Affinage

RORA

Nuclear receptor ROR-alpha · UniProt P35398

Length
523 aa
Mass
59.0 kDa
Annotated
2026-06-10
100 papers in source corpus 41 papers cited in narrative 41 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RORA encodes RORα, a ligand-modulated nuclear receptor that acts as a constitutively active transcription factor binding monomeric ROR-response elements (ROREs) to direct cell-type-specific gene programs across circadian, metabolic, immune, and developmental contexts (PMID:15821743, PMID:12114512, PMID:18055760). As a positive arm of the core circadian clock, RORα directly activates Bmal1 and the clock gene Reverb-α through conserved ROREs, with coactivation by GRIP-1/TIF-2 (PMID:15821743, PMID:12114512). Genetic disruption of the RORα DNA-binding domain phenocopies and fails to complement the staggerer allele, establishing staggerer as a loss-of-function mutation in the shared coding region of co-expressed cerebellar isoforms (PMID:9510031, PMID:9226375). Beyond direct activation, RORα executes gene repression by recruiting HDAC3 to displace coactivators CBP and BRD4 from NF-κB target promoters in intestinal epithelium and to silence PPARγ target genes in liver, linking RORα loss to intestinal inflammation, hepatic steatosis, and insulin resistance (PMID:28757615, PMID:31570593). RORα also represses targets through non-canonical protein partnerships: it binds the heptad/marked-box region of E2F1 and recruits HDAC1 to block E2F1 acetylation and cell-cycle progression, and it forms an HDAC3 complex on the CD274 (PD-L1) promoter that DDX3X antagonizes (PMID:24891616, PMID:38718296). In the immune system RORα cooperates with RORγt at a Rorc cis-element to stabilize the Th17 lineage and is independently required for Th17 pathogenicity and mTORC1-driven T-cell programs, while in thymic progenitors it directs ILC2 over T-cell fate by overriding BCL11B repression of Nfil3/Id2 (PMID:36243007, PMID:33397953, PMID:33432227, PMID:34525365). RORα controls lipid and oxysterol metabolism through targets including Cyp7b1, CPT-1, and caveolin-3, with reciprocal antagonism toward LXRα, and serves as the downstream effector of CH25H/CYP7B1-generated oxysterols driving osteoarthritis (PMID:15199055, PMID:18055760, PMID:30728500). Its activity is tuned by endogenous and synthetic ligands—oxysterols, cholesterol sulfate, hydroxyvitamin D3 metabolites, the pro-resolving mediator maresin-1, and synthetic agonists—and isoform-specific localization, with RORα1 confined to the nucleus and RORα2-4 directed to cytoplasm/membrane by C-terminal helix 12 (PMID:30855276, PMID:24668754, PMID:16806533, PMID:27788394, PMID:30728500).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1997 Medium

    Defining the molecular lesion in staggerer mice established that a deletion in the shared coding region of RORα isoforms, ablating cerebellar RORα1 and RORα4, underlies the cerebellar phenotype.

    Evidence Genetic/physical mapping and RT-PCR isoform analysis in murine and human cerebellum

    PMID:9226375

    Open questions at the time
    • Did not establish which downstream transcriptional targets mediate the cerebellar defect
    • Isoform-specific functional differences not resolved
  2. 1998 High

    Targeted disruption of the RORα DNA-binding domain proved that staggerer is a loss-of-function allele of Rora, formally tying the phenotype to absent functional RORα protein.

    Evidence Gene targeting in ES cells with complementation testing and histological/Northern validation

    PMID:9510031

    Open questions at the time
    • DNA-binding-independent activities not addressed
    • Molecular targets in cerebellum not identified
  3. 2001 High

    First mechanistic link of RORα to inflammation showed it antagonizes NF-κB by transactivating IκBα via a RORE, reducing p65 translocation.

    Evidence Adenoviral overexpression, EMSA, promoter reporter, immunostaining in smooth-muscle cells

    PMID:11252722

    Open questions at the time
    • Coregulators of this repression not defined here
    • Did not address direct vs indirect NF-κB target repression
  4. 2002 High

    Established RORα as a direct monomeric-RORE transcription factor for the clock gene Reverb-α with coactivator selectivity, defining its DNA-binding mode.

    Evidence EMSA, RORE mutagenesis, reporter and coactivator cotransfection, staggerer validation

    PMID:12114512

    Open questions at the time
    • Endogenous ligand control of this activity not addressed
    • Structural basis of GRIP-1 vs SRC-1 selectivity unresolved
  5. 2004 Medium

    Extended RORα's direct target repertoire to skeletal-muscle lipid genes CPT-1 and caveolin-3, with p300/PGC-1 coactivation, implicating it in muscle lipid homeostasis.

    Evidence Dominant-negative RORα, promoter reporter, coactivator cotransfection

    PMID:15199055

    Open questions at the time
    • Direct promoter occupancy not shown by ChIP
    • In vivo metabolic relevance not tested
  6. 2005 High

    Placed RORα as a positive limb of the core circadian clock by demonstrating direct RORE-driven activation of Bmal1.

    Evidence Reporter assays with RORE mutagenesis, RNAi, and staggerer behavioral analysis

    PMID:15821743

    Open questions at the time
    • Ligand regulation of clock activity not addressed
    • Tissue-specific contributions not dissected
  7. 2006 Medium

    Connected RORα to neurodegeneration and defined isoform-localization rules, showing mutant ATXN1 destabilizes RORα in Purkinje cells and that helix 12 vs hinge/LBD dictate membrane vs nuclear localization.

    Evidence Conditional transgenic SCA1 model with Co-IP; domain-swap fractionation/immunofluorescence

    PMID:16806533 PMID:17110330

    Open questions at the time
    • Direct ATXN1-RORA-Tip60 complex stoichiometry not resolved
    • Functional consequence of cytoplasmic isoforms unclear
  8. 2007 High

    Defined RORα as a regulator of oxysterol/cholesterol metabolism by directly activating Cyp7b1 and mutually antagonizing LXRα.

    Evidence Staggerer null analysis, promoter reporters, hepatocyte transfection, LXR-null comparison

    PMID:18055760

    Open questions at the time
    • Mechanism of reciprocal RORα/LXRα antagonism not detailed
    • Ligand identity for endogenous activation not pinned
  9. 2011 High

    Positioned RORα within the DNA-damage/apoptosis axis as both a p53 target and a stabilizer of p53 via HAUSP/Usp7.

    Evidence Genome-wide screen, p53-RE mutagenesis reporters, microarray, Drosophila apoptosis model

    PMID:22152482

    Open questions at the time
    • Direct RORα-Usp7-p53 biochemistry not fully reconstituted
    • Selectivity for apoptotic vs other p53 targets unexplained
  10. 2014 High

    Revealed non-canonical RORα activity by direct binding to E2F1's heptad/marked-box and HDAC1 recruitment to suppress cell-cycle progression, plus identified vitamin D3 derivatives as inverse agonists.

    Evidence Reciprocal Co-IP with domain mapping and HDAC rescue; Tet-on reporter and LBD 2-hybrid with crystal-structure modeling

    PMID:24668754 PMID:24891616

    Open questions at the time
    • Generality of E2F1 repression across cell types not established
    • Vitamin D3 antagonism shown by modeling/reporter, not co-crystal
  11. 2017 High

    Defined RORα's HDAC3-dependent repressive mode genome-wide, showing co-recruitment to PPARγ and NF-κB target promoters that controls hepatic lipid homeostasis and intestinal inflammation, with parallel roles in mitochondrial quality and cardiomyocyte protection.

    Evidence Tissue-specific KO (liver, IEC), transcriptomics, ChIP, Co-IP with HDAC3, disease models; NRVM gain/loss-of-function

    PMID:28757615 PMID:29167529 PMID:30387679 PMID:31570593

    Open questions at the time
    • Determinants of HDAC3 recruitment to specific promoters unresolved
    • Coordination of activator vs repressor functions in same cell unclear
  12. 2019 Medium

    Identified maresin-1 as an endogenous RORα ligand forming a MaR1/RORα/12-LOX autoregulatory circuit, and linked RORα to SIRT1-mediated NF-κB p65 deacetylation control.

    Evidence Ligand-binding, reporter, ChIP, in vivo MaR1 protection; overexpression/knockdown with SIRT1 agonist rescue

    PMID:30855276 PMID:31071300

    Open questions at the time
    • MaR1-RORα binding partially indirect, lacks structural confirmation
    • Physiological relevance of MaR1/12-LOX loop in vivo limited
  13. 2021 High

    Established RORα as a central regulator of immune cell fate—Th17 pathogenicity, ILC2 vs T-cell commitment, mTORC1 programs, and Treg-mediated TL1A sequestration—largely independent of RORγt.

    Evidence Multiple cell-type-specific conditional KOs with ChIP-seq/ATAC-seq/RNA-seq and disease models (EAE, colitis, atopic dermatitis); selective antagonist in human cells

    PMID:29500225 PMID:33397953 PMID:33432227 PMID:34525365

    Open questions at the time
    • Direct vs indirect targets within each immune program not fully separated
    • Ligand control of immune RORα activity unaddressed
  14. 2024 High

    Showed RORα functions as an epigenomic switch establishing cell-type enhancers and chromatin loops, including driving corneal epithelial differentiation via PITX1 and tuning anti-tumor immunity by controlling PD-L1 through an HDAC3/DDX3X-modulated complex.

    Evidence scRNA-seq/ChIP-seq/ATAC-seq/Hi-C with gain/loss-of-function; ChIP and Co-IP with in vivo agonist plus anti-CTLA4

    PMID:38177186 PMID:38718296

    Open questions at the time
    • How RORα reorganizes 3D chromatin mechanistically not resolved
    • Generalizability of PD-L1 DDX3X switch beyond melanoma untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How RORα integrates ligand sensing, isoform-specific localization, and the choice between RORE-driven activation versus HDAC-dependent repression to select context-specific gene programs remains unresolved.
  • No unifying model linking ligand identity to activator vs repressor output
  • Structural basis of partner selection (HDAC3 vs HDAC1 vs DDX3X vs RORγt) undefined
  • Mechanism directing 3D chromatin remodeling unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 10 GO:0003677 DNA binding 6 GO:0098772 molecular function regulator activity 4 GO:0008289 lipid binding 3
Localization
GO:0005634 nucleus 3 GO:0005829 cytosol 1 GO:0005886 plasma membrane 1
Pathway
R-HSA-168256 Immune System 7 R-HSA-1430728 Metabolism 6 R-HSA-74160 Gene expression (Transcription) 6 R-HSA-4839726 Chromatin organization 4 R-HSA-9909396 Circadian clock 2 R-HSA-1640170 Cell Cycle 1 R-HSA-9612973 Autophagy 1
Partners
ATXN1DDX3XE2F1HDAC1HDAC3PPARGRORCSORBS2

Evidence

Reading pass · 41 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2005 RORα directly activates transcription of Bmal1 through two conserved ROR-response elements (ROREs) in the Bmal1 promoter, functioning as a positive component of the cell-autonomous core circadian clock. Loss of endogenous RORα protein dampens circadian rhythm of Bmal1 transcription. Transient transfection reporter assays, RORE mutagenesis, RNAi knockdown in cultured cells, behavioral analysis of RORα-deficient staggerer mice Nature structural & molecular biology High 15821743
2001 RORα1 inhibits TNFα-induced IL-6, IL-8, and COX-2 expression in smooth-muscle cells by reducing p65 translocation and transcriptionally upregulating IκBα via a ROR response element in the IκBα promoter, thereby negatively interfering with the NF-κB signaling pathway. Adenoviral overexpression, Western blotting, immunostaining, EMSA, promoter reporter assays EMBO reports High 11252722
2006 In SCA1 mice, mutant ATXN1 destabilizes RORα, depleting it from Purkinje cells and reducing expression of RORα-controlled genes. Evidence points to existence of a complex containing ATXN1, RORα, and the RORα coactivator Tip60, linking RORα and Tip60 to SCA1 pathogenesis. Conditional transgenic mouse model, Co-immunoprecipitation, gene expression analysis, behavioral assessment Cell Medium 17110330
1998 Targeted disruption of the Rora DNA-binding domain produces mice that phenocopy staggerer mice, demonstrating that staggerer defects are caused by absence of functional RORα protein; the null allele fails to complement staggerer, establishing sg as a loss-of-function allele of Rora. Gene targeting in ES cells (null mutation), histological analysis, Northern blot, complementation testing Mechanisms of development High 9510031
2004 RORα directly regulates the carnitine palmitoyltransferase-1 (CPT-1) and caveolin-3 promoters in skeletal muscle cells, with activity coactivated by p300 and PGC-1, implicating RORα in control of lipid homeostasis in skeletal muscle. Dominant-negative RORα expression, promoter reporter assays, coactivator cotransfection The Journal of biological chemistry Medium 15199055
2002 RORα regulates Reverb-α (NR1D1) transcription via a monomeric ROR response element in the Reverb-α promoter; RORα binds this site (demonstrated by EMSA), and GRIP-1/TIF-2 (but not SRC-1) coactivates RORα-stimulated Reverb-α promoter activity. Northern blot, RT-PCR in staggerer mice, transient transfection reporter assays, EMSA, promoter mutagenesis, coactivator cotransfection The Journal of biological chemistry High 12114512
2007 RORα positively regulates Cyp7b1 (oxysterol 7α-hydroxylase) transcription via ROREs in its promoter; loss of RORα in staggerer mice suppresses Cyp7b1 expression and increases LXRα target gene expression. RORα and LXRα mutually suppress each other in vivo. RORα null (staggerer) mouse analysis, promoter reporter assays, transfection of RORα in hepatocytes, LXR null mouse comparison Molecular pharmacology High 18055760
2011 RORα is a direct transcriptional target of p53 (contains functional p53 response elements); DNA damage-induced RORα stabilizes p53 in a HAUSP/Usp7-dependent manner and activates a subset of p53 target genes specifically involved in apoptosis. Genome-wide screen, luciferase reporter assays with p53-RE mutagenesis, microarray analysis, Drosophila in vivo apoptosis model Molecular cell High 22152482
2012 RORα directly regulates SEMA3F transcription (demonstrated by ChIP and luciferase reporter assay) in breast cancer cells; restoring RORα expression reprograms cancer cells and inhibits tumor invasion in a SEMA3F-dependent manner in 3D culture and nude mouse xenograft. Chromatin immunoprecipitation (ChIP), luciferase reporter assay, 3D culture, siRNA knockdown, xenograft Cancer research High 22350413
2014 RORα binds to the heptad repeat and marked box region of E2F1 in a non-canonical pathway, suppressing E2F1-regulated transcription; RORα recruits HDAC1 to the complex to inhibit E2F1 acetylation and DNA-binding activity, thereby inhibiting cell cycle progression. Co-immunoprecipitation, domain mapping, HDAC inhibition rescue, reporter assays, siRNA knockdown in mammary epithelial cells Molecular and cellular biology High 24891616
2017 Hepatic RORα controls lipid homeostasis by specifically binding and recruiting HDAC3 to PPARγ target gene promoters, causing transcriptional repression of PPARγ; liver-specific Rorα deletion leads to dysregulation of PPARγ signaling, hepatic steatosis, obesity, and insulin resistance on high-fat diet. Liver-specific Rorα knockout mice, global transcriptome analysis, ChIP, Co-immunoprecipitation with HDAC3, PPARγ antagonist rescue Nature communications High 28757615
2017 RORα/HDAC3 co-recruitment to NF-κB target gene promoters causes dismissal of CBP and BRD4, thereby repressing NF-κB transcriptional activity in intestinal epithelial cells; IEC-specific RORα deletion leads to excessive intestinal inflammation. IEC-specific RORα knockout mice, transcriptome analysis, ChIP, DSS colitis model Proceedings of the National Academy of Sciences of the United States of America High 31570593
2019 Maresin 1 (MaR1), a DHA metabolite, was identified as an endogenous ligand of RORα that enhances RORα expression and transcriptional activity; RORα in turn transcriptionally induces 12-lipoxygenase (12-LOX), a key enzyme in MaR1 biosynthesis, forming a MaR1/RORα/12-LOX autoregulatory circuit. Ligand-binding assays, reporter assays, ChIP, RORα-dependent MaR1 protection experiments in vivo The Journal of clinical investigation Medium 30855276
2014 20-hydroxyvitamin D3 [20(OH)D3] and 20,23-dihydroxyvitamin D3 function as antagonists/inverse agonists of RORα, inhibiting RORE-driven reporter activity and RORα-target gene (Bmal1, G6pase) promoter activation; molecular modeling with the RORα LBD crystal structure predicts good binding. Tet-on RORα expression system + RORE-LUC reporter, mammalian 2-hybrid LBD-LXXLL assay, molecular modeling using LBD crystal structure FASEB journal Medium 24668754
2015 RORα directly suppresses SOCS3 gene transcription; loss of RORα leads to decreased proinflammatory and increased anti-inflammatory cytokines in retinopathy. Inhibition of SOCS3 abolishes the vasoprotective effects of RORα deficiency, establishing RORα→SOCS3 as a pathway in pathological retinal angiogenesis. RORα genetic deficiency mouse model (oxygen-induced retinopathy), promoter reporter assays, siRNA inhibition of SOCS3 Proceedings of the National Academy of Sciences of the United States of America Medium 26243880
2017 RORα directly binds to a specific ROR response element on the Sema3e promoter and negatively regulates Sema3e promoter-driven transcription; genetic deficiency of RORα induces Sema3e expression in retinal ganglion cells to suppress pathological retinal neovascularization. Promoter-driven luciferase reporter assay, ChIP, AAV2-shRNA knockdown of Sema3e in RORα-deficient mice FASEB journal Medium 28646017
2009 RORα directly trans-activates the Il-6 gene in astrocytes (necessary for basal IL-6 levels); after inflammatory stimulation, absence of RORα results in excessive IL-6 upregulation via indirect repression of NF-κB signaling, demonstrating bi-directional regulation of IL-6 by RORα. RORα loss-of-function mutant mice (staggerer), reporter assays, cytokine measurement, immunostaining Proceedings of the National Academy of Sciences of the United States of America Medium 19955433
2009 Overexpression of RORα4 in 3T3-L1 cells impairs adipogenesis (decreased adipogenic markers and lipid accumulation); mouse embryonic fibroblasts from staggerer mice differentiate more efficiently into adipocytes, a phenotype reversed by ectopic RORα4 restoration. Overexpression in 3T3-L1, staggerer MEF differentiation assay, ectopic RORα4 rescue FEBS letters Medium 19450581
2006 Subcellular localization of RORα is isoform- and cell line-dependent: RORα1 localizes exclusively to the nucleus (lacks cytoplasmic signal in its A/B domain), while RORα2, 3, and 4 show cytoplasmic and cell-membrane association. The C-terminal α-helix 12 mediates membrane association; the hinge region/LBD mediates nuclear localization. Isoform-specific expression constructs, domain deletion/swap experiments, subcellular fractionation, immunofluorescence microscopy Biochimica et biophysica acta Medium 16806533
1997 The staggerer mutation is a deletion in the common coding region of RORα isoforms; RORα1 and RORα4 are specifically co-expressed in the murine and human cerebellum, generated by alternative promoter usage and exon splicing, indicating that loss of both isoforms underlies the cerebellar phenotype. High-resolution genetic and physical mapping, RT-PCR isoform analysis, Northern blot in cerebellum Genomics Medium 9226375
2022 RORα cooperatively binds with RORγt to a previously unidentified Rorc cis-regulatory element to maintain RORγt expression and Th17 lineage stability in peripheral tissues; RORα is dispensable for initial Th17 differentiation but required for optimal Th17 responses in vivo. T-cell-specific RORα conditional KO mice, RNA-seq, ATAC-seq, ChIP-seq Immunity High 36243007
2021 In skin-resident Tregs, RORα suppresses IL-4 expression and enhances DR3 (death receptor 3/TL1A receptor) expression; deletion of RORα in Tregs prevents sequestration of TL1A, resulting in enhanced ILC2 activation and exaggerated eosinophilia. Treg-specific RORα conditional deletion mouse models of atopic dermatitis, flow cytometry, cytokine measurement Science immunology Medium 29500225
2021 RORα is required for TH17 cell pathogenicity independent of RORγt; T-cell-specific deletion of RORα reduces EAE and colitis development by decreasing TH17 cell development, lowering tissue-homing chemokine receptors/integrins, and increasing Foxp3+ Tregs. A selective RORα antagonist phenocopies the genetic deletion and inhibits human TH17 differentiation. T-cell-specific Rorα conditional KO, EAE and colitis mouse models, pharmacological antagonism with selective small molecule, human TH17 differentiation assay Nature communications High 33397953
2021 RORα expression in thymic progenitors represses T cell development while promoting ILC2 development; mechanistically, RORα overrides BCL11B-mediated repression of Nfil3 and Id2, allowing ID2 to repress E proteins and promote ILC2 differentiation over T cell commitment. RNA-seq, ATAC-seq, ChIP-seq, conditional deletion and overexpression mouse models Nature immunology High 33432227
2021 RORα promotes mTORC1 activation in CD4+ T cells; genome-wide occupancy (ChIP-seq) and transcriptome analysis reveal RORα as a direct transcriptional driver of mTORC1 pathway genes; Rorα deficiency in CD4+ T cells greatly reduces T cell-mediated colitis. CD4-specific Rorα conditional KO, genome-wide ChIP-seq, RNA-seq, T-cell transfer colitis model Cell reports High 34525365
2017 RORα directly represses IL-6 transcription in cardiomyocytes; loss of RORα leads to enhanced IL-6 expression, proinflammatory STAT3 activation, decreased mitochondrial number and function, oxidative stress, hypertrophy, and death of cardiomyocytes upon angiotensin II exposure. Staggerer mouse model (in vivo), neonatal rat ventricular myocyte overexpression/silencing (in vitro), luciferase reporter, Western blot American journal of physiology. Heart and circulatory physiology Medium 30387679
2017 RORα enhances mitochondrial quality by regulating expression of Bnip3 and PGC-1α; liver-specific RORα knockout mice show mitochondrial fission defects with downregulation of Bnip3 and phospho-Drp1, and are more susceptible to NASH. Liver-specific Rorα KO mice, high-fat diet NASH model, gene expression analysis, oxygen consumption measurement Scientific reports Medium 29167529
2021 RORα induces transcription of Atp6v1g1 (a vacuolar H+-ATPase subunit) and other lysosomal function genes, thereby enhancing lysosomal acidification and autophagic flux in hepatocytes; hepatocyte-specific RORα deletion impairs lysosomal acidity, mTOR translocation, cathepsin D maturation, and autophagic flux. Hepatocyte-specific Rorα KO mice, LysoSensor assay, LC3/p62/NBR1 accumulation, adenoviral RORα restoration Hepatology communications Medium 34558854
2016 RORα regulates macrophage M2 polarization via activation of AMPKα; RORα agonist (cholesterol sulfate) induces M2 markers (Arg1, Ym1, Fizz1) and phosphorylation of AMPKα/ACC; RORα antagonism or AMPKα inhibition abolishes this effect. RORα agonist/antagonist pharmacology in RAW264.7 cells, RORα overexpression, AMPKα inhibitor (Compound C) Molecular immunology Medium 27788394
2019 RORα protects against LPS-induced inflammation by regulating SIRT1 expression, which in turn affects deacetylation and nuclear translocation of NF-κB p65; specifically, RORα overexpression suppresses acetylation of NF-κB p65 at lysine 310 via SIRT1 upregulation. Lentiviral overexpression/siRNA knockdown in macrophages, LPS model in vivo, SIRT1 agonist rescue experiment Archives of biochemistry and biophysics Medium 31071300
2024 RORA binds the CD274 (PD-L1) promoter and forms an inhibitory complex with HDAC3 to suppress PD-L1 expression; DDX3X competes with HDAC3 for binding to RORA, and DDX3X overexpression promotes RORA release from the repressive complex, increasing PD-L1 expression. ChIP, Co-immunoprecipitation, overexpression/knockdown in melanoma cells, RORA agonist combined with anti-CTLA4 in vivo Cancer research High 38718296
2021 RORα suppresses superoxide generation in mitochondria by directly targeting respiratory complex I subunit genes NDUFS6 and NDUFA11 (identified by ChIP and gene co-expression), thereby inhibiting ROS-mediated macrophage infiltration and cancer-associated inflammation in breast cancer. Gene co-expression analysis, ChIP, co-culture assay, 4T1 xenograft International journal of molecular sciences Medium 34639006
2013 Neoruscogenin (a steroidal sapogenin) was identified as a potent, high-affinity, bioavailable agonist of RORα (NR1F1) using cell-free reporter assays; it activates RORα target gene expression in vitro and in vivo with selectivity over other nuclear receptors. High-throughput cell-free RORα reporter screening, extract deconvolution, structural elucidation, target gene expression assays in vitro and in vivo, nuclear receptor selectivity panel Journal of biomolecular screening Medium 23896689
2020 RORA agonist RS-2982 increases hepatic MIR122 promoter activity in hepatocytes; in HFD and atherogenic diet mouse models, RS-2982 increases hepatic MIR122 precursors and reduces hepatic triglyceride biosynthesis by reducing expression of lipogenic enzymes. Chemical library screen, luciferase reporter assays (MIR122 promoter), HFD/atherogenic diet mouse models, in vivo injection Gastroenterology Medium 32450149
2019 SORBS2 stabilizes RORA mRNA by directly binding to the 3'UTR of RORA mRNA, reducing its degradation; this post-transcriptional regulation of RORA by SORBS2 mediates SORBS2's anti-tumor effects on HCC cells. RNA immunoprecipitation (RIP), pull-down assay, luciferase reporter (3'UTR), mRNA stability assay Liver international Medium 31365778
2018 The barrel cortex phenotype of staggerer mice results from RORα being cell-autonomously required in the thalamus for thalamocortical axon (TCA) cluster organization, and in the somatosensory cortex for dendritic maturation of layer IV neurons; Sema7a, Neph, and Adcy8 are identified as RORα-regulated genes in this process. Conditional RORα deletion in thalamus or cortex, microarray analysis, histological analysis of barrels/barreloids Cerebral cortex Medium 29040410
2024 RORA acts as a CEC-specific molecular switch driving limbal stem cell (LSC) differentiation into corneal epithelial cells by activating PITX1; RORA establishes CEC-specific enhancers and chromatin interactions between CEC gene promoters and distal regulatory elements, while silencing LSC-specific promoters and disrupting promoter-anchored chromatin loops. Single-cell RNA-seq, ChIP-seq, ATAC-seq, Hi-C chromatin interaction analysis, RORA gain/loss-of-function Nature communications High 38177186
2017 RORα and RORγt co-regulate a defined set of human Th17 signature genes including IL-17A, IL-17F, IL-23R, CCL20, and CCR6; siRNA knockdown of RORα in human Th17 cells reduces expression of these key Th17 genes, demonstrating an overlapping but weaker role of RORα versus RORγt. siRNA knockdown (RORγt, RORα), RNA-seq, selective RORγt small molecule modulators as pharmacological controls PloS one Medium 28763457
2019 RORα mediates induction of osteoarthritis by oxysterol metabolites produced by CH25H and CYP7B1 in chondrocytes; overexpression of CH25H or CYP7B1 causes experimental OA, while knockdown abrogates OA pathogenesis, with RORα acting as downstream effector of cholesterol metabolism changes. Adenoviral overexpression/knockout/knockdown in mouse joints, in vivo OA induction models, epistasis experiments with RORα Nature High 30728500
2014 miR-137 directly targets the 3'UTR of RORα in a site-specific manner, establishing a direct biological link between MIR137 and RORA as autism candidate genes. Luciferase 3'UTR reporter assay with site-specific mutagenesis Scientific reports Medium 24500708
2020 In skeletal muscle, specific knockout of Rorα (secondary feedback loop) results in aberrant expression of a large number of non-oscillating genes and proteins (rather than primarily affecting circadian oscillation), leading to distinct metabolic and contractile phenotypes compared to PER2 knockout. Muscle-specific Rorα KO mice, global gene expression analysis, metabolomics, muscle function assessment The Journal of physiology Medium 38850551

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 The orphan nuclear receptor RORalpha regulates circadian transcription of the mammalian core-clock Bmal1. Nature structural & molecular biology 401 15821743
2019 The CH25H-CYP7B1-RORα axis of cholesterol metabolism regulates osteoarthritis. Nature 255 30728500
2001 The orphan nuclear receptor ROR alpha is a negative regulator of the inflammatory response. EMBO reports 241 11252722
2014 RORα and ROR γ are expressed in human skin and serve as receptors for endogenously produced noncalcemic 20-hydroxy- and 20,23-dihydroxyvitamin D. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 238 24668754
2006 RORalpha-mediated Purkinje cell development determines disease severity in adult SCA1 mice. Cell 194 17110330
1998 Orphan nuclear receptor ROR alpha-deficient mice display the cerebellar defects of staggerer. Mechanisms of development 156 9510031
2004 RORalpha regulates the expression of genes involved in lipid homeostasis in skeletal muscle cells: caveolin-3 and CPT-1 are direct targets of ROR. The Journal of biological chemistry 146 15199055
2019 A maresin 1/RORα/12-lipoxygenase autoregulatory circuit prevents inflammation and progression of nonalcoholic steatohepatitis. The Journal of clinical investigation 130 30855276
2017 RORα controls hepatic lipid homeostasis via negative regulation of PPARγ transcriptional network. Nature communications 126 28757615
2016 Endogenously produced nonclassical vitamin D hydroxy-metabolites act as "biased" agonists on VDR and inverse agonists on RORα and RORγ. The Journal of steroid biochemistry and molecular biology 122 27693422
2017 RORγt and RORα signature genes in human Th17 cells. PloS one 114 28763457
2003 Dynamic patterned expression of orphan nuclear receptor genes RORalpha and RORbeta in developing mouse forebrain. Developmental neuroscience 108 12966220
2018 RORα-expressing T regulatory cells restrain allergic skin inflammation. Science immunology 107 29500225
2012 RORα suppresses breast tumor invasion by inducing SEMA3F expression. Cancer research 100 22350413
2007 Identification of oxysterol 7alpha-hydroxylase (Cyp7b1) as a novel retinoid-related orphan receptor alpha (RORalpha) (NR1F1) target gene and a functional cross-talk between RORalpha and liver X receptor (NR1H3). Molecular pharmacology 91 18055760
2020 Single-cell analysis of RORα tracer mouse lung reveals ILC progenitors and effector ILC2 subsets. The Journal of experimental medicine 90 31816636
2022 Transcription factor RORα enforces stability of the Th17 cell effector program by binding to a Rorc cis-regulatory element. Immunity 81 36243007
2006 ROR alpha in genetic control of cerebellum development: 50 staggering years. Brain research 79 16427031
2021 RORα is a critical checkpoint for T cell and ILC2 commitment in the embryonic thymus. Nature immunology 75 33432227
2020 Agonist of RORA Attenuates Nonalcoholic Fatty Liver Progression in Mice via Up-regulation of MicroRNA 122. Gastroenterology 74 32450149
2011 DNA damage-induced RORα is crucial for p53 stabilization and increased apoptosis. Molecular cell 71 22152482
2018 miR-652 Promotes Tumor Proliferation and Metastasis by Targeting RORA in Endometrial Cancer. Molecular cancer research : MCR 70 30093563
2015 Investigation of sex differences in the expression of RORA and its transcriptional targets in the brain as a potential contributor to the sex bias in autism. Molecular autism 68 26056561
2009 The nuclear receptor ROR(alpha) exerts a bi-directional regulation of IL-6 in resting and reactive astrocytes. Proceedings of the National Academy of Sciences of the United States of America 67 19955433
1999 Cerebellar Purkinje cell loss during life span of the heterozygous staggerer mouse (Rora(+)/Rora(sg)) is gender-related. The Journal of comparative neurology 66 10404252
2019 RORα is crucial for attenuated inflammatory response to maintain intestinal homeostasis. Proceedings of the National Academy of Sciences of the United States of America 65 31570593
1997 The structural integrity of ROR alpha isoforms is mutated in staggerer mice: cerebellar coexpression of ROR alpha1 and ROR alpha4. Genomics 64 9226375
2015 Nuclear receptor RORα regulates pathologic retinal angiogenesis by modulating SOCS3-dependent inflammation. Proceedings of the National Academy of Sciences of the United States of America 61 26243880
2016 RORα and RORγ expression inversely correlates with human melanoma progression. Oncotarget 58 27542227
2002 Age-related phenotypes in the staggerer mouse expand the RORalpha nuclear receptor's role beyond the cerebellum. Molecular and cellular endocrinology 58 11850116
2020 MiR-18a-downregulated RORA inhibits the proliferation and tumorigenesis of glioma using the TNF-α-mediated NF-κB signaling pathway. EBioMedicine 57 32062354
2002 Identification of Reverb(alpha) as a novel ROR(alpha) target gene. The Journal of biological chemistry 53 12114512
2006 RORalpha, a pivotal nuclear receptor for Purkinje neuron survival and differentiation: from development to ageing. Cerebellum (London, England) 51 16818384
2021 Genetic and pharmacological inhibition of the nuclear receptor RORα regulates TH17 driven inflammatory disorders. Nature communications 49 33397953
2020 Dp44mT, an iron chelator, suppresses growth and induces apoptosis via RORA-mediated NDRG2-IL6/JAK2/STAT3 signaling in glioma. Cellular oncology (Dordrecht, Netherlands) 49 32207044
2002 Expression and regulation of the nuclear receptor RORalpha in human vascular cells. FEBS letters 46 11821045
2019 The RNA-binding protein SORBS2 suppresses hepatocellular carcinoma tumourigenesis and metastasis by stabilizing RORA mRNA. Liver international : official journal of the International Association for the Study of the Liver 45 31365778
2014 A direct molecular link between the autism candidate gene RORa and the schizophrenia candidate MIR137. Scientific reports 45 24500708
2021 Inhibition of nuclear receptor RORα attenuates cartilage damage in osteoarthritis by modulating IL-6/STAT3 pathway. Cell death & disease 44 34584074
2018 RORα controls inflammatory state of human macrophages. PloS one 44 30485323
2015 Investigation of associations between NR1D1, RORA and RORB genes and bipolar disorder. PloS one 44 25789810
2002 Retinoic acid receptor-related orphan receptor (ROR) alpha4 is the predominant isoform of the nuclear receptor RORalpha in the liver and is up-regulated by hypoxia in HepG2 human hepatoma cells. The Biochemical journal 44 12023888
2017 Liver-specific deletion of RORα aggravates diet-induced nonalcoholic steatohepatitis by inducing mitochondrial dysfunction. Scientific reports 43 29167529
2021 CircGSK3B promotes RORA expression and suppresses gastric cancer progression through the prevention of EZH2 trans-inhibition. Journal of experimental & clinical cancer research : CR 42 34666800
2013 The identification of naturally occurring neoruscogenin as a bioavailable, potent, and high-affinity agonist of the nuclear receptor RORα (NR1F1). Journal of biomolecular screening 42 23896689
2020 Maresin-1 resolution with RORα and LGR6. Progress in lipid research 40 32360520
2016 Circadian genes and lithium response in bipolar disorders: associations with PPARGC1A (PGC-1α) and RORA. Genes, brain, and behavior 39 27324142
2021 Mapping Rora expression in resting and activated CD4+ T cells. PloS one 37 34003838
2021 T-bet and RORα control lymph node formation by regulating embryonic innate lymphoid cell differentiation. Nature immunology 37 34556887
2013 The retinoid-related orphan receptor alpha (RORA) gene and fear-related psychopathology. Journal of affective disorders 36 24007783
2008 The emerging role of nuclear receptor RORalpha and its crosstalk with LXR in xeno- and endobiotic gene regulation. Experimental biology and medicine (Maywood, N.J.) 36 18535165
2001 A comparative study of Purkinje cells in two RORalpha gene mutant mice: staggerer and RORalpha(-/-). Brain research. Developmental brain research 36 11335003
2016 RAR-related orphan receptor A (RORA): A new susceptibility gene for multiple sclerosis. Journal of the neurological sciences 35 27653902
2017 Retinoic acid-related orphan receptor alpha (RORA) variants are associated with autism spectrum disorder. Metabolic brain disease 34 28608249
2009 Inhibition of adipocyte differentiation by RORalpha. FEBS letters 34 19450581
2019 ROR alpha protects against LPS-induced inflammation by down-regulating SIRT1/NF-kappa B pathway. Archives of biochemistry and biophysics 33 31071300
2018 The nuclear receptor RORα protects against angiotensin II-induced cardiac hypertrophy and heart failure. American journal of physiology. Heart and circulatory physiology 33 30387679
2024 The Circadian Clock Component RORA Increases Immunosurveillance in Melanoma by Inhibiting PD-L1 Expression. Cancer research 32 38718296
2021 Requirement of RORα for maintenance and antitumor immunity of liver-resident natural killer cells/ILC1s. Hepatology (Baltimore, Md.) 29 34510508
2021 RORα is critical for mTORC1 activity in T cell-mediated colitis. Cell reports 29 34525365
2013 Interaction between retinoid acid receptor-related orphan receptor alpha (RORA) and neuropeptide S receptor 1 (NPSR1) in asthma. PloS one 27 23565190
2022 Identification of TIMELESS and RORA as key clock molecules of non-small cell lung cancer and the comprehensive analysis. BMC cancer 26 35078435
2021 RORα Suppresses Cancer-Associated Inflammation by Repressing Respiratory Complex I-Dependent ROS Generation. International journal of molecular sciences 26 34639006
2020 The conserved molting/circadian rhythm regulator NHR-23/NR1F1 serves as an essential co-regulator of C. elegans spermatogenesis. Development (Cambridge, England) 26 33060131
2022 POU6F1 cooperates with RORA to suppress the proliferation of lung adenocarcinoma by downregulation HIF1A signaling pathway. Cell death & disease 25 35504868
2017 RORα modulates semaphorin 3E transcription and neurovascular interaction in pathological retinal angiogenesis. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 24 28646017
2017 Retinoic acid receptor-related orphan receptor RORα regulates differentiation and survival of keratinocytes during hypoxia. Journal of cellular physiology 23 28332183
2016 RORα and 25-Hydroxycholesterol Crosstalk Regulates Lipid Droplet Homeostasis in Macrophages. PloS one 23 26812621
2016 Retinoid acid receptor-related orphan receptor alpha (RORα) regulates macrophage M2 polarization via activation of AMPKα. Molecular immunology 23 27788394
2012 Is retinoic acid-related orphan receptor-alpha (RORA) a target for gene-environment interactions contributing to autism? Neurotoxicology 23 22967355
2022 Maresin-1 and its receptors RORα/LGR6 as potential therapeutic target for respiratory diseases. Pharmacological research 22 35781060
2020 Long non-coding RNA TUG1 participates in LPS-induced periodontitis by regulating miR-498/RORA pathway. Oral diseases 22 32762066
2020 lncRNA FGD5 antisense RNA 1 upregulates RORA to suppress hypoxic injury of human cardiomyocyte cells by inhibiting oxidative stress and apoptosis via miR‑195. Molecular medicine reports 22 33174051
2015 RORA and posttraumatic stress trajectories: main effects and interactions with childhood physical abuse history. Brain and behavior 22 25798337
2014 RORα binds to E2F1 to inhibit cell proliferation and regulate mammary gland branching morphogenesis. Molecular and cellular biology 22 24891616
2024 Paris saponin VII reverses resistance to PARP inhibitors by regulating ovarian cancer tumor angiogenesis and glycolysis through the RORα/ECM1/VEGFR2 signaling axis. International journal of biological sciences 21 38725854
2021 RORα Enhances Lysosomal Acidification and Autophagic Flux in the Hepatocytes. Hepatology communications 21 34558854
2011 Altered expression of NFY-C and RORA in colorectal adenocarcinomas. Acta histochemica 21 22104449
2022 Maternal diabetes-mediated RORA suppression in mice contributes to autism-like offspring through inhibition of aromatase. Communications biology 20 35027651
2021 Circ_0081572 inhibits the progression of periodontitis through regulating the miR-378h/RORA axis. Archives of oral biology 20 33524877
2015 Associations of PER3 and RORA Circadian Gene Polymorphisms and Depressive Symptoms in Older Adults. The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry 20 25892098
2023 Targeting RORα in macrophages to boost diabetic bone regeneration. Cell proliferation 19 37051760
2019 RORA Overexpression Alleviates Nasal Mucosal Injury and Enhances Red Blood Cell Immune Adhesion Function in a Mouse Model of Allergic Rhinitis via Inactivation of the Wnt/β-Catenin Signaling Pathway. International archives of allergy and immunology 19 31340215
2012 RORalpha, a key to the development and functioning of the brain. Cerebellum (London, England) 19 22223133
2018 RORα Coordinates Thalamic and Cortical Maturation to Instruct Barrel Cortex Development. Cerebral cortex (New York, N.Y. : 1991) 17 29040410
2017 CYP19A1, MIF and ABCA1 genes are targets of the RORα in monocyte and endothelial cells. Cell biology international 17 27925372
2007 Expression of zebrafish ROR alpha gene in cerebellar-like structures. Developmental dynamics : an official publication of the American Association of Anatomists 17 17685489
2023 Cerebellum and neurodevelopmental disorders: RORα is a unifying force. Frontiers in cellular neuroscience 16 37066074
2022 Rora Regulates Neutrophil Migration and Activation in Zebrafish. Frontiers in immunology 16 35309302
2021 Functions for Retinoic Acid-Related Orphan Receptor Alpha (RORα) in the Activation of Macrophages During Lipopolysaccharide-Induced Septic Shock. Frontiers in immunology 16 33767712
2018 Genetic variants in RORA and DNMT1 associated with cutaneous melanoma survival. International journal of cancer 16 29313974
2020 Role for Retinoic Acid-Related Orphan Receptor Alpha (RORα) Expressing Macrophages in Diet-Induced Obesity. Frontiers in immunology 15 32973801
2020 ROR-α-1 inhibits the proliferation, invasion, and migration of hepatocellular carcinoma MHCC97H via downregulation of chemokine CXCL5. Cytokine 14 32058275
2020 Aberrant functional connectivity between the suprachiasmatic nucleus and the superior temporal gyrus: Bridging RORA gene polymorphism with diurnal mood variation in major depressive disorder. Journal of psychiatric research 14 33091686
2019 Retinoid-related orphan nuclear receptor alpha (RORα)-deficient mice display morphological testicular defects. Laboratory investigation; a journal of technical methods and pathology 14 31409890
2017 Retinoic acid-related orphan receptor alpha (RORA) variants and risk of breast cancer. Breast disease 14 28598825
2010 Evaluation of GPR50, hMel-1B, and ROR-alpha melatonin-related receptors and the etiology of adolescent idiopathic scoliosis. Journal of pediatric orthopedics 14 20733416
2006 Intracellular localization of RORalpha is isoform and cell line-dependent. Biochimica et biophysica acta 14 16806533
2024 The single-cell transcriptomic atlas and RORA-mediated 3D epigenomic remodeling in driving corneal epithelial differentiation. Nature communications 13 38177186
2024 More than the clock: distinct regulation of muscle function and metabolism by PER2 and RORα. The Journal of physiology 13 38850551

Missed literature

Know a paper Affinage missed for RORA? Flag it for the maintainers and the community.

No submissions yet.