Summary

Name NR1D1
Full Name Nuclear receptor subfamily 1 group D member 1
Synonyms Rev-erbA-alpha, V-erbA-related protein 1, EAR-1 | EAR1, HREV, THRAL
Primary ID P20393
Links - -
Type protein
Relations 14
Pathways Circadian clock
Function 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 ARTNL/BMAL1, CLOCK and CRY1. Also regulates genes involved in metabolic functions, including lipid and bile acid metabolism, adipogenesis, gluconeogenesis and the macrophage 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 nucleotides (RevDR-2). Acts as a potent competitive repressor of ROR alpha (RORA) function and regulates the levels of its ligand heme by repressing the expression of PPARGC1A, a potent inducer of heme synthesis. Regulates lipid metabolism by repressing the expression of APOC3 and by influencing the activity of sterol response element binding proteins (SREBPs); represses INSIG2 which interferes with the proteolytic activation of SREBPs which in turn govern the rhythmic expression of enzymes with key functions in sterol and fatty acid synthesis. Regulates gluconeogenesis via repression of G6PC1 and PEPCK and adipocyte differentiation via repression of PPARG. Regulates glucagon release in pancreatic alpha-cells via the AMPK-NAMPT-SIRT1 pathway and the proliferation, glucose-induced insulin secretion and expression of key lipogenic genes in pancreatic-beta cells. Positively regulates bile acid synthesis by increasing hepatic expression of CYP7A1 via repression of NR0B2 and NFIL3 which are negative regulators of CYP7A1. Modulates skeletal muscle oxidative capacity by regulating mitochondrial biogenesis and autophagy; controls mitochondrial biogenesis and respiration by interfering with the STK11-PRKAA1/2-SIRT1-PPARGC1A signaling pathway. Represses the expression of SERPINE1/PAI1, an important modulator of cardiovascular disease and the expression of inflammatory cytokines and chemokines in macrophages. Represses gene expression at a distance in macrophages by inhibiting the transcription of enhancer-derived RNAs (eRNAs). Plays a role in the circadian regulation of body temperature and negatively regulates thermogenic transcriptional programs in brown adipose tissue (BAT); imposes a circadian oscillation in BAT activity, increasing body temperature when awake and depressing thermogenesis during sleep. In concert with NR2E3, regulates transcriptional networks critical for photoreceptor development and function. In addition to its activity as a repressor, can also act as a transcriptional activator. In the ovarian granulosa cells acts as a transcriptional activator of STAR which plays a role in steroid biosynthesis. In collaboration with SP1, activates GJA1 transcription in a heme-independent manner. Represses the transcription of CYP2B10, CYP4A10 and CYP4A14 (By similarity). Represses the transcription of CES2 (By similarity). Represses and regulates the circadian expression of TSHB in a NCOR1-dependent manner (By similarity). Negatively regulates the protein stability of NR3C1 and influences the time-dependent subcellular distribution of NR3C1, thereby affecting its transcriptional regulatory activity (By similarity). Plays a critical role in the circadian control of neutrophilic inflammation in the lung; under resting, non-stress conditions, acts as a rhythmic repressor to limit inflammatory activity whereas in the presence of inflammatory triggers undergoes ubiquitin-mediated degradation thereby relieving inhibition of the inflammatory response (By similarity). Plays a key role in the circadian regulation of microglial activation and neuroinflammation; suppresses microglial activation through the NF-kappaB pathway in the central nervous system (By similarity). Plays a role in the regulation of the diurnal rhythms of lipid and protein metabolism in the skeletal muscle via transcriptional repression of genes controlling lipid and amino acid metabolism in the muscle (By similarity).

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▶Modifications Tables

Relations

Regulator Mechanism target score ℹ
+ GSK3Bup-regulates img/direct-activation.png phosphorylation NR1D1 0.288
Publications: 2 Organism: Homo Sapiens
+ PPARGup-regulates quantity by expression img/direct-activation.png transcriptional regulation NR1D1 0.282
Publications: 1 Organism: Mus Musculus
Pathways:Circadian clock
+ NR1D1up-regulates img/indirect-activation.png NR2E3 0.41
Publications: 1 Organism: Homo Sapiens
+ NR2E3up-regulates img/direct-activation.png binding NR1D1 0.41
Publications: 1 Organism: Homo Sapiens
+ NR1D1down-regulates quantity by repression img/direct_inhibition.png transcriptional regulation NPAS2 0.618
Publications: 1 Organism: Homo Sapiens
Pathways:Circadian clock
+ RORAdown-regulates activity img/direct_inhibition.png binding NR1D1 0.434
Publications: 1 Organism: Homo Sapiens
Pathways:Circadian clock
+ NR1D1up-regulates activity img/direct-activation.png binding OPHN1 0.2
Publications: 1 Organism: Homo Sapiens
+ NR1D1down-regulates quantity by repression img/direct_inhibition.png transcriptional regulation ARNTL 0.661
Publications: 2 Organism: Homo Sapiens
Pathways:Circadian clock
+ C1Dup-regulates activity img/direct-activation.png binding NR1D1 0.319
Publications: 1 Organism: Homo Sapiens
+ NR1D1down-regulates quantity by repression img/indirect_inhibition.png transcriptional regulation ARNTL 0.661
Publications: 1 Organism: Homo Sapiens
Pathways:Circadian clock
+ NR1D1up-regulates img/indirect-activation.png Adipogenesis 0.7
Publications: 1 Organism: Mus Musculus
Pathways:Circadian clock
+ PPARGC1Aup-regulates quantity by expression img/direct-activation.png transcriptional regulation NR1D1 0.5
Publications: 1 Organism: Homo Sapiens
Pathways:Circadian clock