RORA encodes ROR-alpha, a monomeric nuclear receptor and sequence-specific RNA polymerase II transcription factor. RORA binds ROR response elements in chromatin, recruits coactivators or corepressors according to promoter and cell context, and is modulated by oxysterol ligands. This core receptor activity controls multiple tissue-specific programs, including circadian clock-gene expression, lipid and glucose metabolism, inflammatory responses, and cell differentiation. RORA also has an essential developmental role in the cerebellum; damaging human variants cause neurodevelopmental disease that can include ataxia and cerebellar atrophy.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004879 nuclear receptor activity | IBA GO_REF:0000033 | ACCEPT | Summary: Core molecular function: RORA is an oxysterol-modulated nuclear receptor transcription factor. Reason: Nuclear receptor activity integrates ligand binding, ROR-response-element recognition, and RNA polymerase II transcriptional regulation. Supporting Evidence: PMID:7926749 Binding site selection using in vitro-synthesized proteins reveals that the ROR alpha 1 and ROR alpha 2 isoforms bind DNA as monomers to hormone response elements composed of a 6-bp AT-rich sequence preceding a half-site core motif PuGGTCA (RORE). PMID:19965867 Here, we demonstrate that 7-oxygenated sterols function as high affinity ligands for both RORalpha and RORgamma by directly binding to their ligand-binding domains (K(i) approximately 20 nM), modulating coactivator binding, and suppressing the transcriptional activity of the receptors. |
| GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding | IBA GO_REF:0000033 | ACCEPT | Summary: Core sequence-specific binding of RORA to RNA polymerase II cis-regulatory ROR response elements. Reason: Direct binding to ROREs is the DNA-recognition step of RORA nuclear-receptor transcriptional activity. Supporting Evidence: PMID:7926749 Binding site selection using in vitro-synthesized proteins reveals that the ROR alpha 1 and ROR alpha 2 isoforms bind DNA as monomers to hormone response elements composed of a 6-bp AT-rich sequence preceding a half-site core motif PuGGTCA (RORE). |
| GO:0006357 regulation of transcription by RNA polymerase II | IBA GO_REF:0000033 | ACCEPT | Summary: Core regulation of RNA polymerase II transcription by DNA-bound RORA. Reason: RORA recruits context-dependent coactivators or corepressors and directly controls transcription from ROR response elements. Supporting Evidence: PMID:9328355 Mutational analysis revealed that RORalpha contains both transcriptional activation and transcriptional repression domains, with the repression domain being more active in some cell types. PMID:10478845 GRIP-1 functioned as a coactivator for the RORalpha both in yeast and in mammalian cells. |
| GO:0005634 nucleus | IBA GO_REF:0000033 | ACCEPT | Summary: Supported nucleus localization of the RORA transcription factor. Reason: RORA performs its direct DNA-binding and transcription-regulatory activity in the nuclear compartment. |
| GO:0008142 oxysterol binding | IBA GO_REF:0000033 | ACCEPT | Summary: Core binding of oxysterol ligands by the RORA ligand-binding domain. Reason: Direct high-affinity binding of 7-oxygenated sterols modulates RORA coactivator association and transcriptional activity. Supporting Evidence: PMID:19965867 Here, we demonstrate that 7-oxygenated sterols function as high affinity ligands for both RORalpha and RORgamma by directly binding to their ligand-binding domains (K(i) approximately 20 nM), modulating coactivator binding, and suppressing the transcriptional activity of the receptors. |
| GO:0050728 negative regulation of inflammatory response | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Supported context-specific role in negative regulation of inflammatory responses. Reason: The annotation is compatible with phylogenetic inference and direct anti-inflammatory experiments, but it is a downstream physiological or developmental output of RORA transcriptional regulation rather than the receptor's core molecular activity. |
| GO:0003677 DNA binding | IEA GO_REF:0000002 | MODIFY | Summary: The generic DNA-binding annotation should be replaced by RORA's sequence-specific RNA polymerase II cis-regulatory DNA-binding activity. Reason: RORA binds defined ROR response elements rather than DNA nonspecifically. Proposed replacements: RNA polymerase II cis-regulatory region sequence-specific DNA binding Supporting Evidence: PMID:7926749 Binding site selection using in vitro-synthesized proteins reveals that the ROR alpha 1 and ROR alpha 2 isoforms bind DNA as monomers to hormone response elements composed of a 6-bp AT-rich sequence preceding a half-site core motif PuGGTCA (RORE). |
| GO:0003700 DNA-binding transcription factor activity | IEA GO_REF:0000120 | MODIFY | Summary: The generic transcription-factor annotation should be narrowed to nuclear-receptor and RNA polymerase II-specific transcription-factor activity. Reason: The replacements describe both the receptor class and the polymerase system regulated by RORA. Proposed replacements: nuclear receptor activity DNA-binding transcription factor activity, RNA polymerase II-specific Supporting Evidence: PMID:7926749 Binding site selection using in vitro-synthesized proteins reveals that the ROR alpha 1 and ROR alpha 2 isoforms bind DNA as monomers to hormone response elements composed of a 6-bp AT-rich sequence preceding a half-site core motif PuGGTCA (RORE). PMID:19965867 Here, we demonstrate that 7-oxygenated sterols function as high affinity ligands for both RORalpha and RORgamma by directly binding to their ligand-binding domains (K(i) approximately 20 nM), modulating coactivator binding, and suppressing the transcriptional activity of the receptors. |
| GO:0004879 nuclear receptor activity | IEA GO_REF:0000002 | ACCEPT | Summary: Core molecular function: RORA is an oxysterol-modulated nuclear receptor transcription factor. Reason: Nuclear receptor activity integrates ligand binding, ROR-response-element recognition, and RNA polymerase II transcriptional regulation. Supporting Evidence: PMID:7926749 Binding site selection using in vitro-synthesized proteins reveals that the ROR alpha 1 and ROR alpha 2 isoforms bind DNA as monomers to hormone response elements composed of a 6-bp AT-rich sequence preceding a half-site core motif PuGGTCA (RORE). PMID:19965867 Here, we demonstrate that 7-oxygenated sterols function as high affinity ligands for both RORalpha and RORgamma by directly binding to their ligand-binding domains (K(i) approximately 20 nM), modulating coactivator binding, and suppressing the transcriptional activity of the receptors. |
| GO:0005634 nucleus | IEA GO_REF:0000120 | ACCEPT | Summary: Supported nucleus localization of the RORA transcription factor. Reason: RORA performs its direct DNA-binding and transcription-regulatory activity in the nuclear compartment. |
| GO:0006355 regulation of DNA-templated transcription | IEA GO_REF:0000120 | MODIFY | Summary: The broad transcription/gene-expression term should be narrowed to regulation of transcription by RNA polymerase II. Reason: RORA directly regulates RNA polymerase II target-gene transcription from cis-regulatory response elements. Proposed replacements: regulation of transcription by RNA polymerase II Supporting Evidence: PMID:7926749 Binding site selection using in vitro-synthesized proteins reveals that the ROR alpha 1 and ROR alpha 2 isoforms bind DNA as monomers to hormone response elements composed of a 6-bp AT-rich sequence preceding a half-site core motif PuGGTCA (RORE). |
| GO:0008270 zinc ion binding | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: Valid zinc-ion binding by the nuclear-receptor DNA-binding domain. Reason: Zinc coordination is a structural feature supporting DNA recognition, not the most informative statement of RORA's molecular activity. |
| GO:0010468 regulation of gene expression | IEA GO_REF:0000117 | MODIFY | Summary: The broad transcription/gene-expression term should be narrowed to regulation of transcription by RNA polymerase II. Reason: RORA directly regulates RNA polymerase II target-gene transcription from cis-regulatory response elements. Proposed replacements: regulation of transcription by RNA polymerase II Supporting Evidence: PMID:7926749 Binding site selection using in vitro-synthesized proteins reveals that the ROR alpha 1 and ROR alpha 2 isoforms bind DNA as monomers to hormone response elements composed of a 6-bp AT-rich sequence preceding a half-site core motif PuGGTCA (RORE). |
| GO:0043565 sequence-specific DNA binding | IEA GO_REF:0000120 | ACCEPT | Summary: Core sequence-specific binding of RORA to RNA polymerase II cis-regulatory ROR response elements. Reason: Direct binding to ROREs is the DNA-recognition step of RORA nuclear-receptor transcriptional activity. Supporting Evidence: PMID:7926749 Binding site selection using in vitro-synthesized proteins reveals that the ROR alpha 1 and ROR alpha 2 isoforms bind DNA as monomers to hormone response elements composed of a 6-bp AT-rich sequence preceding a half-site core motif PuGGTCA (RORE). |
| GO:0005515 protein binding | IPI PMID:16713569 A protein-protein interaction network for human inherited at... | MARK AS OVER ANNOTATED | Summary: Protein binding is uninformative for this experimentally detected RORA interaction. Reason: The interaction may be real, but GO:0005515 does not identify the partner-specific regulatory mechanism; RORA's receptor, DNA-binding, and coregulator-binding terms are more informative. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | MARK AS OVER ANNOTATED | Summary: Protein binding is uninformative for this experimentally detected RORA interaction. Reason: The interaction may be real, but GO:0005515 does not identify the partner-specific regulatory mechanism; RORA's receptor, DNA-binding, and coregulator-binding terms are more informative. |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | IEA GO_REF:0000107 | ACCEPT | Summary: Core regulation of RNA polymerase II transcription by DNA-bound RORA. Reason: RORA recruits context-dependent coactivators or corepressors and directly controls transcription from ROR response elements. Supporting Evidence: PMID:9328355 Mutational analysis revealed that RORalpha contains both transcriptional activation and transcriptional repression domains, with the repression domain being more active in some cell types. PMID:10478845 GRIP-1 functioned as a coactivator for the RORalpha both in yeast and in mammalian cells. |
| GO:0001223 transcription coactivator binding | IEA GO_REF:0000107 | ACCEPT | Summary: Supported coactivator binding used by RORA to regulate transcription. Reason: Recruitment of a transcription coactivator is a direct mechanistic component of RORA nuclear-receptor activity. Supporting Evidence: PMID:10478845 GRIP-1 functioned as a coactivator for the RORalpha both in yeast and in mammalian cells. |
| GO:0006357 regulation of transcription by RNA polymerase II | IEA GO_REF:0000107 | ACCEPT | Summary: Core regulation of RNA polymerase II transcription by DNA-bound RORA. Reason: RORA recruits context-dependent coactivators or corepressors and directly controls transcription from ROR response elements. Supporting Evidence: PMID:9328355 Mutational analysis revealed that RORalpha contains both transcriptional activation and transcriptional repression domains, with the repression domain being more active in some cell types. PMID:10478845 GRIP-1 functioned as a coactivator for the RORalpha both in yeast and in mammalian cells. |
| GO:0006805 xenobiotic metabolic process | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Supported context-specific role in xenobiotic metabolism. Reason: The annotation is compatible with orthology and experimental literature, but it is a downstream physiological or developmental output of RORA transcriptional regulation rather than the receptor's core molecular activity. |
| GO:0008013 beta-catenin binding | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Supported context-specific role in beta-catenin binding. Reason: The annotation is compatible with orthology transfer and the reviewed interaction record, but it is a downstream physiological or developmental output of RORA transcriptional regulation rather than the receptor's core molecular activity. |
| GO:0008589 regulation of smoothened signaling pathway | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Supported context-specific role in regulation of the smoothened signaling pathway. Reason: The annotation is compatible with mouse orthology transfer relevant to cerebellar development, but it is a downstream physiological or developmental output of RORA transcriptional regulation rather than the receptor's core molecular activity. |
| GO:0010906 regulation of glucose metabolic process | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Supported context-specific role in regulation of glucose metabolism. Reason: The annotation is compatible with orthology and experimental literature, but it is a downstream physiological or developmental output of RORA transcriptional regulation rather than the receptor's core molecular activity. |
| GO:0019218 regulation of steroid metabolic process | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Supported context-specific role in regulation of steroid metabolism. Reason: The annotation is compatible with orthology and experimental literature, but it is a downstream physiological or developmental output of RORA transcriptional regulation rather than the receptor's core molecular activity. |
| GO:0021930 cerebellar granule cell precursor proliferation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Supported context-specific role in cerebellar granule-cell-precursor proliferation. Reason: The annotation is compatible with mouse orthology transfer and human neurodevelopmental genetics, but it is a downstream physiological or developmental output of RORA transcriptional regulation rather than the receptor's core molecular activity. |
| GO:0032922 circadian regulation of gene expression | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Supported context-specific role in circadian regulation of gene expression. Reason: The annotation is compatible with orthology transfer and direct BMAL1-promoter evidence, but it is a downstream physiological or developmental output of RORA transcriptional regulation rather than the receptor's core molecular activity. |
| GO:0042632 cholesterol homeostasis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Supported context-specific role in cholesterol homeostasis. Reason: The annotation is compatible with orthology and experimental literature, but it is a downstream physiological or developmental output of RORA transcriptional regulation rather than the receptor's core molecular activity. |
| GO:0042752 regulation of circadian rhythm | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Supported context-specific role in regulation of circadian rhythm. Reason: The annotation is compatible with orthology transfer and direct clock-promoter evidence, but it is a downstream physiological or developmental output of RORA transcriptional regulation rather than the receptor's core molecular activity. |
| GO:0042753 positive regulation of circadian rhythm | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Supported context-specific role in positive regulation of circadian rhythm. Reason: The annotation is compatible with orthology transfer and direct clock-promoter evidence, but it is a downstream physiological or developmental output of RORA transcriptional regulation rather than the receptor's core molecular activity. |
| GO:0045599 negative regulation of fat cell differentiation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Supported context-specific role in negative regulation of adipocyte differentiation. Reason: The annotation is compatible with orthology and experimental literature, but it is a downstream physiological or developmental output of RORA transcriptional regulation rather than the receptor's core molecular activity. |
| GO:0045893 positive regulation of DNA-templated transcription | IEA GO_REF:0000107 | MODIFY | Summary: The positive transcription annotation should be made RNA polymerase II-specific. Reason: The direct target-gene and reporter evidence concerns RORA-dependent activation of RNA polymerase II promoters. Proposed replacements: positive regulation of transcription by RNA polymerase II Supporting Evidence: PMID:7926749 Binding site selection using in vitro-synthesized proteins reveals that the ROR alpha 1 and ROR alpha 2 isoforms bind DNA as monomers to hormone response elements composed of a 6-bp AT-rich sequence preceding a half-site core motif PuGGTCA (RORE). |
| GO:0070328 triglyceride homeostasis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Supported context-specific role in triglyceride homeostasis. Reason: The annotation is compatible with orthology transfer and direct APOC3-promoter evidence, but it is a downstream physiological or developmental output of RORA transcriptional regulation rather than the receptor's core molecular activity. |
| GO:0072539 T-helper 17 cell differentiation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Supported context-specific role in T-helper 17 cell differentiation. Reason: The annotation is compatible with orthology transfer and human T-cell transcriptional evidence, but it is a downstream physiological or developmental output of RORA transcriptional regulation rather than the receptor's core molecular activity. |
| GO:0005730 nucleolus | IDA GO_REF:0000052 | KEEP AS NON CORE | Summary: HPA immunofluorescence supports a nucleolar RORA pool. Reason: Nucleolar localization is plausible but is less informative for direct function than nuclear/chromatin-associated transcriptional activity. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-376419 | ACCEPT | Summary: Supported nucleoplasm localization of the RORA transcription factor. Reason: RORA performs its direct DNA-binding and transcription-regulatory activity in the nuclear compartment. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-382096 | ACCEPT | Summary: Supported nucleoplasm localization of the RORA transcription factor. Reason: RORA performs its direct DNA-binding and transcription-regulatory activity in the nuclear compartment. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-4719413 | ACCEPT | Summary: Supported nucleoplasm localization of the RORA transcription factor. Reason: RORA performs its direct DNA-binding and transcription-regulatory activity in the nuclear compartment. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-4719436 | ACCEPT | Summary: Supported nucleoplasm localization of the RORA transcription factor. Reason: RORA performs its direct DNA-binding and transcription-regulatory activity in the nuclear compartment. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-6790036 | ACCEPT | Summary: Supported nucleoplasm localization of the RORA transcription factor. Reason: RORA performs its direct DNA-binding and transcription-regulatory activity in the nuclear compartment. |
| GO:0005634 nucleus | EXP PMID:18354202 Isoform-specific inhibition of ROR alpha-mediated transcript... | ACCEPT | Summary: Supported nucleus localization of the RORA transcription factor. Reason: RORA performs its direct DNA-binding and transcription-regulatory activity in the nuclear compartment. |
| GO:0001221 transcription coregulator binding | IPI PMID:14701856 Transcription factors and nuclear receptors interact with th... | ACCEPT | Summary: Supported coregulator binding used by RORA to regulate transcription. Reason: Recruitment of a transcription coregulator is a direct mechanistic component of RORA nuclear-receptor activity. Supporting Evidence: PMID:10478845 GRIP-1 functioned as a coactivator for the RORalpha both in yeast and in mammalian cells. |
| GO:0005515 protein binding | IPI PMID:18658046 Transcriptional activation of HIF-1 by RORalpha and its role... | MARK AS OVER ANNOTATED | Summary: Protein binding is uninformative for this experimentally detected RORA interaction. Reason: The interaction may be real, but GO:0005515 does not identify the partner-specific regulatory mechanism; RORA's receptor, DNA-binding, and coregulator-binding terms are more informative. |
| GO:0005515 protein binding | IPI PMID:9862959 Exogenous expression of a dominant negative RORalpha1 vector... | MARK AS OVER ANNOTATED | Summary: Protein binding is uninformative for this experimentally detected RORA interaction. Reason: The interaction may be real, but GO:0005515 does not identify the partner-specific regulatory mechanism; RORA's receptor, DNA-binding, and coregulator-binding terms are more informative. |
| GO:0045599 negative regulation of fat cell differentiation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Supported context-specific role in negative regulation of adipocyte differentiation. Reason: The annotation is compatible with orthology and experimental literature, but it is a downstream physiological or developmental output of RORA transcriptional regulation rather than the receptor's core molecular activity. |
| GO:0000785 chromatin | ISA GO_REF:0000113 | ACCEPT | Summary: Core chromatin association of sequence-specific RORA transcriptional activity. Reason: RORA functions at chromatin cis-regulatory response elements to control target-gene transcription. Supporting Evidence: PMID:7926749 Binding site selection using in vitro-synthesized proteins reveals that the ROR alpha 1 and ROR alpha 2 isoforms bind DNA as monomers to hormone response elements composed of a 6-bp AT-rich sequence preceding a half-site core motif PuGGTCA (RORE). |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | ISA GO_REF:0000113 | ACCEPT | Summary: Core regulation of RNA polymerase II transcription by DNA-bound RORA. Reason: RORA recruits context-dependent coactivators or corepressors and directly controls transcription from ROR response elements. Supporting Evidence: PMID:9328355 Mutational analysis revealed that RORalpha contains both transcriptional activation and transcriptional repression domains, with the repression domain being more active in some cell types. PMID:10478845 GRIP-1 functioned as a coactivator for the RORalpha both in yeast and in mammalian cells. |
| GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding | IDA PMID:21628546 Modulation of clock gene expression by the transcriptional c... | ACCEPT | Summary: Direct RORE binding at the BMAL1 RNA polymerase II regulatory region. Reason: The full-text study shows RIP140 recruitment to ROR-binding sites and RORA-dependent BMAL1 promoter activation. Supporting Evidence: PMID:21628546 RIP140 is recruited to retinoid-related orphan receptor (ROR) binding sites on the BMAL1 promoter, directly interacts with RORΞ±, and increases transcription from the BMAL1 promoter in a RORΞ±-dependent manner. |
| GO:0000977 RNA polymerase II transcription regulatory region sequence-specific DNA binding | IDA PMID:19955433 The nuclear receptor ROR(alpha) exerts a bi-directional regu... | ACCEPT | Summary: Core sequence-specific binding of RORA to RNA polymerase II cis-regulatory ROR response elements. Reason: Direct binding to ROREs is the DNA-recognition step of RORA nuclear-receptor transcriptional activity. Supporting Evidence: PMID:7926749 Binding site selection using in vitro-synthesized proteins reveals that the ROR alpha 1 and ROR alpha 2 isoforms bind DNA as monomers to hormone response elements composed of a 6-bp AT-rich sequence preceding a half-site core motif PuGGTCA (RORE). |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IDA PMID:19955433 The nuclear receptor ROR(alpha) exerts a bi-directional regu... | ACCEPT | Summary: Core regulation of RNA polymerase II transcription by DNA-bound RORA. Reason: RORA recruits context-dependent coactivators or corepressors and directly controls transcription from ROR response elements. Supporting Evidence: PMID:9328355 Mutational analysis revealed that RORalpha contains both transcriptional activation and transcriptional repression domains, with the repression domain being more active in some cell types. PMID:10478845 GRIP-1 functioned as a coactivator for the RORalpha both in yeast and in mammalian cells. |
| GO:0005515 protein binding | IPI PMID:22170608 Cryptochromes mediate rhythmic repression of the glucocortic... | MARK AS OVER ANNOTATED | Summary: Protein binding is uninformative for this experimentally detected RORA interaction. Reason: The interaction may be real, but GO:0005515 does not identify the partner-specific regulatory mechanism; RORA's receptor, DNA-binding, and coregulator-binding terms are more informative. |
| GO:0036315 cellular response to sterol | IMP PMID:18658046 Transcriptional activation of HIF-1 by RORalpha and its role... | KEEP AS NON CORE | Summary: Supported context-specific role in cellular response to sterol. Reason: The annotation is compatible with a ligand-treatment study in the hypoxia-signaling context, but it is a downstream physiological or developmental output of RORA transcriptional regulation rather than the receptor's core molecular activity. |
| GO:0071456 cellular response to hypoxia | IMP PMID:18658046 Transcriptional activation of HIF-1 by RORalpha and its role... | KEEP AS NON CORE | Summary: Supported context-specific role in cellular response to hypoxia. Reason: The annotation is compatible with direct perturbation and interaction evidence, but it is a downstream physiological or developmental output of RORA transcriptional regulation rather than the receptor's core molecular activity. |
| GO:0001525 angiogenesis | IMP PMID:18658046 Transcriptional activation of HIF-1 by RORalpha and its role... | KEEP AS NON CORE | Summary: Supported context-specific role in angiogenesis. Reason: The annotation is compatible with endothelial capillary-tube experiments, but it is a downstream physiological or developmental output of RORA transcriptional regulation rather than the receptor's core molecular activity. |
| GO:0003700 DNA-binding transcription factor activity | IDA PMID:18658046 Transcriptional activation of HIF-1 by RORalpha and its role... | MODIFY | Summary: The generic transcription-factor annotation should be narrowed to nuclear-receptor and RNA polymerase II-specific transcription-factor activity. Reason: The replacements describe both the receptor class and the polymerase system regulated by RORA. Proposed replacements: nuclear receptor activity DNA-binding transcription factor activity, RNA polymerase II-specific Supporting Evidence: PMID:7926749 Binding site selection using in vitro-synthesized proteins reveals that the ROR alpha 1 and ROR alpha 2 isoforms bind DNA as monomers to hormone response elements composed of a 6-bp AT-rich sequence preceding a half-site core motif PuGGTCA (RORE). PMID:19965867 Here, we demonstrate that 7-oxygenated sterols function as high affinity ligands for both RORalpha and RORgamma by directly binding to their ligand-binding domains (K(i) approximately 20 nM), modulating coactivator binding, and suppressing the transcriptional activity of the receptors. |
| GO:0005634 nucleus | IDA PMID:18658046 Transcriptional activation of HIF-1 by RORalpha and its role... | ACCEPT | Summary: Supported nucleus localization of the RORA transcription factor. Reason: RORA performs its direct DNA-binding and transcription-regulatory activity in the nuclear compartment. |
| GO:0010575 positive regulation of vascular endothelial growth factor production | IMP PMID:18658046 Transcriptional activation of HIF-1 by RORalpha and its role... | UNDECIDED | Summary: The cached abstract supports enhanced endothelial capillary-tube formation but does not state that RORA positively regulates VEGF production. Reason: The publication is abstract-only in the local cache, so the specific VEGF-production claim cannot be verified without the curator-accessed full text; the experimental annotation is therefore not overruled. |
| GO:0001222 transcription corepressor binding | IPI PMID:9328355 Transcriptional activation and repression by RORalpha, an or... | ACCEPT | Summary: Direct binding of RORA to nuclear-receptor corepressors. Reason: N-CoR/SMRT association is part of RORA's context-dependent transcriptional repression mechanism. Supporting Evidence: PMID:9328355 The abilities of RORalpha polypeptides to repress transcription correlate with their abilities to interact with the nuclear receptor corepressors N-CoR and SMRT in vitro. |
| GO:0001223 transcription coactivator binding | IPI PMID:9862959 Exogenous expression of a dominant negative RORalpha1 vector... | ACCEPT | Summary: Direct RORA binding to the p300 transcription coactivator. Reason: p300 association is a specific coregulator interaction within the RORA transcriptional mechanism. Supporting Evidence: PMID:9862959 The E region of RORalpha1 interacts with p300, a cofactor that functions as a coactivator in nuclear receptor and MyoD-mediated transactivation. |
| GO:0003677 DNA binding | IDA PMID:11053433 Transcriptional regulation of apolipoprotein C-III gene expr... | MODIFY | Summary: The generic DNA-binding annotation should be replaced by RORA's sequence-specific RNA polymerase II cis-regulatory DNA-binding activity. Reason: RORA binds defined ROR response elements rather than DNA nonspecifically. Proposed replacements: RNA polymerase II cis-regulatory region sequence-specific DNA binding Supporting Evidence: PMID:7926749 Binding site selection using in vitro-synthesized proteins reveals that the ROR alpha 1 and ROR alpha 2 isoforms bind DNA as monomers to hormone response elements composed of a 6-bp AT-rich sequence preceding a half-site core motif PuGGTCA (RORE). |
| GO:0003677 DNA binding | IDA PMID:7926749 Isoform-specific amino-terminal domains dictate DNA-binding ... | MODIFY | Summary: The generic DNA-binding annotation should be replaced by RORA's sequence-specific RNA polymerase II cis-regulatory DNA-binding activity. Reason: RORA binds defined ROR response elements rather than DNA nonspecifically. Proposed replacements: RNA polymerase II cis-regulatory region sequence-specific DNA binding Supporting Evidence: PMID:7926749 Binding site selection using in vitro-synthesized proteins reveals that the ROR alpha 1 and ROR alpha 2 isoforms bind DNA as monomers to hormone response elements composed of a 6-bp AT-rich sequence preceding a half-site core motif PuGGTCA (RORE). |
| GO:0003677 DNA binding | IDA PMID:9328355 Transcriptional activation and repression by RORalpha, an or... | MODIFY | Summary: The generic DNA-binding annotation should be replaced by RORA's sequence-specific RNA polymerase II cis-regulatory DNA-binding activity. Reason: RORA binds defined ROR response elements rather than DNA nonspecifically. Proposed replacements: RNA polymerase II cis-regulatory region sequence-specific DNA binding Supporting Evidence: PMID:7926749 Binding site selection using in vitro-synthesized proteins reveals that the ROR alpha 1 and ROR alpha 2 isoforms bind DNA as monomers to hormone response elements composed of a 6-bp AT-rich sequence preceding a half-site core motif PuGGTCA (RORE). |
| GO:0003700 DNA-binding transcription factor activity | IDA PMID:11053433 Transcriptional regulation of apolipoprotein C-III gene expr... | MODIFY | Summary: The generic transcription-factor annotation should be narrowed to nuclear-receptor and RNA polymerase II-specific transcription-factor activity. Reason: The replacements describe both the receptor class and the polymerase system regulated by RORA. Proposed replacements: nuclear receptor activity DNA-binding transcription factor activity, RNA polymerase II-specific Supporting Evidence: PMID:7926749 Binding site selection using in vitro-synthesized proteins reveals that the ROR alpha 1 and ROR alpha 2 isoforms bind DNA as monomers to hormone response elements composed of a 6-bp AT-rich sequence preceding a half-site core motif PuGGTCA (RORE). PMID:19965867 Here, we demonstrate that 7-oxygenated sterols function as high affinity ligands for both RORalpha and RORgamma by directly binding to their ligand-binding domains (K(i) approximately 20 nM), modulating coactivator binding, and suppressing the transcriptional activity of the receptors. |
| GO:0003700 DNA-binding transcription factor activity | IDA PMID:7926749 Isoform-specific amino-terminal domains dictate DNA-binding ... | MODIFY | Summary: The generic transcription-factor annotation should be narrowed to nuclear-receptor and RNA polymerase II-specific transcription-factor activity. Reason: The replacements describe both the receptor class and the polymerase system regulated by RORA. Proposed replacements: nuclear receptor activity DNA-binding transcription factor activity, RNA polymerase II-specific Supporting Evidence: PMID:7926749 Binding site selection using in vitro-synthesized proteins reveals that the ROR alpha 1 and ROR alpha 2 isoforms bind DNA as monomers to hormone response elements composed of a 6-bp AT-rich sequence preceding a half-site core motif PuGGTCA (RORE). PMID:19965867 Here, we demonstrate that 7-oxygenated sterols function as high affinity ligands for both RORalpha and RORgamma by directly binding to their ligand-binding domains (K(i) approximately 20 nM), modulating coactivator binding, and suppressing the transcriptional activity of the receptors. |
| GO:0003700 DNA-binding transcription factor activity | IDA PMID:9328355 Transcriptional activation and repression by RORalpha, an or... | MODIFY | Summary: The generic transcription-factor annotation should be narrowed to nuclear-receptor and RNA polymerase II-specific transcription-factor activity. Reason: The replacements describe both the receptor class and the polymerase system regulated by RORA. Proposed replacements: nuclear receptor activity DNA-binding transcription factor activity, RNA polymerase II-specific Supporting Evidence: PMID:7926749 Binding site selection using in vitro-synthesized proteins reveals that the ROR alpha 1 and ROR alpha 2 isoforms bind DNA as monomers to hormone response elements composed of a 6-bp AT-rich sequence preceding a half-site core motif PuGGTCA (RORE). PMID:19965867 Here, we demonstrate that 7-oxygenated sterols function as high affinity ligands for both RORalpha and RORgamma by directly binding to their ligand-binding domains (K(i) approximately 20 nM), modulating coactivator binding, and suppressing the transcriptional activity of the receptors. |
| GO:0006355 regulation of DNA-templated transcription | IDA PMID:9328355 Transcriptional activation and repression by RORalpha, an or... | MODIFY | Summary: The broad transcription/gene-expression term should be narrowed to regulation of transcription by RNA polymerase II. Reason: RORA directly regulates RNA polymerase II target-gene transcription from cis-regulatory response elements. Proposed replacements: regulation of transcription by RNA polymerase II Supporting Evidence: PMID:7926749 Binding site selection using in vitro-synthesized proteins reveals that the ROR alpha 1 and ROR alpha 2 isoforms bind DNA as monomers to hormone response elements composed of a 6-bp AT-rich sequence preceding a half-site core motif PuGGTCA (RORE). |
| GO:0042692 muscle cell differentiation | IMP PMID:9862959 Exogenous expression of a dominant negative RORalpha1 vector... | KEEP AS NON CORE | Summary: Supported context-specific role in muscle-cell differentiation. Reason: Dominant-negative RORA delayed myogenic marker expression and morphological differentiation, but this is a tissue-specific output of transcriptional regulation. Supporting Evidence: PMID:9862959 Immunohistochemistry demonstrates that morpho-logical differentiation is delayed in cells expressing the RORDeltaE transcript. |
| GO:0043565 sequence-specific DNA binding | IDA PMID:11053433 Transcriptional regulation of apolipoprotein C-III gene expr... | ACCEPT | Summary: Core sequence-specific binding of RORA to RNA polymerase II cis-regulatory ROR response elements. Reason: Direct binding to ROREs is the DNA-recognition step of RORA nuclear-receptor transcriptional activity. Supporting Evidence: PMID:7926749 Binding site selection using in vitro-synthesized proteins reveals that the ROR alpha 1 and ROR alpha 2 isoforms bind DNA as monomers to hormone response elements composed of a 6-bp AT-rich sequence preceding a half-site core motif PuGGTCA (RORE). |
| GO:0045893 positive regulation of DNA-templated transcription | IDA PMID:7926749 Isoform-specific amino-terminal domains dictate DNA-binding ... | MODIFY | Summary: The positive transcription annotation should be made RNA polymerase II-specific. Reason: The reporter and target-gene evidence concerns RORA-dependent activation of RNA polymerase II promoters. Proposed replacements: positive regulation of transcription by RNA polymerase II Supporting Evidence: PMID:7926749 Binding site selection using in vitro-synthesized proteins reveals that the ROR alpha 1 and ROR alpha 2 isoforms bind DNA as monomers to hormone response elements composed of a 6-bp AT-rich sequence preceding a half-site core motif PuGGTCA (RORE). |
| GO:0070328 triglyceride homeostasis | IMP PMID:11053433 Transcriptional regulation of apolipoprotein C-III gene expr... | KEEP AS NON CORE | Summary: Supported context-specific role in triglyceride homeostasis. Reason: Human APOC3-promoter activation and staggerer-mouse lipid phenotypes support this metabolic output, but it is downstream of RORA transcriptional activity. Supporting Evidence: PMID:11053433 Transient transfection experiments in human hepatoma HepG2, human colonic CaCO2, and rabbit kidney RK13 cells demonstrated that overexpression of the human RORalpha1 isoform specifically increases human apo C-III promoter activity, indicating that RORalpha1 enhances human apo C-III gene transcription. |
| GO:0006805 xenobiotic metabolic process | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Supported context-specific role in xenobiotic metabolism. Reason: The annotation is compatible with orthology and experimental literature, but it is a downstream physiological or developmental output of RORA transcriptional regulation rather than the receptor's core molecular activity. |
| GO:0008589 regulation of smoothened signaling pathway | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Supported context-specific role in regulation of the smoothened signaling pathway. Reason: The annotation is compatible with mouse orthology transfer relevant to cerebellar development, but it is a downstream physiological or developmental output of RORA transcriptional regulation rather than the receptor's core molecular activity. |
| GO:0019218 regulation of steroid metabolic process | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Supported context-specific role in regulation of steroid metabolism. Reason: The annotation is compatible with orthology and experimental literature, but it is a downstream physiological or developmental output of RORA transcriptional regulation rather than the receptor's core molecular activity. |
| GO:0021930 cerebellar granule cell precursor proliferation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Supported contextual role in cerebellar granule-cell-precursor proliferation. Reason: The term captures a developmental output of RORA activity, transferred from mouse and consistent with human RORA-associated cerebellar pathology, but it is not the receptor's core molecular function. Supporting Evidence: PMID:29656859 RORΞ±, the RAR-related orphan nuclear receptor alpha, is essential for cerebellar development. |
| GO:0042632 cholesterol homeostasis | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Supported context-specific role in cholesterol homeostasis. Reason: The annotation is compatible with orthology and experimental literature, but it is a downstream physiological or developmental output of RORA transcriptional regulation rather than the receptor's core molecular activity. |
| GO:0001223 transcription coactivator binding | IPI PMID:10478845 Coactivators for the orphan nuclear receptor RORalpha. | ACCEPT | Summary: Supported coactivator binding used by RORA to regulate transcription. Reason: Recruitment of a transcription coactivator is a direct mechanistic component of RORA nuclear-receptor activity. Supporting Evidence: PMID:10478845 GRIP-1 functioned as a coactivator for the RORalpha both in yeast and in mammalian cells. |
| GO:0043124 negative regulation of canonical NF-kappaB signal transduction | IMP PMID:11252722 The orphan nuclear receptor ROR alpha is a negative regulato... | KEEP AS NON CORE | Summary: Supported context-specific inhibition of canonical NF-kappaB signaling. Reason: ROR alpha1 induces the NF-kappaB inhibitor I-kappa-B-alpha in smooth-muscle cells; this anti-inflammatory pathway is a downstream output of transcriptional regulation. Supporting Evidence: PMID:11252722 ROR alpha1 negatively interferes with the NF-kappaB signalling pathway by reducing p65 translocation as demonstrated by western blotting, immunostaining and electrophoretic mobility shift assays. |
| GO:0050728 negative regulation of inflammatory response | IMP PMID:11252722 The orphan nuclear receptor ROR alpha is a negative regulato... | KEEP AS NON CORE | Summary: Supported context-specific negative regulation of inflammatory responses. Reason: The smooth-muscle-cell study directly demonstrates suppression of inflammatory target-gene expression, but this remains a context-specific physiological output. Supporting Evidence: PMID:11252722 ROR alpha1 negatively interferes with the NF-kappaB signalling pathway by reducing p65 translocation as demonstrated by western blotting, immunostaining and electrophoretic mobility shift assays. |
| GO:0005634 nucleus | IDA PMID:19965867 Modulation of retinoic acid receptor-related orphan receptor... | ACCEPT | Summary: Supported nucleus localization of the RORA transcription factor. Reason: RORA performs its direct DNA-binding and transcription-regulatory activity in the nuclear compartment. |
| GO:0008142 oxysterol binding | IDA PMID:19965867 Modulation of retinoic acid receptor-related orphan receptor... | ACCEPT | Summary: Direct binding of 7-oxygenated sterol ligands by RORA. Reason: High-affinity ligand binding modulates coactivator association and receptor transcriptional activity. Supporting Evidence: PMID:19965867 Here, we demonstrate that 7-oxygenated sterols function as high affinity ligands for both RORalpha and RORgamma by directly binding to their ligand-binding domains (K(i) approximately 20 nM), modulating coactivator binding, and suppressing the transcriptional activity of the receptors. |
| GO:0030522 intracellular receptor signaling pathway | IDA PMID:19965867 Modulation of retinoic acid receptor-related orphan receptor... | ACCEPT | Summary: Core intracellular nuclear-receptor signaling by ligand-modulated RORA. Reason: RORA converts intracellular sterol-ligand occupancy into altered transcriptional output. Supporting Evidence: PMID:19965867 Here, we demonstrate that 7-oxygenated sterols function as high affinity ligands for both RORalpha and RORgamma by directly binding to their ligand-binding domains (K(i) approximately 20 nM), modulating coactivator binding, and suppressing the transcriptional activity of the receptors. |
| GO:0036315 cellular response to sterol | IDA PMID:19965867 Modulation of retinoic acid receptor-related orphan receptor... | KEEP AS NON CORE | Summary: Supported cellular response to 7-oxygenated sterols. Reason: Sterol-dependent changes in RORA target-gene expression and hepatocyte glucose output are downstream physiological responses to ligand modulation. Supporting Evidence: PMID:19965867 Here, we demonstrate that 7-oxygenated sterols function as high affinity ligands for both RORalpha and RORgamma by directly binding to their ligand-binding domains (K(i) approximately 20 nM), modulating coactivator binding, and suppressing the transcriptional activity of the receptors. |
| GO:0098531 ligand-modulated transcription factor activity | IDA PMID:19965867 Modulation of retinoic acid receptor-related orphan receptor... | ACCEPT | Summary: Core ligand-modulated transcription-factor activity of RORA. Reason: 7-oxygenated sterols directly bind the receptor and suppress its transcriptional activity, establishing ligand modulation. Supporting Evidence: PMID:19965867 Here, we demonstrate that 7-oxygenated sterols function as high affinity ligands for both RORalpha and RORgamma by directly binding to their ligand-binding domains (K(i) approximately 20 nM), modulating coactivator binding, and suppressing the transcriptional activity of the receptors. |
| GO:0010906 regulation of glucose metabolic process | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Supported context-specific role in regulation of glucose metabolism. Reason: The annotation is compatible with orthology transfer and sterol-dependent hepatocyte experiments, but it is a downstream physiological or developmental output of RORA transcriptional regulation rather than the receptor's core molecular activity. |
| GO:0032922 circadian regulation of gene expression | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Supported circadian regulation of clock-gene expression. Reason: RORA-dependent BMAL1 promoter activation is a major physiological output, but it is one target program of the receptor's general transcriptional mechanism. Supporting Evidence: PMID:21628546 We show that the absence of RIP140 disturbs the basal levels of BMAL1 and other clock genes, reducing the amplitude of their oscillations. |
| GO:0042753 positive regulation of circadian rhythm | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Supported positive regulation of circadian rhythm. Reason: Clock-gene transcription is a major RORA output but remains context-specific relative to the receptor's core molecular activity. Supporting Evidence: PMID:21628546 We show that the absence of RIP140 disturbs the basal levels of BMAL1 and other clock genes, reducing the amplitude of their oscillations. |
| GO:0003700 DNA-binding transcription factor activity | IDA PMID:17545671 Cytosolic aspartate aminotransferase, a new partner in adipo... | MODIFY | Summary: The generic transcription-factor annotation should be narrowed to nuclear-receptor and RNA polymerase II-specific transcription-factor activity. Reason: The replacements describe both the receptor class and the polymerase system regulated by RORA. Proposed replacements: nuclear receptor activity DNA-binding transcription factor activity, RNA polymerase II-specific Supporting Evidence: PMID:7926749 Binding site selection using in vitro-synthesized proteins reveals that the ROR alpha 1 and ROR alpha 2 isoforms bind DNA as monomers to hormone response elements composed of a 6-bp AT-rich sequence preceding a half-site core motif PuGGTCA (RORE). PMID:19965867 Here, we demonstrate that 7-oxygenated sterols function as high affinity ligands for both RORalpha and RORgamma by directly binding to their ligand-binding domains (K(i) approximately 20 nM), modulating coactivator binding, and suppressing the transcriptional activity of the receptors. |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IDA PMID:17545671 Cytosolic aspartate aminotransferase, a new partner in adipo... | ACCEPT | Summary: Direct activation of RNA polymerase II transcription from a RORA-bound adipocyte promoter. Reason: The study maps a RORA-binding promoter element and shows RORA-dependent transcriptional activation. Supporting Evidence: PMID:17545671 RORalpha ectopic expression activated the cAspAT gene transcription in absence of rosiglitazone, and its protein amount in nuclear extracts is 1.8-fold increased by rosiglitazone treatment of adipocytes. |
Loading supporting contentβ¦
Download this section (compressed HTML)Q: Which RORA-bound genes in human Purkinje cells directly mediate cerebellar maturation and non-cell-autonomous granule-cell-precursor proliferation, and is SHH a direct human target?
Suggested experts: human cerebellar-development experts, nuclear-receptor chromatin experts
Q: Which of the four human RORA isoforms supplies the relevant receptor activity in Purkinje cells, and do their distinct amino termini change target-site selection in vivo?
Suggested experts: RORA isoform experts, Purkinje-cell developmental biologists
Experiment: Perform isoform-resolved CUT&RUN and nascent-RNA profiling after acute endogenous RORA degradation in human iPSC-derived Purkinje cells, followed by wild-type and DNA-binding- or ligand-binding-domain rescue.
Hypothesis: RORA directly occupies a defined Purkinje-cell enhancer set and activates genes that couple Purkinje differentiation to granule-cell-precursor expansion.
Type: acute perturbation, chromatin occupancy, and nascent-transcription assay
Experiment: Co-culture isogenic RORA-null and rescued human Purkinje-like cells with granule-cell precursors; quantify secreted SHH, precursor cell-cycle entry, and Smoothened-pathway output, and test rescue with recombinant SHH or pathway agonist.
Hypothesis: Purkinje-cell RORA activity drives a secreted signal, potentially SHH, that promotes human granule-cell-precursor proliferation.
Type: human cerebellar co-culture and pathway-rescue assay
Loading supporting contentβ¦
Download this section (compressed HTML)Loading supporting contentβ¦
Download this section (compressed HTML)