Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJ38PTB)

• DOT Name: Nuclear receptor subfamily 1 group D member 1 (NR1D1)
• Synonyms: Rev-erbA-alpha; V-erbA-related protein 1; EAR-1
• Gene Name: NR1D1
• UniProt ID: NR1D1_HUMAN
• PDB ID: 1A6Y; 1GA5; 1HLZ; 3N00; 8D8I
• Pfam ID: PF00104 ; PF00105
• Sequence:
  MTTLDSNNNTGGVITYIGSSGSSPSRTSPESLYSDNSNGSFQSLTQGCPTYFPPSPTGSL
  TQDPARSFGSIPPSLSDDGSPSSSSSSSSSSSSFYNGSPPGSLQVAMEDSSRVSPSKSTS
  NITKLNGMVLLCKVCGDVASGFHYGVHACEGCKGFFRRSIQQNIQYKRCLKNENCSIVRI
  NRNRCQQCRFKKCLSVGMSRDAVRFGRIPKREKQRMLAEMQSAMNLANNQLSSQCPLETS
  PTQHPTPGPMGPSPPPAPVPSPLVGFSQFPQQLTPPRSPSPEPTVEDVISQVARAHREIF
  TYAHDKLGSSPGNFNANHASGSPPATTPHRWENQGCPPAPNDNNTLAAQRHNEALNGLRQ
  APSSYPPTWPPGPAHHSCHQSNSNGHRLCPTHVYAAPEGKAPANSPRQGNSKNVLLACPM
  NMYPHGRSGRTVQEIWEDFSMSFTPAVREVVEFAKHIPGFRDLSQHDQVTLLKAGTFEVL
  MVRFASLFNVKDQTVMFLSRTTYSLQELGAMGMGDLLSAMFDFSEKLNSLALTEEELGLF
  TAVVLVSADRSGMENSASVEQLQETLLRALRALVLKNRPLETSRFTKLLLKLPDLRTLNN
  MHSEKLLSFRVDAQ
• 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, 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. Represses the transcription of CES2. Represses and regulates the circadian expression of TSHB in a NCOR1-dependent manner. Negatively regulates the protein stability of NR3C1 and influences the time-dependent subcellular distribution of NR3C1, thereby affecting its transcriptional regulatory activity. 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. 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. 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.
• Tissue Specificity: Widely expressed. Expressed at high levels in the liver, adipose tissue, skeletal muscle and brain. Also expressed in endothelial cells (ECs), vascular smooth muscle cells (VSMCs) and macrophages. Expression oscillates diurnally in the suprachiasmatic nucleus (SCN) of the hypothalamus as well as in peripheral tissues. Expression increases during the differentiation of pre-adipocytes into mature adipocytes. Expressed at high levels in some squamous carcinoma cell lines.
• KEGG Pathway: Circadian rhythm (hsa04710)
• Reactome Pathway:
  PPARA activates gene expression (R-HSA-1989781)
  Transcriptional activation of mitochondrial biogenesis (R-HSA-2151201)
  Nuclear Receptor transcription pathway (R-HSA-383280)
  Circadian Clock (R-HSA-400253)
  Heme signaling (R-HSA-9707616)
  NR1D1 (REV-ERBA) represses gene expression (R-HSA-1368071)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Lithium	DMZ3OU6	Phase 2	Nuclear receptor subfamily 1 group D member 1 (NR1D1) affects the response to substance of Lithium.	[20]

2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Nuclear receptor subfamily 1 group D member 1 (NR1D1).	[1]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Nuclear receptor subfamily 1 group D member 1 (NR1D1).	[12]

17 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Nuclear receptor subfamily 1 group D member 1 (NR1D1).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Nuclear receptor subfamily 1 group D member 1 (NR1D1).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Nuclear receptor subfamily 1 group D member 1 (NR1D1).	[4]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Nuclear receptor subfamily 1 group D member 1 (NR1D1).	[5]
Dexamethasone	DMMWZET	Approved	Dexamethasone decreases the expression of Nuclear receptor subfamily 1 group D member 1 (NR1D1).	[6]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Nuclear receptor subfamily 1 group D member 1 (NR1D1).	[7]
Cannabidiol	DM0659E	Approved	Cannabidiol increases the expression of Nuclear receptor subfamily 1 group D member 1 (NR1D1).	[8]
Prednisolone	DMQ8FR2	Approved	Prednisolone decreases the expression of Nuclear receptor subfamily 1 group D member 1 (NR1D1).	[9]
Chenodiol	DMQ8JIK	Approved	Chenodiol affects the expression of Nuclear receptor subfamily 1 group D member 1 (NR1D1).	[10]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Nuclear receptor subfamily 1 group D member 1 (NR1D1).	[11]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Nuclear receptor subfamily 1 group D member 1 (NR1D1).	[13]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Nuclear receptor subfamily 1 group D member 1 (NR1D1).	[14]
Flavonoid derivative 1	DMCQP0B	Patented	Flavonoid derivative 1 decreases the expression of Nuclear receptor subfamily 1 group D member 1 (NR1D1).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Nuclear receptor subfamily 1 group D member 1 (NR1D1).	[16]
Paraquat	DMR8O3X	Investigative	Paraquat increases the expression of Nuclear receptor subfamily 1 group D member 1 (NR1D1).	[17]
geraniol	DMS3CBD	Investigative	geraniol increases the expression of Nuclear receptor subfamily 1 group D member 1 (NR1D1).	[18]
CGS 21680	DMZ0TGY	Investigative	CGS 21680 increases the expression of Nuclear receptor subfamily 1 group D member 1 (NR1D1).	[19]

References

• [1] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [2] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [3] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [4] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [5] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [6] Functional characterization of an orphan nuclear receptor, Rev-ErbAalpha, in chondrocytes and its potential role in osteoarthritis. Arthritis Rheum. 2006 Nov;54(11):3513-22. doi: 10.1002/art.22170.
• [7] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [8] Cannabidiol enhances cytotoxicity of anti-cancer drugs in human head and neck squamous cell carcinoma. Sci Rep. 2020 Nov 26;10(1):20622. doi: 10.1038/s41598-020-77674-y.
• [9] Chronic treatment with prednisolone represses the circadian oscillation of clock gene expression in mouse peripheral tissues. Mol Endocrinol. 2006 Mar;20(3):573-83. doi: 10.1210/me.2005-0165. Epub 2005 Nov 3.
• [10] System analysis of cross-talk between nuclear receptors reveals an opposite regulation of the cell cycle by LXR and FXR in human HepaRG liver cells. PLoS One. 2019 Aug 22;14(8):e0220894. doi: 10.1371/journal.pone.0220894. eCollection 2019.
• [11] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [12] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [13] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [14] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [15] Cytotoxicity of flavones and flavonols to a human esophageal squamous cell carcinoma cell line (KYSE-510) by induction of G2/M arrest and apoptosis. Toxicol In Vitro. 2009 Aug;23(5):797-807. doi: 10.1016/j.tiv.2009.04.007. Epub 2009 May 3.
• [16] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.
• [17] CD34+ derived macrophage and dendritic cells display differential responses to paraquat. Toxicol In Vitro. 2021 Sep;75:105198. doi: 10.1016/j.tiv.2021.105198. Epub 2021 Jun 9.
• [18] Geraniol suppresses prostate cancer growth through down-regulation of E2F8. Cancer Med. 2016 Oct;5(10):2899-2908.
• [19] Adenosine A2A receptor and TNF- regulate the circadian machinery of the human monocytic THP-1 cells. Inflammation. 2013 Feb;36(1):152-62. doi: 10.1007/s10753-012-9530-x.
• [20] Nuclear receptor rev-erb-{alpha} circadian gene variants and lithium carbonate prophylaxis in bipolar affective disorder. J Biol Rhythms. 2010 Apr;25(2):132-7. doi: 10.1177/0748730410362713.