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: 450.22   (req: < 5)

Gene RIFs: 47   (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: 450.22   (req: >= 5)

Gene RIFs: 47   (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: 9

Tclin

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

Active Drug: 0

Expression Data (0 Tissues)

tutorial

No expression data found

Protein Sequence and Structure

Residue Counts

Protein Sequence

Find Targets by Sequence

Show Full Sequence

ProtVista Viewer

Related Tools (4)

Target Illumination GWAS Analytics (TIGA)

TIGA scores and ranks GWAS discovered associations according to the quantity and quality of the evidence supporting the association.

Go To Tool

GENEVA

GENEVA (GENe Expression Variance Analysis) allows you to identify RNA-sequencing datasets from the Gene Expression Omnibus (GEO) that contain conditions modulating a gene or a gene signature.

Go To Tool

GlyGen

GlyGen is a data integration and dissemination project for carbohydrate and glycoconjugate related data.

Go To Tool

ARCHS4

ARCHS4 provides access to gene-function predictions based on RNA-seq co-expression, and gene expression levels across cell and tissues.

Go To Tool

Approved Drugs (0)

No approved drugs found

Active Ligands (9)

Explore Active Ligands

1 – 9 of 9

SR9009

NR1D1Tchem NR

pIC50 : 6.17

SR9011

NR1D1Tchem NR

pIC50 : 6.25

GSK4112

NR1D1Tchem NR

pEC50 : 6.4

SR8278

NR1D1Tchem NR

-log(-) : 6.5

CHEMBL2381196

NR1D1Tchem NR

pEC50 : 7.3

CHEMBL2381198

NR1D1Tchem NR

pEC50 : 7.2

CHEMBL2030074

NR1D1Tchem NR

pEC50 : 7.11

CHEMBL2030073

NR1D1Tchem NR

pEC50 : 7.01

CHEMBL2381197

NR1D1Tchem NR

pEC50 : 7

Protein-Protein Interactions (56)

Explore Interacting Targets

1 – 10 of 56

• See Interactions on String-DB

NR1D2

Tchem

Family:  NR

Novelty:  0.01394655

p_int:  0.978675871

p_wrong:  0.021324128

Score:  0.897

Data Source:  BioPlex,STRINGDB

ARNTL

Tbio

Family:  TF

Novelty:  0.00102829

Score:  0.993

Data Source:  STRINGDB

NCOR1

Tchem

Family:  TF

Novelty:  0.0021926

Score:  0.99

Data Source:  Reactome,STRINGDB

CRY2

Tbio

Novelty:  0.00156961

Score:  0.984

Data Source:  STRINGDB

BHLHE41

Tbio

Family:  TF

Novelty:  0.01015053

Score:  0.981

Data Source:  STRINGDB

NPAS2

Tbio

Family:  TF

Novelty:  0.00728451

Score:  0.979

Data Source:  STRINGDB

CLOCK

Tbio

Family:  TF; Epigenetic

Novelty:  0.00159625

Score:  0.979

Data Source:  STRINGDB

PPARGC1A

Tbio

Novelty:  0.0003625

Score:  0.943

Data Source:  STRINGDB

HDAC3

Tclin

Family:  Epigenetic

Novelty:  0.00393172

Score:  0.941

Data Source:  Reactome,STRINGDB

EP300

Tchem

Family:  Epigenetic

Novelty:  0.00055009

Score:  0.94

Data Source:  STRINGDB

Nearest Tclin Targets

Nearest Tclin calculations are only available for targets with KEGG Pathway annotations.

Pathways (16)

Reactome (13)

KEGG (1)

PathwayCommons (1)

WikiPathways (1)

Circadian Clock (R-HSA-400253)

Click on a row in the table to change the structure displayed.

Find Similar Targets

Items per page:

5

1 – 5 of 13

Data Source	Name	Explore in Pharos	Explore in Source
Reactome	Circadian Clock	69 targets	R-HSA-400253
Reactome	Gene expression (Transcription)	1452 targets	R-HSA-74160
Reactome	Generic Transcription Pathway	1195 targets	R-HSA-212436
Reactome	Metabolism	2112 targets	R-HSA-1430728
Reactome	Metabolism of lipids	740 targets	R-HSA-556833

Name	Explore in Pharos	Explore in Source
Circadian Clock	69 targets	R-HSA-400253
Gene expression (Transcription)	1452 targets	R-HSA-74160
Generic Transcription Pathway	1195 targets	R-HSA-212436
Metabolism	2112 targets	R-HSA-1430728
Metabolism of lipids	740 targets	R-HSA-556833

Viral Interactions (0)

No viral interactions found

Gene Ontology Terms (51)

Functions (16)

Components (8)

Processes (27)

Find Similar Targets

Items per page:

10

1 – 10 of 16

GO Term	Evidence	Assigned by
heme binding	Inferred from Direct Assay (IDA)	UniProtKB
proximal promoter DNA-binding transcription repressor activity, RNA polymerase II-specific	Inferred from Direct Assay (IDA)	NTNU_SB
RNA polymerase II proximal promoter sequence-specific DNA binding	Inferred from Direct Assay (IDA)	UniProtKB
RNA polymerase II regulatory region sequence-specific DNA binding	Inferred from Direct Assay (IDA)	MGI
transcription corepressor binding	Inferred from Direct Assay (IDA)	UniProtKB
transcription regulatory region DNA binding	Inferred from Direct Assay (IDA)	BHF-UCL
nuclear receptor transcription coactivator activity	Inferred from Biological aspect of Ancestor (IBA)	GO_Central
signaling receptor activity	Inferred from Biological aspect of Ancestor (IBA)	GO_Central
transcription factor binding	Inferred from Biological aspect of Ancestor (IBA)	GO_Central
transcription regulatory region sequence-specific DNA binding	Inferred from Biological aspect of Ancestor (IBA)	GO_Central

Disease Associations (null)

No disease associations found

GWAS Traits (37)

• Explore on Target Illumination GWAS Analytics (TIGA)

Items per page:

5

1 – 5 of 37

GWAS Trait	EFO ID	Study Count	SNP Count	Beta Count	Odds Ratio	Evidence (Mean Rank Score)	Provenance
neutrophil count	EFO_0004833	9	12	20		99.9
leukocyte count	EFO_0004308	10	11	24		99.7
myeloid white cell count	EFO_0007988	4	6	6		99.2
neutrophil percentage of leukocytes	EFO_0007990	2	5	6		98.5
granulocyte count	EFO_0007987	2	4	4		98.1

• Explore on Target Illumination GWAS Analytics (TIGA)

Items per page:

5

1 – 5 of 37

GWAS Trait	EFO ID	Beta Count	Odds Ratio	Evidence (Mean Rank Score)	Provenance
neutrophil count	EFO_0004833	20		99.9
leukocyte count	EFO_0004308	24		99.7
myeloid white cell count	EFO_0007988	6		99.2
neutrophil percentage of leukocytes	EFO_0007990	6		98.5
granulocyte count	EFO_0007987	4		98.1

Reset Zoom  Beta Count   Odds Ratio

Find similar targets by:

UniProt Keyword Find Similar Targets

No Header	No Header
3D-structure
Acetylation
Activator
Biological rhythms
Cell projection
Complete proteome
Cytoplasm
Differentiation
DNA-binding
Heme

GWAS Trait Find Similar Targets

No Header	No Header
aging
apolipoprotein A 1 measurement
asthma
basophil count
basophil percentage of leukocytes
C-reactive protein measurement
chronic obstructive pulmonary disease
chronotype measurement
creatine kinase measurement
eosinophil count

MGI Phenotype Find Similar Targets

No Header	No Header
adipose tissue phenotype
behavior/neurological phenotype
cardiovascular system phenotype
cellular phenotype
growth/size/body region phenotype
homeostasis/metabolism phenotype
liver/biliary system phenotype
mortality/aging
muscle phenotype
nervous system phenotype

IDG Resources

No IDG generated resources found

Orthologs (10)

1 – 5 of 10

Species	Name	Source ID	Gene ID	OMA	EggNOG	Inparanoid
Chimp	nuclear receptor subfamily 1 group D member 1	VGNC:9481	454644
Mouse	nuclear receptor subfamily 1, group D, member 1	MGI:2444210	217166
Rat	nuclear receptor subfamily 1, group D, member 1	RGD:628827	252917
Dog	nuclear receptor subfamily 1 group D member 1	VGNC:43940	100688236
Horse	nuclear receptor subfamily 1 group D member 1	VGNC:20858	100054466

Species	Name	OMA	EggNOG	Inparanoid
Chimp	nuclear receptor subfamily 1 group D member 1
Mouse	nuclear receptor subfamily 1, group D, member 1
Rat	nuclear receptor subfamily 1, group D, member 1
Dog	nuclear receptor subfamily 1 group D member 1
Horse	nuclear receptor subfamily 1 group D member 1

Publication Statistics

PubMed Score 450.22

PubMed score by year

Reset Zoom

PubTator Score 83.26

PubTator score by year

Reset Zoom

Patents

Patents by year

Reset Zoom

Related Publications

Text Mined References (80)

GeneRif Annotations (47)

Items per page:

10

0 of 0

PMID	Year	Title