Detailed entry information

Protein Information (annotations from UniProt)

Database IDHIV0001998
UniProt IDP20393
Primary gene name(s)NR1D1
Synonym gene name(s)EAR1, HREV, THRAL
Protein nameNuclear receptor subfamily 1 group D member 1
Protein functionTranscriptional 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. {ECO:0000269|PubMed:12021280, ECO:0000269|PubMed:15761026, ECO:0000269|PubMed:16968709, ECO:0000269|PubMed:18006707, ECO:0000269|PubMed:19710360, ECO:0000269|PubMed:1971514, ECO:0000269|PubMed:21479263, ECO:0000269|PubMed:22184247, ECO:0000269|PubMed:23398316, ECO:0000269|PubMed:2539258}.
Subcellular locationNucleus. Cytoplasm {ECO:0000250}. Cell projection, dendrite {ECO:0000250}. Cell projection, dendritic spine {ECO:0000250}. Note=Localizes to the cytoplasm, dendrites and dendritic spine in the presence of OPHN1. {ECO:0000250}.
ECO codeClick here for more information.
Amino acid sequence
FASTA format: P20393
Gene Ontology
(Biological Process)
Complete annatation
cell differentiation [GO:0030154];
cellular response to lipopolysaccharide [GO:0071222];
circadian regulation of gene expression [GO:0032922];
circadian rhythm [GO:0007623];
circadian temperature homeostasis [GO:0060086];
glycogen biosynthetic process [GO:0005978];
negative regulation of receptor biosynthetic process [GO:0010871];
negative regulation of toll-like receptor 4 signaling pathway [GO:0034144];
negative regulation of transcription, DNA-templated [GO:0045892];
negative regulation of transcription from RNA polymerase II promoter [GO:0000122];
positive regulation of bile acid biosynthetic process [GO:0070859];
positive regulation of transcription, DNA-templated [GO:0045893];
proteasomal protein catabolic process [GO:0010498];
regulation of cholesterol homeostasis [GO:2000188];
regulation of circadian rhythm [GO:0042752];
regulation of fat cell differentiation [GO:0045598];
regulation of gluconeogenesis by regulation of transcription from RNA polymerase II promoter [GO:0035947];
regulation of insulin secretion involved in cellular response to glucose stimulus [GO:0061178];
regulation of lipid metabolic process [GO:0019216];
regulation of type B pancreatic cell proliferation [GO:0061469];
response to leptin [GO:0044321];
transcription initiation from RNA polymerase II promoter [GO:0006367]
Gene Ontology
(Molecular Function)
Complete annatation
core promoter sequence-specific DNA binding [GO:0001046];
heme binding [GO:0020037];
RNA polymerase II core promoter proximal region sequence-specific DNA binding [GO:0000978];
RNA polymerase II regulatory region sequence-specific DNA binding [GO:0000977];
RNA polymerase II transcription factor activity, ligand-activated sequence-specific DNA binding [GO:0004879];
steroid hormone receptor activity [GO:0003707];
transcriptional repressor activity, RNA polymerase II core promoter proximal region sequence-specific binding [GO:0001078];
transcription corepressor activity [GO:0003714];
transcription corepressor binding [GO:0001222];
transcription regulatory region DNA binding [GO:0044212];
zinc ion binding [GO:0008270]
Gene Ontology
(Cellular Component)
Complete annatation
cytoplasm [GO:0005737];
dendrite [GO:0030425];
dendritic spine [GO:0043197];
nuclear chromatin [GO:0000790];
nucleoplasm [GO:0005654];
nucleus [GO:0005634]
Protein-protein interaction114941
Phylogenetic treeP20393
HIV replication factor status Zhou et al., Cell. Host. Microbe., 2008
Brass et al., Science, 2008
Smith et al., J. Immunol, 2010
gene status
Lu et al., J. Virol., 2011
      Folds changes 8h: unknown; Folds changes 16h: unknown; Tested: unknown;
Schoggins JW and Rice CM, Curr. Opin. Virol., 2011
      Targeted viruses: unknown
      Viral life cycle: unknown
      Mechanism related to antiviral activity: unknown
Anti-viral restriction factor Liu et al., Retrovirology, 2011
      unknown (Triplicates)

Gene Expression Profile       top

            Up-regulated;            Down-regulated

For brief introduction to each study, please go to the help page.

Gene expression during HIV latency

(1). Mohammadi et al., PLoS Pathog., 2014

Differentially expressed transcripts (Pairwise) during latency and subsequent viral reactivation using several agents - Primary CD4+ T-cell based model

DMSO: Dimethyl suloxyde (negative control) - 0.0033% final
SAHA: Vorinostat (Histone deacetylase inhibitor) - 0.5 μM
CD3: TCR Stimulation by IL-2+ antiCD3/anti-CD28 antibodies
IL7: Interleukin-7 based stimulation
DISU: Disulfiram (alcohol dehydrogenase inhibitor) - 0.5 μM
AZA: 5-azacytidine (AZA; DNA methylation inhibitor) - 1 μM
Experimental Condition Log2 Fold Change P value Adjusted P value
AZA vs. CD30.6481274164679270.06207034884717850.119008306554468
AZA vs. DISU0.3048545893660590.4582444356344080.922366250032841
AZA vs. IL7-0.1961589399951080.3431659811787130.999311006273513
AZA vs. SAHA-0.1990631087678750.4958273269655190.818851364943352
DISU vs. CD3-0.3557610190172730.5057774024949450.630715467009332
DISU vs. IL7-0.5112702029769970.2153339238652770.596470805094579
DISU vs. SAHA-0.5047521998884520.2761540540144790.65603999811668
DMSO vs. AZA0.1104332391725490.547080853761991
DMSO vs. CD3-0.5571659892063050.1062591751914060.179541775937476
DMSO vs. DISU-0.1992650706732940.6253661968740950.944878155252929
DMSO vs. IL7-0.2967406424514830.1253614724727490.620616381394679
DMSO vs. SAHA-0.3129922378935180.2849828015304280.635633535868741
HIV vs. Mock in Activation0.1126161342094380.8789245138990190.999983755607037
HIV vs. Mock in Latency-0.5412038280735790.08292183156119040.999834320637052
IL7 vs. CD3-0.8406348258715150.01617484259163940.0442313864992344
SAHA vs. CD3-0.8723822128377810.04484344637028140.0907098451958881
SAHA vs. IL7-0.006405761378310870.982647551158110.993710617125574
(2). Iglesias-Ussel et al., J. Virol., 2013

Up and Downregulated transcripts during Latency (Latently infected CD4+ T cells vs Uninfected)- Primary CD4+Tcell based model
Log2 Fold Change P Value
unknown unknown

Gene expression during HIV infection and replication

(1). Imbeault et al., PloS Pathog., 2012

Transcriptomic profiling of HIV-1 infected CD4+ T cells - Primary CD4+ T cells
Experiment type Log2 Fold Change P Value Adjusted P Value
Infected vs. Mock unknown unknown unknown
Infected vs. Bystander unknown unknown unknown
(2). Lefebvre et al., J. Virol., 2011

Transcriptome analysis of T-cell line (Sup T1)
Log2 Fold Change unknown
(3). Li et al., J. Immunol., 2013

Lymphatic tissue
Acute Fold Change Acute P Value Asymt Fold Change Asypt P Value AIDS Fold Change AIDS P Value
unknown unknown unknown unknown unknown unknown
(4). Chang et al., MBio., 2011

Transcriptome analysis of T-cell line (Sup T1)

Derived from Sherrill-Mix et al., BMC Retrovirol., 2015 cross validation
Up-regulated (True) TRUE
(5). Sherrill-Mix et al., BMC Retrovirol., 2015

Deep RNA-seq analysis of primary human T cell infected with low passage HIV isolate HIV89.6 - Primary CD4+ T cell based
Test Status Log2 Fold Change P Value
OK -0.945466 0.000305467
(6). Rotger et al., PLoS Pathog., 2010

Genome-wide mRNA expression of CD4+ T cells from HIV-infected patient
(Genes differentially expressed (at adjusted p<0.01) according to the empirical Bayes approach)
Log2 Fold Change P Value
unknown unknown

Proteomic/Transcriptomics studies indicating differentially expressed genes mediated by HIV

(1). Greenwood et al., Elife, 2016

Activated (CD3/CD28) Primary human CD4+ T cells infected with pNL4-3-dE-EGFP. The table shows the complete (unfiltered) TMT (tandem mass tag)-based proteomic time course dataset
6 h 24 h 48 h 72 h RTi
unknown unknown unknown unknown unknown
(2). Navare et al., Virology, 2012

SUP-T1 cell line
FC-4hpi P-value FC-8hpi P-value FC-20hpi P-value Category
unknown unknown unknown unknown unknown unknown unknown
(3). Hyrcza et al., J. Virolo., 2007

Primary human CD4+ and CD8+ T Cells
Affymetrix Prob ID Fold Change In CD8? Category
204760_s_at 3.42 No downregulated in CD8+ cells

Protein Overview       top

Drug-protein Interaction       (annotations from DrugBank)      top

not found

Protein Secondary Structure       (annotations from PDB)      top

PDB Accession Method Resolution Chain Structure Preview
1A6Y X-ray 2.3Å A/B=123-216.
1EF6 Model - A=281-301# B=430-614.
1GA5 X-ray 2.4Å A/B/E/F=123-216.
1HLZ X-ray 2.8Å A/B=123-216.
3N00 X-ray 2.6Å A=281-614.

HIV-1 Interaction       (annotations from NCBI HIV-1 Interaction Database)      top

not found

Metabolic/Signalling Pathway       (annotations from KEGG database)      top

Pathway Accession Number Description
hsa04710 Circadian rhythm - Homo sapiens (human)