Tchem NR1D1 Nuclear receptor subfamily 1 group D member 1

Protein Summary

Description

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 G6PC 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. This gene encodes a transcription factor that is a member of the nuclear receptor subfamily 1. The encoded protein is a ligand-sensitive transcription factor that negatively regulates the expression of core clock proteins. In particular this protein represses the circadian clock transcription factor aryl hydrocarbon receptor nuclear translocator-like protein 1 (ARNTL). This protein may also be involved in regulating genes that function in metabolic, inflammatory and cardiovascular processes. [provided by RefSeq, Jan 2013]

Uniprot Accession IDs

• P20393
• Q0P5Z4
• Q15304

Gene Name

• NR1D1

Ensembl ID

• ENST00000246672
• ENSP00000246672
• ENSG00000126368

Symbol

• EAR1
• HREV
• THRAL
• EAR1
• hRev
• THRA1
• THRAL
• ear-1
• REVERBA
• REVERBalpha

Knowledge Table

Most Knowledge About	Knowledge Value (0 to 1 scale)
molecular function	1
biological process	0.99
virus perturbation	0.96
transcription factor	0.95
transcription factor binding site profile	0.87

Protein Classes

PANTHER Classes

Protein / Transcription Factor / Nuclear Receptor Subfamily 1 Group D Member 1

Protein / Receptor / Nuclear Receptor Subfamily 1 Group D Member 1

Protein / Nucleic Acid Binding / Nuclear Receptor Subfamily 1 Group D Member 1

Protein / ... / C4 Zinc Finger Nuclear Receptor / Nuclear Receptor Subfamily 1 Group D Member 1

DTO Classes

Protein / Nuclear Receptor / Rev-erb Receptors / Nuclear Receptor Subfamily 1 Group D Member 1

IDG Development Level Summary

Tdark

These are targets about which virtually nothing is known. They do not have known drug or small molecule activities
- AND - satisfy two or more of the following criteria:

Pubmed score: 572.36   (req: < 5)

Gene RIFs: 62   (req: <= 3)

Antibodies: 477   (req: <= 50)

Tbio

These targets do not have known drug or small molecule activities
- AND - satisfy two or more of the following criteria:

Pubmed score: 572.36   (req: >= 5)

Gene RIFs: 62   (req: > 3)

Antibodies: 477   (req: > 50)

- OR - satisfy the following criterion:

Gene Ontology Terms: 43

Tchem

Target has at least one ChEMBL compound with an activity cutoff of < 30 nM - AND - satisfies the preceding conditions

Active Ligands: 11

Tclin

Target has at least one approved drug - AND - satisfies the preceding conditions

Active Drug: 0