NR1D2

Summary

NR1D2 (nuclear receptor subfamily 1 group D member 2, HGNC:7963) is a protein-coding gene on chromosome 3p24.2, encoding Nuclear receptor subfamily 1 group D member 2 (Q14995). Transcriptional repressor which coordinates circadian rhythm and metabolic pathways in a heme-dependent manner.

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.

Source: NCBI Gene 9975 — RefSeq curated summary.

At a glance

• GWAS associations: 13
• Clinical variants (ClinVar): 88 total — 1 likely-pathogenic
• Druggable target: yes
• MANE Select transcript: NM_005126

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7963
Approved symbol	NR1D2
Name	nuclear receptor subfamily 1 group D member 2
Location	3p24.2
Locus type	gene with protein product
Status	Approved
Aliases	BD73, RVR, EAR-1r, HZF2, Hs.37288, REVERBB, REVERBbeta
Ensembl gene	ENSG00000174738
Ensembl biotype	protein_coding
OMIM	602304
Entrez	9975

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 6 protein_coding, 2 retained_intron, 1 nonsense_mediated_decay

ENST00000312521, ENST00000383773, ENST00000468700, ENST00000472780, ENST00000492552, ENST00000873728, ENST00000873729, ENST00000873730, ENST00000947380

RefSeq mRNA: 2 — MANE Select: NM_005126 NM_001145425, NM_005126

CCDS: CCDS33718

Canonical transcript exons

ENST00000312521 — 8 exons

Exon	Start	End
ENSE00001730590	23945286	23945594
ENSE00003261048	23977223	23980617
ENSE00003541797	23967813	23968023
ENSE00003573393	23959671	23959815
ENSE00003603896	23956037	23956125
ENSE00003610683	23961977	23962605
ENSE00003614986	23954537	23954803
ENSE00003633084	23964977	23965162

Expression profiles

Bgee: expression breadth ubiquitous, 294 present calls, max score 97.03.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 25.1780 / max 339.1526, expressed in 1773 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
35733	15.8222	1752
35734	7.1447	1508
35732	1.4951	911
35735	0.7161	343

Top tissues by expression

300 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
calcaneal tendon	UBERON:0003701	97.03	gold quality
biceps brachii	UBERON:0001507	96.32	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	96.25	gold quality
caput epididymis	UBERON:0004358	95.83	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	95.59	gold quality
tendon	UBERON:0000043	95.39	gold quality
cauda epididymis	UBERON:0004360	95.30	gold quality
parietal pleura	UBERON:0002400	94.87	gold quality
superficial temporal artery	UBERON:0001614	94.53	gold quality
pigmented layer of retina	UBERON:0001782	94.33	gold quality
corpus epididymis	UBERON:0004359	94.33	gold quality
amniotic fluid	UBERON:0000173	94.30	gold quality
retina	UBERON:0000966	94.30	gold quality
gluteal muscle	UBERON:0002000	94.27	gold quality
eye	UBERON:0000970	94.14	gold quality
palpebral conjunctiva	UBERON:0001812	94.09	gold quality
corpus callosum	UBERON:0002336	94.02	gold quality
vastus lateralis	UBERON:0001379	93.83	gold quality
mucosa of paranasal sinus	UBERON:0005030	93.82	gold quality
skin of hip	UBERON:0001554	93.55	gold quality
seminal vesicle	UBERON:0000998	93.23	gold quality
lateral nuclear group of thalamus	UBERON:0002736	92.90	gold quality
mammalian vulva	UBERON:0000997	92.88	gold quality
quadriceps femoris	UBERON:0001377	92.86	gold quality
esophagus squamous epithelium	UBERON:0006920	92.71	gold quality
pons	UBERON:0000988	92.47	gold quality
oral cavity	UBERON:0000167	92.39	gold quality
primary visual cortex	UBERON:0002436	92.25	gold quality
trigeminal ganglion	UBERON:0001675	92.20	gold quality
superior vestibular nucleus	UBERON:0007227	92.18	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.01

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

7 targets.

Target	Regulation
AFP	Repression
APOC3	Repression
BMAL1	Repression
CYP7A1	Unknown
MYCN	Repression
NR1D1	Unknown
SREBF1	Repression

JASPAR motifs

Motif	Name	Family
MA1532.1	NR1D2	Thyroid hormone receptor-related factors (NR1)
MA1532.2	NR1D2	Thyroid hormone receptor-related factors (NR1)

JASPAR matrix evidence (PMIDs): PMID:14559106

Upstream regulators (CollecTRI, top): BMAL1, CLOCK, RORA

miRNA regulators (miRDB)

223 targeting NR1D2, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-3925-3P	100.00	69.95	1237
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-371A-3P	99.99	66.77	91
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-485-3P	99.98	70.68	1585
HSA-MIR-539-3P	99.98	70.74	1616
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-27A-3P	99.98	72.13	2955

Literature-anchored findings (GeneRIF, showing 24)

• Rev-erbbeta modulates the apoCIII gene expression by recruiting different transcription co-activator or co-repressor. (PMID:17996965)
• heme regulation of REV-ERBs may link the control of metabolism and the mammalian clock (PMID:18037887)
• Nuclear receptor rev-erb-{alpha} circadian gene variants have a role in response to lithium carbonate in bipolar affective disorder (PMID:20348464)
• oxidative stress leads to oxidation of cysteine(s), thus releasing heme from Rev-erbbeta and altering its transcriptional activity. (PMID:21123168)
• Our results suggest that the REV-ERBalpha rs2071427 polymorphism modulates body fat mass in both adult and young people. (PMID:22828941)
• REV-ERB-ALPHA circadian gene variant associates with obesity in two independent populations: Mediterranean and North American. (PMID:24173768)
• Cobalt protoporphyrin IX (CoPP) and zinc protoporphyrin IX (ZnPP) are ligands that bind directly to the REV-ERBs. However, instead of mimicking the agonist action of heme, CoPP and ZnPP function as antagonists of REV-ERB function. (PMID:24872411)
• REV-ERBbeta plays a role in supporting cancer cell viability when autophagy is compromised. (PMID:25023698)
• Together, the findings demonstrate an anti-inflammatory effect, downregulating of MMP-9 and CCL2 transcription, of astroglial REV-ERBs activation through HDAC3-dependent and HDAC3-independent mechanisms. (PMID:26616049)
• heme is involved in regulating the degradation of Rev-erbbeta in a manner consistent with its role in circadian rhythm maintenance (PMID:26670607)
• Data show that miR-210 inhibits the expression of nuclear receptor subfamily 1, group D, member 2 (NR1D2), particularly in cryptorchidic tissues. (PMID:27562222)
• These results demonstrate the importance of the Rev-erbbeta HRM in regulating interactions with heme and NCoR1 and advance our understanding of how signaling through HRMs affects the major cellular processes of circadian rhythm maintenance and metabolism. (PMID:28500133)
• REVIEW: Redox Regulation of Heme Oxygenase-2 and the Transcription Factor, Rev-Erb, Through Heme Regulatory Motifs (PMID:28990415)
• Rev-erbalpha regulates Cyp7a1 and cholesterol metabolism through its repression of the Lrh-1 receptor. (PMID:29237721)
• A GBM-promoting role of NR1D2. (PMID:29773903)
• Burkholderia pseudomallei interferes with host lipid metabolism via NR1D2-mediated PNPLA2/ATGL suppression to block autophagy-dependent inhibition of infection. (PMID:32777979)
• Determination of genetic changes of Rev-erb beta and Rev-erb alpha genes in Type 2 diabetes mellitus by next-generation sequencing. (PMID:32798635)
• Ferric heme as a CO/NO sensor in the nuclear receptor Rev-Erbss by coupling gas binding to electron transfer. (PMID:33436410)
• RORalpha and REV-ERBalpha are Associated With Clinicopathological Parameters and are Independent Biomarkers of Prognosis in Gastric Cancer. (PMID:34931925)
• Role of Circadian Transcription Factor Rev-Erb in Metabolism and Tissue Fibrosis. (PMID:36361737)
• Novel CLOCK and NR1D2 variants in 64 sighted Japanese individuals with non-24-hour sleep-wake rhythm disorder. (PMID:36897197)
• Human nuclear hormone receptor activity contributes to malaria parasite liver stage development. (PMID:37172592)
• Functional Characterization of Circadian Nuclear Receptors REV-ERBalpha and REV-ERBbeta in Human Osteosarcoma Cell Cultures. (PMID:38255844)
• Association between glucose metabolism, the circadian cycle and hypoxia: Evaluation of the NPAS2 and Rev-Erb-alpha protein serum levels in obstructive sleep apnea patients - a pilot study. (PMID:38804230)

Cross-species orthologs

189 orthologs

Organism	Symbol	Gene ID
danio_rerio	nr1d2a	ENSDARG00000003820
danio_rerio	nr1d2b	ENSDARG00000009594
mus_musculus	Nr1d2	ENSMUSG00000021775
rattus_norvegicus	Nr1d2	ENSRNOG00000046912
drosophila_melanogaster	EcR	FBGN0000546
drosophila_melanogaster	Hr96	FBGN0015240
caenorhabditis_elegans		WBGENE00001062
caenorhabditis_elegans	nhr-2	WBGENE00003601
caenorhabditis_elegans		WBGENE00003608
caenorhabditis_elegans		WBGENE00003611
caenorhabditis_elegans		WBGENE00003614
caenorhabditis_elegans		WBGENE00003615
caenorhabditis_elegans		WBGENE00003617
caenorhabditis_elegans		WBGENE00003618
caenorhabditis_elegans		WBGENE00003620
caenorhabditis_elegans	nhr-23	WBGENE00003622
caenorhabditis_elegans		WBGENE00003624
caenorhabditis_elegans		WBGENE00003632
caenorhabditis_elegans		WBGENE00003634
caenorhabditis_elegans		WBGENE00003638
caenorhabditis_elegans		WBGENE00003640
caenorhabditis_elegans		WBGENE00003641
caenorhabditis_elegans		WBGENE00003642
caenorhabditis_elegans		WBGENE00003643
caenorhabditis_elegans		WBGENE00003644
caenorhabditis_elegans		WBGENE00003645
caenorhabditis_elegans		WBGENE00003646
caenorhabditis_elegans		WBGENE00003648
caenorhabditis_elegans		WBGENE00003649
caenorhabditis_elegans		WBGENE00003651
caenorhabditis_elegans		WBGENE00003653
caenorhabditis_elegans		WBGENE00003655
caenorhabditis_elegans		WBGENE00003658
caenorhabditis_elegans		WBGENE00003660
caenorhabditis_elegans		WBGENE00003662
caenorhabditis_elegans	nhr-73	WBGENE00003663
caenorhabditis_elegans	nhr-77	WBGENE00003667
caenorhabditis_elegans		WBGENE00003669
caenorhabditis_elegans	nhr-81	WBGENE00003671
caenorhabditis_elegans	nhr-82	WBGENE00003672
caenorhabditis_elegans		WBGENE00003676
caenorhabditis_elegans		WBGENE00003677
caenorhabditis_elegans		WBGENE00003680
caenorhabditis_elegans		WBGENE00003682
caenorhabditis_elegans		WBGENE00003684
caenorhabditis_elegans		WBGENE00003685
caenorhabditis_elegans		WBGENE00003686
caenorhabditis_elegans		WBGENE00003688
caenorhabditis_elegans		WBGENE00003689
caenorhabditis_elegans		WBGENE00003692
caenorhabditis_elegans		WBGENE00003693
caenorhabditis_elegans		WBGENE00003694
caenorhabditis_elegans		WBGENE00003696
caenorhabditis_elegans		WBGENE00003698
caenorhabditis_elegans		WBGENE00003699
caenorhabditis_elegans		WBGENE00003700
caenorhabditis_elegans		WBGENE00003702
caenorhabditis_elegans		WBGENE00003704
caenorhabditis_elegans		WBGENE00003705
caenorhabditis_elegans		WBGENE00003707
caenorhabditis_elegans		WBGENE00003708
caenorhabditis_elegans		WBGENE00003712
caenorhabditis_elegans		WBGENE00003713
caenorhabditis_elegans		WBGENE00003714
caenorhabditis_elegans		WBGENE00003715
caenorhabditis_elegans		WBGENE00003716
caenorhabditis_elegans		WBGENE00003717
caenorhabditis_elegans		WBGENE00003718
caenorhabditis_elegans		WBGENE00003720
caenorhabditis_elegans		WBGENE00003721
caenorhabditis_elegans		WBGENE00003722
caenorhabditis_elegans		WBGENE00003723
caenorhabditis_elegans		WBGENE00003724
caenorhabditis_elegans		WBGENE00003725
caenorhabditis_elegans		WBGENE00003728
caenorhabditis_elegans		WBGENE00004786
caenorhabditis_elegans		WBGENE00006471
caenorhabditis_elegans	unc-55	WBGENE00006790
caenorhabditis_elegans		WBGENE00007367
caenorhabditis_elegans		WBGENE00008056
caenorhabditis_elegans	nhr-165	WBGENE00008158
caenorhabditis_elegans		WBGENE00008208
caenorhabditis_elegans	nhr-169	WBGENE00008289
caenorhabditis_elegans		WBGENE00008309
caenorhabditis_elegans	nhr-174	WBGENE00008474
caenorhabditis_elegans		WBGENE00008619
caenorhabditis_elegans		WBGENE00008630
caenorhabditis_elegans		WBGENE00008778
caenorhabditis_elegans		WBGENE00008830
caenorhabditis_elegans		WBGENE00008884
caenorhabditis_elegans		WBGENE00008901
caenorhabditis_elegans	nhr-265	WBGENE00009608
caenorhabditis_elegans		WBGENE00010017
caenorhabditis_elegans		WBGENE00010180
caenorhabditis_elegans		WBGENE00010186
caenorhabditis_elegans		WBGENE00010215
caenorhabditis_elegans		WBGENE00010410
caenorhabditis_elegans		WBGENE00010600
caenorhabditis_elegans		WBGENE00010601
caenorhabditis_elegans		WBGENE00010602
caenorhabditis_elegans		WBGENE00010603
caenorhabditis_elegans		WBGENE00010604
caenorhabditis_elegans		WBGENE00011002
caenorhabditis_elegans		WBGENE00011150
caenorhabditis_elegans		WBGENE00011396
caenorhabditis_elegans		WBGENE00011520
caenorhabditis_elegans		WBGENE00011565
caenorhabditis_elegans		WBGENE00011566
caenorhabditis_elegans		WBGENE00011568
caenorhabditis_elegans	nhr-217	WBGENE00011651
caenorhabditis_elegans		WBGENE00011750
caenorhabditis_elegans		WBGENE00012050
caenorhabditis_elegans		WBGENE00012056
caenorhabditis_elegans		WBGENE00012446
caenorhabditis_elegans		WBGENE00012449
caenorhabditis_elegans		WBGENE00012596
caenorhabditis_elegans		WBGENE00012703
caenorhabditis_elegans		WBGENE00013067
caenorhabditis_elegans		WBGENE00013483
caenorhabditis_elegans	nhr-276	WBGENE00013512
caenorhabditis_elegans		WBGENE00013584
caenorhabditis_elegans		WBGENE00013940
caenorhabditis_elegans		WBGENE00014068
caenorhabditis_elegans	nhr-245	WBGENE00014189
caenorhabditis_elegans		WBGENE00014193
caenorhabditis_elegans		WBGENE00015497
caenorhabditis_elegans		WBGENE00015758
caenorhabditis_elegans		WBGENE00015897
caenorhabditis_elegans		WBGENE00015900
caenorhabditis_elegans		WBGENE00015901
caenorhabditis_elegans		WBGENE00015902
caenorhabditis_elegans		WBGENE00016091
caenorhabditis_elegans		WBGENE00016233
caenorhabditis_elegans		WBGENE00016364
caenorhabditis_elegans		WBGENE00016365
caenorhabditis_elegans		WBGENE00016366
caenorhabditis_elegans		WBGENE00016367
caenorhabditis_elegans		WBGENE00016368
caenorhabditis_elegans		WBGENE00016517
caenorhabditis_elegans		WBGENE00016772
caenorhabditis_elegans		WBGENE00016926
caenorhabditis_elegans		WBGENE00016927
caenorhabditis_elegans		WBGENE00017503
caenorhabditis_elegans		WBGENE00017512
caenorhabditis_elegans		WBGENE00017961
caenorhabditis_elegans		WBGENE00018189
caenorhabditis_elegans		WBGENE00018265
caenorhabditis_elegans		WBGENE00018266
caenorhabditis_elegans		WBGENE00018404
caenorhabditis_elegans		WBGENE00018412
caenorhabditis_elegans		WBGENE00018415
caenorhabditis_elegans		WBGENE00018539
caenorhabditis_elegans		WBGENE00018541
caenorhabditis_elegans		WBGENE00018542
caenorhabditis_elegans		WBGENE00018544
caenorhabditis_elegans		WBGENE00018545
caenorhabditis_elegans		WBGENE00018622
caenorhabditis_elegans		WBGENE00019115
caenorhabditis_elegans		WBGENE00019116
caenorhabditis_elegans		WBGENE00019741
caenorhabditis_elegans		WBGENE00019742
caenorhabditis_elegans		WBGENE00019743
caenorhabditis_elegans		WBGENE00020015
caenorhabditis_elegans		WBGENE00020062
caenorhabditis_elegans		WBGENE00020152
caenorhabditis_elegans		WBGENE00020153
caenorhabditis_elegans		WBGENE00020385
caenorhabditis_elegans		WBGENE00020460
caenorhabditis_elegans		WBGENE00020555
caenorhabditis_elegans		WBGENE00020750
caenorhabditis_elegans		WBGENE00020849
caenorhabditis_elegans		WBGENE00020850
caenorhabditis_elegans		WBGENE00020851
caenorhabditis_elegans		WBGENE00020852
caenorhabditis_elegans		WBGENE00021163
caenorhabditis_elegans		WBGENE00021522
caenorhabditis_elegans		WBGENE00021610
caenorhabditis_elegans		WBGENE00021611
caenorhabditis_elegans		WBGENE00021617
caenorhabditis_elegans		WBGENE00022097
caenorhabditis_elegans		WBGENE00022637
caenorhabditis_elegans		WBGENE00022639
caenorhabditis_elegans		WBGENE00022640
caenorhabditis_elegans		WBGENE00022726
caenorhabditis_elegans		WBGENE00022756
caenorhabditis_elegans		WBGENE00022805
caenorhabditis_elegans		WBGENE00044353
caenorhabditis_elegans		WBGENE00044699
caenorhabditis_elegans		WBGENE00045515

Paralogs (18): NR1H4 (ENSG00000012504), NR1H3 (ENSG00000025434), RORA (ENSG00000069667), RARB (ENSG00000077092), VDR (ENSG00000111424), PPARD (ENSG00000112033), THRA (ENSG00000126351), NR1D1 (ENSG00000126368), NR1H2 (ENSG00000131408), RARA (ENSG00000131759), PPARG (ENSG00000132170), NR1I3 (ENSG00000143257), RORC (ENSG00000143365), NR1I2 (ENSG00000144852), THRB (ENSG00000151090), RARG (ENSG00000172819), PPARA (ENSG00000186951), RORB (ENSG00000198963)

Protein

Protein identifiers

Nuclear receptor subfamily 1 group D member 2 — Q14995 (reviewed: Q14995)

Alternative names: Orphan nuclear hormone receptor BD73, Rev-erb alpha-related receptor, Rev-erb-beta, V-erbA-related protein 1-related

All UniProt accessions (4): B4DXD3, F1D8P2, Q14995, Q6NSM0

UniProt curated annotations — full annotation on UniProt →

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 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. Plays a role in the regulation of circadian sleep/wake cycle; essential for maintaining wakefulness during the dark phase or active period. 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. May play a role in the circadian control of neutrophilic inflammation in the lung.

Subunit / interactions. Binds DNA as a monomer or a homodimer. Interacts with NCOA5 coactivator, leading to a strong increase of transcription of target genes. Interacts (via N-terminus) with KAT5. Interacts (via C-terminus) with HDAC1. Interacts with ZNHIT1. Interacts with SIAH2.

Subcellular location. Nucleus. Cytoplasm.

Tissue specificity. Widely expressed. Expressed at high levels in the liver, adipose tissue, skeletal muscle and brain. Expression oscillates diurnally in the suprachiasmatic nucleus (SCN) of the hypothalamus as well as in peripheral tissues.

Post-translational modifications. 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.

Activity regulation. The heme-bound form can bind gaseous signaling molecules such as CO and nitric oxide (NO) and NO can reverse its transcriptional repressor activity.

Domain organisation. Composed of three domains: a modulating N-terminal domain, a DNA-binding domain and a C-terminal ligand-binding domain.

Similarity. Belongs to the nuclear hormone receptor family. NR1 subfamily.

RefSeq proteins (2): NP_001138897, NP_005117* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000536	Nucl_hrmn_rcpt_lig-bd	Domain
IPR001628	Znf_hrmn_rcpt	Domain
IPR001723	Nuclear_hrmn_rcpt	Family
IPR013088	Znf_NHR/GATA	Homologous_superfamily
IPR035500	NHR-like_dom_sf	Homologous_superfamily
IPR050234	Nuclear_hormone_rcpt_NR1	Family

Pfam: PF00104, PF00105

UniProt features (38 total): helix 11, region of interest 5, sequence variant 4, modified residue 3, compositionally biased region 2, binding site 2, disulfide bond 2, strand 2, zinc finger region 2, chain 1, domain 1, DNA-binding region 1, sequence conflict 1, turn 1

Structure

Experimental structures (PDB)

6 structures.

PDB	Method	Resolution (Å)
4N73	X-RAY DIFFRACTION	1.87
3CQV	X-RAY DIFFRACTION	1.9
6WMS	X-RAY DIFFRACTION	2
2V0V	X-RAY DIFFRACTION	2.4
2V7C	X-RAY DIFFRACTION	2.4
6WMQ	X-RAY DIFFRACTION	2.55

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q14995-F1	65.39	0.34

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (2): 384; 568

Post-translational modifications (3): 46, 162, 163

Disulfide bonds (2): 337–343, 374–384

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-383280	Nuclear Receptor transcription pathway

MSigDB gene sets: 333 (showing top): GSE45365_HEALTHY_VS_MCMV_INFECTION_CD8_TCELL_IFNAR_KO_UP, GOBP_CIRCADIAN_RHYTHM, GOBP_MUSCLE_TISSUE_DEVELOPMENT, GOBP_BEHAVIOR, GOBP_INFLAMMATORY_RESPONSE, GOBP_REGULATION_OF_SKELETAL_MUSCLE_CELL_DIFFERENTIATION, GOLDRATH_IMMUNE_MEMORY, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, GOBP_LIPID_HOMEOSTASIS, GOBP_REGULATION_OF_CIRCADIAN_RHYTHM, CAIRO_HEPATOBLASTOMA_CLASSES_DN, GOBP_HORMONE_MEDIATED_SIGNALING_PATHWAY, GOBP_REGULATION_OF_LIPID_METABOLIC_PROCESS, WIEMANN_TELOMERE_SHORTENING_AND_CHRONIC_LIVER_DAMAGE_DN

GO Biological Process (19): negative regulation of transcription by RNA polymerase II (GO:0000122), regulation of DNA-templated transcription (GO:0006355), hormone-mediated signaling pathway (GO:0009755), regulation of lipid metabolic process (GO:0019216), cell differentiation (GO:0030154), intracellular receptor signaling pathway (GO:0030522), regulation of circadian rhythm (GO:0042752), negative regulation of DNA-templated transcription (GO:0045892), positive regulation of DNA-templated transcription (GO:0045893), positive regulation of transcription by RNA polymerase II (GO:0045944), circadian behavior (GO:0048512), regulation of inflammatory response (GO:0050727), negative regulation of inflammatory response (GO:0050728), lipid homeostasis (GO:0055088), energy homeostasis (GO:0097009), regulation of skeletal muscle cell differentiation (GO:2001014), regulation of gene expression (GO:0010468), rhythmic process (GO:0048511), regulation of primary metabolic process (GO:0080090)

GO Molecular Function (13): RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA-binding transcription repressor activity, RNA polymerase II-specific (GO:0001227), nuclear receptor activity (GO:0004879), zinc ion binding (GO:0008270), sequence-specific double-stranded DNA binding (GO:1990837), transcription cis-regulatory region binding (GO:0000976), cis-regulatory region sequence-specific DNA binding (GO:0000987), DNA binding (GO:0003677), DNA-binding transcription factor activity (GO:0003700), protein binding (GO:0005515), sequence-specific DNA binding (GO:0043565), metal ion binding (GO:0046872)

GO Cellular Component (4): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Generic Transcription Pathway	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of transcription by RNA polymerase II	3
DNA-templated transcription	3
regulation of DNA-templated transcription	3
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
cellular anatomical structure	3
transcription by RNA polymerase II	2
circadian rhythm	2
inflammatory response	2
DNA-binding transcription factor activity, RNA polymerase II-specific	2
transcription cis-regulatory region binding	2
negative regulation of DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
signal transduction	1
cellular response to hormone stimulus	1
lipid metabolic process	1
regulation of primary metabolic process	1
cellular developmental process	1
intracellular signal transduction	1
regulation of biological process	1
negative regulation of RNA biosynthetic process	1
positive regulation of RNA biosynthetic process	1
positive regulation of DNA-templated transcription	1
rhythmic behavior	1
regulation of defense response	1
regulation of response to external stimulus	1
negative regulation of defense response	1
negative regulation of response to external stimulus	1
regulation of inflammatory response	1
chemical homeostasis	1
multicellular organismal-level homeostasis	1
skeletal muscle cell differentiation	1
regulation of cell differentiation	1
gene expression	1
regulation of macromolecule biosynthetic process	1
biological_process	1
regulation of metabolic process	1
primary metabolic process	1
cis-regulatory region sequence-specific DNA binding	1
chromatin	1

Protein interactions and networks

STRING

962 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NR1D2	PER2	O15055	963
NR1D2	PER3	P56645	960
NR1D2	BMAL1	O00327	950
NR1D2	CRY1	Q16526	949
NR1D2	NPAS2	Q99743	938
NR1D2	NFIL3	Q16649	924
NR1D2	BHLHE41	Q9C0J9	918
NR1D2	CRY2	Q49AN0	897
NR1D2	BHLHE40	O14503	890
NR1D2	CLOCK	O15516	886
NR1D2	TIMELESS	Q9UNS1	752
NR1D2	NCOR1	O75376	703
NR1D2	CSNK1E	P49674	698
NR1D2	TEF	Q10587	688
NR1D2	NCOR2	Q9Y618	655

IntAct

70 interactions, top by confidence:

A	B	Type	Score
NR1D2	DMWD	psi-mi:“MI:0915”(physical association)	0.560
NR1D2		psi-mi:“MI:0915”(physical association)	0.560
NR1D2	FGFR3	psi-mi:“MI:0915”(physical association)	0.560
GPR37	NR1D2	psi-mi:“MI:0915”(physical association)	0.560
NR1D2	GRN	psi-mi:“MI:0915”(physical association)	0.560
NR1D2	GSN	psi-mi:“MI:0915”(physical association)	0.560
NR1D2	HSPB1	psi-mi:“MI:0915”(physical association)	0.560
NEFL	NR1D2	psi-mi:“MI:0915”(physical association)	0.560
NR1D2	PMP22	psi-mi:“MI:0915”(physical association)	0.560
TSC1	NR1D2	psi-mi:“MI:0915”(physical association)	0.560
NR1D2	WFS1	psi-mi:“MI:0915”(physical association)	0.560
NR1D2	KIF1B	psi-mi:“MI:0915”(physical association)	0.560
NR1D2	RNF11	psi-mi:“MI:0915”(physical association)	0.560
NR1D2	UBQLN1	psi-mi:“MI:0915”(physical association)	0.560
NR1D2	SPRED1	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (74): NR1D2 (Two-hybrid), RBPMS (Two-hybrid), MID2 (Two-hybrid), KRTAP4-2 (Two-hybrid), KRT40 (Two-hybrid), KRTAP10-9 (Two-hybrid), NOTCH2NL (Two-hybrid), NR1D2 (Two-hybrid), RORC (Two-hybrid), NR1D2 (Two-hybrid), NR1D2 (Two-hybrid), NR1D2 (Two-hybrid), NR1D2 (Two-hybrid), CLOCK (Affinity Capture-Luminescence), USP48 (Affinity Capture-MS)

ESM2 similar proteins: A4IIG7, B3SV56, O13012, O42132, P03372, P06211, P06212, P16058, P16375, P19785, P20393, P35398, P43354, P49883, P49884, P50240, P50241, P50242, P51128, P51129, P51179, P51448, P57717, P57781, P57783, P81559, Q04913, Q06219, Q07917, Q08E02, Q08E53, Q14995, Q29040, Q3UV55, Q53AD2, Q5R5Y4, Q60674, Q63503, Q63504, Q64249

Diamond homologs: A4IIG7, B3SV56, F1QJF4, F1QLY4, G5EDJ0, O01639, O08580, O09017, O09018, O45436, O76202, O77245, O95718, P10588, P10589, P11474, P11475, P12813, P13055, P16375, P16376, P17671, P17672, P18515, P20153, P20393, P22736, P22829, P24468, P28702, P33242, P35398, P41235, P41830, P43135, P43136, P43354, P45446, P45447, P49700

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
NR1D2	“down-regulates quantity by repression”	ARNTL	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

88 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	1
Uncertain significance	64
Likely benign	4
Benign	1

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
690345	NM_005126.5(NR1D2):c.523C>T (p.Arg175Trp)	Likely pathogenic

SpliceAI

1278 predictions. Top by Δscore:

Variant	Effect	Δscore
3:23945593:AGGT:A	donor_loss	1.0000
3:23945595:GTA:G	donor_loss	1.0000
3:23946319:ATAC:A	donor_loss	1.0000
3:23946320:TACCT:T	donor_loss	1.0000
3:23946321:A:C	donor_loss	1.0000
3:23946322:C:CT	donor_loss	1.0000
3:23954799:GACAA:G	donor_gain	1.0000
3:23954802:AA:A	donor_gain	1.0000
3:23954802:AAGTA:A	donor_loss	1.0000
3:23954803:AGTA:A	donor_loss	1.0000
3:23954804:G:GG	donor_gain	1.0000
3:23954804:GTA:G	donor_loss	1.0000
3:23956035:A:AG	acceptor_gain	1.0000
3:23956036:G:GG	acceptor_gain	1.0000
3:23956036:GA:G	acceptor_gain	1.0000
3:23956117:GGCT:G	donor_gain	1.0000
3:23956118:GCTG:G	donor_gain	1.0000
3:23956121:GTAAG:G	donor_loss	1.0000
3:23956122:TAAGG:T	donor_loss	1.0000
3:23956123:AAG:A	donor_loss	1.0000
3:23956124:AGG:A	donor_loss	1.0000
3:23956125:GGTAA:G	donor_loss	1.0000
3:23956126:G:GC	donor_loss	1.0000
3:23959666:CTTA:C	acceptor_loss	1.0000
3:23959667:TTA:T	acceptor_loss	1.0000
3:23959668:TAG:T	acceptor_loss	1.0000
3:23959669:A:AG	acceptor_gain	1.0000
3:23959669:A:T	acceptor_loss	1.0000
3:23959670:G:GG	acceptor_gain	1.0000
3:23959812:GATG:G	donor_gain	1.0000

AlphaMissense

3914 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:23956060:T:A	C103S	1.000
3:23956060:T:C	C103R	1.000
3:23956060:T:G	C103G	1.000
3:23956061:G:A	C103Y	1.000
3:23956061:G:C	C103S	1.000
3:23956061:G:T	C103F	1.000
3:23956062:T:G	C103W	1.000
3:23956067:T:A	V105D	1.000
3:23956069:T:A	C106S	1.000
3:23956069:T:C	C106R	1.000
3:23956070:G:A	C106Y	1.000
3:23956070:G:C	C106S	1.000
3:23956070:G:T	C106F	1.000
3:23956071:T:G	C106W	1.000
3:23956075:G:C	D108H	1.000
3:23956076:A:C	D108A	1.000
3:23956076:A:G	D108G	1.000
3:23956076:A:T	D108V	1.000
3:23956082:C:A	A110E	1.000
3:23956087:G:A	G112R	1.000
3:23956087:G:C	G112R	1.000
3:23956088:G:A	G112E	1.000
3:23956088:G:T	G112V	1.000
3:23956090:T:C	F113L	1.000
3:23956091:T:C	F113S	1.000
3:23956092:C:A	F113L	1.000
3:23956092:C:G	F113L	1.000
3:23956093:C:A	H114N	1.000
3:23956093:C:G	H114D	1.000
3:23956094:A:G	H114R	1.000

dbSNP variants (sampled 300 via entrez): RS1000066365 (3:23946154 G>A,T), RS1000199906 (3:23979157 A>G), RS1000220944 (3:23950161 A>G,T), RS1000266795 (3:23943828 G>A), RS1000300175 (3:23950411 G>T), RS1000428072 (3:23956386 C>G,T), RS1000525911 (3:23968156 C>A,T), RS1000557103 (3:23967757 A>G,T), RS1000559827 (3:23949061 A>G), RS1000697423 (3:23956256 AT>A), RS1000715610 (3:23955028 T>G), RS1000746960 (3:23955330 T>C), RS1000768717 (3:23961877 A>G), RS1000849144 (3:23973611 T>C), RS1000860083 (3:23950674 A>G)

Disease associations

OMIM: gene MIM:602304 | disease phenotypes: MIM:606215

GenCC curated gene-disease

Mondo (1): familial atrioventricular septal defect (MONDO:0020290)

Orphanet (1): Atrioventricular septal defect (Orphanet:98722)

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

13 associations (top):

Study	Trait	p-value
GCST002481_10	Acne (severe)	1.000000e-06
GCST004029_43	Angiotensin-converting enzyme inhibitor intolerance	3.000000e-06
GCST004364_24	Intelligence	2.000000e-09
GCST004364_6	Intelligence	2.000000e-08
GCST005142_1	Cognitive ability	2.000000e-08
GCST005212_16	Asthma	9.000000e-06
GCST005316_107	Intelligence (MTAG)	2.000000e-15
GCST005316_108	Intelligence (MTAG)	2.000000e-08
GCST006269_615	General cognitive ability	1.000000e-12
GCST007044_10	Extremely high intelligence	3.000000e-11
GCST009391_1786	Metabolite levels	4.000000e-06
GCST010002_417	Refractive error	4.000000e-34
GCST011037_3	Parkinson’s disease progression (cognitive)	2.000000e-06

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0005325	response to angiotensin-converting enzyme inhibitor
EFO:0004337	intelligence
EFO:0004468	glucose measurement
EFO:0010477	fructose measurement
EFO:0010481	galactose measurement
EFO:0008336	disease progression measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL1961784 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: nhr — 1D. Rev-Erb receptors

Most potent curated ligand interactions (4 total), top 4:

Ligand	Action	Affinity	Parameter
heme	Agonist	6.45	pKd
SR9011	Agonist	6.25	pIC50
SR9009	Agonist	6.1	pIC50
cobalt protoporphyrin IX	Antagonist	5.59	pKd

ChEMBL bioactivities

4 potent at pChembl≥5 of 6 total, top 4 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.25	IC50	560	nM	SR9011
6.10	IC50	800	nM	SR9009
5.87	IC50	1340	nM	CHEMBL3590573
5.52	EC50	3000	nM	SR9011

PubChem BioAssay actives

3 with measured affinity, of 24 total; 3 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
3-[[(4-chlorophenyl)methyl-[(5-nitrothiophen-2-yl)methyl]amino]methyl]-N-pentylpyrrolidine-1-carboxamide	651467: Increased REV-ERB-beta LBD dependent repressor activity in HEK293 cell reporter assay	ic50	0.5600	uM
ethyl 3-[[(4-chlorophenyl)methyl-[(5-nitrothiophen-2-yl)methyl]amino]methyl]pyrrolidine-1-carboxylate	651467: Increased REV-ERB-beta LBD dependent repressor activity in HEK293 cell reporter assay	ic50	0.8000	uM
1-(4-fluorophenyl)-N-[[3-[(1-methylpiperidin-4-yl)methyl]phenyl]methyl]cyclopentan-1-amine	1234214: Inhibition of REV-ERBbeta (unknown origin) expressed in HEK293 cells incubated for 24 hrs assessed as inhibition of receptor-mediated transcriptional repression by REV-ERB luciferase reporter assay	ic50	1.3400	uM

CTD chemical–gene interactions

71 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression, affects expression, increases expression	7
Cyclosporine	increases expression, affects expression	4
sodium arsenite	decreases expression, increases expression	3
Benzo(a)pyrene	affects methylation, decreases expression, increases expression	3
trichostatin A	affects cotreatment, decreases expression	2
Acetaminophen	increases expression	2
Air Pollutants	decreases expression, increases abundance	2
aristolochic acid I	decreases expression	1
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases expression	1
GSK-J4	increases expression	1
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
propionaldehyde	decreases expression	1
bisphenol A	increases expression	1
geraniol	increases expression	1
arsenite	affects binding, decreases reaction	1
methylparaben	increases expression	1
sulforaphane	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
cobaltous chloride	increases expression	1
butyraldehyde	decreases expression	1
pentanal	decreases expression	1
avobenzone	increases expression	1
4-phenylbutyric acid	increases expression	1
motexafin gadolinium	affects reaction, increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	decreases expression, affects cotreatment	1
beta-hydroxy simvastatin acid	increases expression	1
abrine	increases expression	1
2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amide	affects cotreatment, increases expression	1
dorsomorphin	decreases expression, affects cotreatment	1

ChEMBL screening assays

12 unique, capped per target: 10 binding, 2 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1961799	Binding	Increased REV-ERB-beta LBD dependent repressor activity in HEK293 cell reporter assay	Regulation of circadian behaviour and metabolism by synthetic REV-ERB agonists. — Nature
CHEMBL5723465	Functional	Affinity On-target Cellular interaction: (Reporter gene assay (HEK293T cells)) EUB0001152a NR1D2	Affinity On-target Cellular Literature for EUbOPEN Chemogenomic Library

Cellosaurus cell lines

3 cell lines: 3 embryonic stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_A4S7	SEES3-1V human NR1D2, clone1	Embryonic stem cell	Male
CVCL_A4S8	SEES3-1V human NR1D2, clone2	Embryonic stem cell	Male
CVCL_A4S9	SEES3-1V human NR1D2, clone3	Embryonic stem cell	Male

Clinical trials (associated diseases)

9 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT02314312	PHASE3	UNKNOWN	Efficacy and Safety of Everolimus in de Novo Kidney Transplant Recipients of ECD or AKI Donors
NCT05253209	PHASE3	TERMINATED	A Study Evaluating the Efficacy and Safety of IV L-Citrulline for the Prevention of Clinical Sequelae of Acute Lung Injury Induced by Cardiopulmonary Bypass in Pediatric Patients Undergoing Surgery for Congenital Heart Defects
NCT00199771	PHASE2	COMPLETED	Hypertonic Saline Dextran in Pediatric Cardiac Surgery
NCT05092815	PHASE2	UNKNOWN	The Efficacy and Safety of HLX208 in Adult Langerhans Cell Histiocytosis (LCH) and Erdheim-Chester Disease (ECD) With BRAF V600E Mutation
NCT01825369	PHASE1	WITHDRAWN	Aberrations in Carnitine Homeostasis in Congenital Heart Disease With Increased Pulmonary Blood Flow
NCT01120964	PHASE1/PHASE2	COMPLETED	Intravenous L-Citrulline to Treat Children Undergoing Heart Bypass Surgery : Revised Protocol
NCT00005322	Not specified	COMPLETED	Molecular Genetic Epidemiology of Endocardial Cushion Defects - SCOR in Pediatric Cardiovascular Disease
NCT00005546	Not specified	COMPLETED	Molecular Genetic Epidemiology of Three Cardiac Defects -SCOR in Pediatric Cardiovascular Disease
NCT00229827	Not specified	TERMINATED	Optimal Timing for Repair of Left to Right Shunt Lesions