExperimentTAS:UniProtKB

Nucleus
Cytoplasm
Phosphorylation by CSNK1E enhances its cytoplasmic localization.

Deacetylated by HDAC1. Acetylation and deacetylation regulate its transcriptional regulatory activity.
Under more reducing intracellular redox conditions, Cys-384 is in its heme-bound state, which is optimal for recruitment of the NCOR1/HDAC3 corepressor complex and repression of target genes. When subjected to oxidative stress conditions, Cys-384 undergoes oxidation to form a disulfide bridge with Cys-374, also triggering a ligand switch that results in release of bound heme and derepression of target genes.
Ubiquitinated by SIAH2; leading to proteasomal degradation.
Phosphorylated by CSNK1E; phosphorylation enhances its cytoplasmic localization.