ESRRB

Summary: Retain phylogenetically supported chromatin association.

Reason: The verified PTHR48092 target path and exact 433-residue alignment support this IBD inheritance; the complete dated donor and absence-of-NOT audit is in the source guide. The GO:0000785 IBD is at PTN002377694. Mouse Esrrb chromatin occupancy and DNA-site-dependent bookmarking in PMID:27723719, together with human DNA/chromatin transcription assays in PMID:36646760, are consistent with the conserved role. No claim of identical chromatin occupancy for the three human products is made.

Summary: Retain chromatin association supported independently of the classification mapping.

Reason: GO_REF:0000113 describes manual TFClass DNA-binding-domain classification for transcription-factor and chromatin annotations. The live TFClass endpoint timed out, so the current target membership was not independently replayed; this is an access limit, not evidence of a bad source. Actual mouse Esrrb chromatin binding/bookmarking in PMID:27723719 and human sequence-dependent transcription assays in PMID:36646760 independently support the biological claim. The imported TFClass identifier and term remain unchanged.

Summary: Retain contextual mitotic-chromosome localization.

Reason: The actual mouse Q61539 donor has a PMID:27723719 experimental assertion for this location. PMID:27723719 Results, Figure 1 and Methods show mouse Esrrb on condensed mitotic chromosomes using ectopic GFP, an endogenous TdTomato knock-in and antibody labeling, with Dox-withdrawal controls. Mouse embryonic stem cells and injected mouse embryos are distinguished from human ESRRB. The conserved DNA-binding domain supports the transfer, without assigning every human product an identical mitotic distribution.

Summary: Retain sequence-specific binding to polymerase-II cis-regulatory DNA.

Reason: The mouse Q61539 source chain includes PMID:18662995 and PMID:27723719. The former measures Esrrb binding to the Nanog regulatory region, with EMSA, response-element mutation and Oct4/Sox2 dependence; the latter measures motif-dependent chromatin binding. Human ERRβ-L/S binds the regulatory DNA and activates polymerase-II transcription in PMID:36646760 Supplementary Figure S5j/k. The full construct and separate chromatin-reaction limits are retained in that reference review and the source guide.

Summary: Retain RNA-polymerase-II transcription-factor activity.

Reason: The official GO_REF:0000113 describes a manually evaluated TFClass DNA-binding-domain classification; its live target page was inaccessible, rather than shown to be incorrect. Independent human assays establish the same activity. PMID:36646760 Supplementary Figure S5j/k directly demonstrates DNA binding and polymerase-II activation by human ERRβ-L/S. This supports the transcription-factor activity; the source guide and reference review retain the tested-product and preparation limits.

Summary: Retain conserved RNA-polymerase-II transcription-factor activity.

Reason: Mouse Q61539 has actual motif-dependent transcriptional regulatory experiments, including PMID:18662995 and PMID:27723719. Independent target-specific evidence resolves the human activity. Human ERRβ-L/S DNA binding and polymerase-II activation in PMID:36646760 Supplementary Figure S5j/k independently establish the target activity. The tested constructs and separate chromatin assay are bounded in the source guide and reference review.

Summary: Specify polymerase-II cis-regulatory DNA binding.

Reason: The donor source includes mouse trophoblast stem-cell ChIP and Eomes/Elf5 enhancer reporters with response-element mutants in PMID:26206133, Results and Figure 3. These identify transcriptional regulatory sites rather than arbitrary DNA. The human DNA-binding and polymerase-II transcription assays in PMID:36646760 independently support the more precise existing GO:0000978 context. The pertinent human experiments are Supplementary Figure S5j/k (DNA binding and polymerase-II activation by ERRβ-L/S); the complete construct and preparation limits are retained with PMID:36646760 in the reference review and source guide.

Proposed replacements: RNA polymerase II cis-regulatory region sequence-specific DNA binding

Summary: Retain context-dependent association with the polymerase-II complex.

Reason: Actual mouse PMID:23019124 Figure 6F–H shows Esrrb/Ncoa3/RNA-polymerase-II co-immunoprecipitation and reduced Esrrb–polymerase association after Ncoa3 depletion. This is positive complex-mediated binding, not a purified binary Esrrb–polymerase interaction. Human PMID:36646760 Supplementary Figure S5h/i instead supports contacts with TFIIB and TFIIH and does not establish direct polymerase binding. The two assay contexts are compatible; retain the mouse-derived association without turning Esrrb into a polymerase subunit.

Summary: Retain polymerase-II transcriptional activator activity.

Reason: The mouse donor has experimental self-renewal/reprogramming assertions in PMID:23040477. Independent human assays directly establish the activator activity rather than relying only on cell-state outcomes. PMID:36646760 Supplementary Figure S5k measures increased polymerase-II transcript output with human ERRβ-L/S; S5j establishes DNA binding. The source guide and reference review retain the construct correspondence and separate trace-extract chromatin assay.

Summary: The inherited NOT assertion is not resolved by the human-versus-mouse embryonic stem-cell expression comparison.

Reason: PMID:19196830 (doi:10.1210/me.2008-0465), Methods human and mouse ESC culture and quantitative PCR, Results nuclear-receptor expression and Discussion ERR-family comparison, measures expression in human H1/H9 ESCs and early embryoid bodies versus mouse ESCs. ERRbeta was undetectable in the tested human cultures, whereas mouse expression and previously published mouse trophoblast phenotypes are discussed. The human experiment does not perturb ESRRB in embryonic placental tissue or test a placental developmental outcome. GO:0001892 concerns progression of embryonically driven placental development, so absence of expression in these particular cultured states does not establish absence of that function in humans. Preserve negated:true and the NAS source exactly, withhold both acceptance of the functional negative and conversion to a positive assertion, and seek the actual basis for the human NOT annotation. This is an unresolved scope bridge, not a claim that the mouse experiments were attributed to the wrong gene.

Summary: Refine generic DNA binding to sequence-specific double-stranded DNA binding.

Reason: IPR024178 and IPR027289 are genuine target family mappings, but GO:0003677 is less precise than the supported sequence-specific activity. Human ESRRB DNA-binding-domain HT-SELEX data in PMID:28473536 identify an exact current 109-residue target fragment and its selected motifs; human full-reagent experiments in PMID:36646760 Supplementary Figure S5j support sequence-dependent DNA binding. This refinement is already represented by the specific imported rows and does not imply equivalent activity of all natural products.

Proposed replacements: sequence-specific double-stranded DNA binding

Summary: Specify polymerase-II DNA-binding transcription-factor activity.

Reason: IPR001628 genuinely identifies the nuclear-receptor DNA-binding domain, but its generic transcription-factor mapping is broader than the actual polymerase-II function. Human ERRβ-L/S binds DNA and activates polymerase-II transcription in PMID:36646760 Supplementary Figure S5j/k, supporting the specific replacement. Construct and preparation limits remain explicit in that reference review and the source guide.

Proposed replacements: DNA-binding transcription factor activity, RNA polymerase II-specific

Summary: Specify polymerase-II transcription-factor activity in the ortholog transfer.

Reason: The actual mouse donor has promoter-binding and transcription assays, including PMID:18662995 and PMID:26206133, rather than evidence for a different polymerase system. PMID:36646760 Supplementary Figure S5j/k independently demonstrates human ERRβ-L/S DNA binding and polymerase-II activation. The reference review and source guide delimit the tested products and separate chromatin experiment.

Proposed replacements: DNA-binding transcription factor activity, RNA polymerase II-specific

Summary: Steroid-dependent receptor specificity remains unresolved.

Reason: The current InterPro mappings from IPR024178 and IPR027289 really do supply this steroid-specific claim; the family labels are not a ligand assay. Current GO definitions require steroid-dependent receptor activity or steroid binding as appropriate. The available ERRβ reporter pharmacology in PMID:20534447 does not identify a steroid ligand, and the verified PMID:24315836 abstract positively reports marine 4-methylenesterol antagonists. Its partial human LBD/GAL4 preview does not expose the complete reporter or direct binding experiments, so steroid modulation cannot be excluded or fully adjudicated. Orphan-receptor nomenclature is not evidence against pharmacological modulation. Retain uncertainty about the steroid-specific assertion rather than assert that ESRRB cannot bind a ligand.

Summary: Retain the conserved nuclear-receptor activity with ligand limits explicit.

Reason: The verified PTHR48092 target path and exact 433-residue alignment support this IBD inheritance; the complete dated donor and absence-of-NOT audit is in the source guide. The GO:0004879 IBD is at PTN002377694. The current definition combines DNA-binding transcriptional regulation and ligand-regulated activity; it does not require identification of a native physiological ligand. Human ERRβ-L/S DNA binding and polymerase-II activation are directly measured in PMID:36646760 Supplementary Figure S5j/k; that experiment does not identify a physiological ligand. Its construct and preparation limits are retained in the source guide and reference review. PMID:20534447 Results and Figure 1K show ERRβ-dependent rhodopsin-promoter reporter activation enhanced by DY131 and inhibited by 4-hydroxytamoxifen; mutating the response elements reduces activation. The reporter host is 293T, but the inspected main text does not map the receptor insert to a human accession. Mouse retinal genetics, rescue and pharmacology are separate experiments. PMID:24315836 exposes a human ERRβ-LBD/GAL4 construction and partial reporter Methods in the publisher preview, but complete Results and direct binding measurements were unavailable. These support pharmacologically responsive receptor function without establishing a physiological endogenous ligand, measured steroid binding, or equal responsiveness of all three human products.

Summary: Retain nuclear-receptor activity without inferring a steroid ligand.

Reason: The mouse Q61539 source includes developmental studies, which do not themselves resolve ligand chemistry. Independently inspected functional assays support the receptor activity. PMID:36646760 Supplementary Figure S5j/k supplies positive human ERRβ-L/S DNA-binding and polymerase-II activation evidence, while ligand responsiveness is addressed by the distinct experiments below. Construct and preparation limits remain in the source guide and reference review. PMID:20534447 Results and Figure 1K show ERRβ-dependent rhodopsin-promoter reporter activation enhanced by DY131 and inhibited by 4-hydroxytamoxifen; mutating the response elements reduces activation. The reporter host is 293T, but the inspected main text does not map the receptor insert to a human accession. Mouse retinal genetics, rescue and pharmacology are separate experiments. PMID:24315836 exposes a human ERRβ-LBD/GAL4 construction and partial reporter Methods in the publisher preview, but complete Results and direct binding measurements were unavailable. These support pharmacologically responsive receptor function without establishing a physiological endogenous ligand, measured steroid binding, or equal responsiveness of all three human products.

Summary: Direct steroid-binding specificity is unresolved.

Reason: The current InterPro mappings from IPR024178 and IPR027289 really do supply this steroid-specific claim; the family labels are not a ligand assay. Current GO definitions require steroid-dependent receptor activity or steroid binding as appropriate. The available ERRβ reporter pharmacology in PMID:20534447 does not identify a steroid ligand, and the verified PMID:24315836 abstract positively reports marine 4-methylenesterol antagonists. Its partial human LBD/GAL4 preview does not expose the complete reporter or direct binding experiments, so steroid modulation cannot be excluded or fully adjudicated. Orphan-receptor nomenclature is not evidence against pharmacological modulation. Retain uncertainty about the steroid-specific assertion rather than assert that ESRRB cannot bind a ligand. A cellular response is not automatically a physical binding measurement, and the present uncertainty is about target and ligand attribution, not a requirement that every GO binding assay use a purified isolated protein.

Summary: Human ESRRB has directly observed nuclear localization, with independent human evidence supporting the more precise nucleoplasm compartment.

Reason: PMID:18775884 (doi:10.1093/humrep/den298), Methods immunohistochemistry and confocal microscopy and Results/Figures 3–5, establishes nuclear staining in human endometrial cells using an antibody shared by the long and short products. Those experiments do not resolve nucleoplasm, and their endogenous staining cannot be assigned to a single product. The refinement instead uses independent positive human evidence: the ESRRB Human Protein Atlas record shows supported nucleoplasmic staining in K-562 cells with HPA074772, whose antigen spans shared residues 36–65, and Reactome R-HSA-376419 and R-HSA-382096 explicitly reach human ESRRB/O95718 entity 446173, residues 1–433, in nucleoplasm through candidate set 376224. Thus GO:0005654 describes an established subnuclear location of the gene product, rather than inferring it from the endometrial study or applying a rule by evidence code. The HPA antibody cannot distinguish the three products; the Reactome entity covers the 433-residue product. This does not establish nucleoplasmic localization for every product in every tissue, or exclude the separately observed cytosolic pool. Main endometrial Methods, Results and captions were read, but its figure pixels and supplemental Figure S1 were not; the separate HPA and Reactome access scopes are recorded in the source guide.

Proposed replacements: nucleoplasm

Summary: Refine the inherited nuclear location to nucleoplasm.

Reason: The verified PTHR48092 target path and exact 433-residue alignment support this IBD inheritance; the complete dated donor and absence-of-NOT audit is in the source guide. The nucleus IBD is PTN001182563 and legitimately includes human ESRRB among its experimental descendants. The current HPA record for human ESRRB has supported nucleoplasm and additional cytosol localization in K-562 cells with HPA074772. Its antigen maps to residues 36–65 shared by all three products, so the antibody does not resolve them. The actual XML and selected blue/red/green image were inspected; no new image quantification or universal tissue distribution is claimed. Both current human Reactome routes explicitly reach ESRRB entity 446173 (O95718, residues 1–433) in nucleoplasm through nuclear-receptor set 376224. This is the participant compartment, not an inference from the reaction label.

Proposed replacements: nucleoplasm

Summary: Refine the broad nuclear mapping to nucleoplasm.

Reason: Actual ARBA00026330 target-matching disjuncts are set 0 (IPR013088 and Primates) and set 1 (IPR000536, IPR035500 and Haplorrhini); the imported InterPro and SL-0191 nucleus mappings are also genuine. The current HPA record for human ESRRB has supported nucleoplasm and additional cytosol localization in K-562 cells with HPA074772. Its antigen maps to residues 36–65 shared by all three products, so the antibody does not resolve them. The actual XML and selected blue/red/green image were inspected; no new image quantification or universal tissue distribution is claimed. Both current human Reactome routes explicitly reach ESRRB entity 446173 (O95718, residues 1–433) in nucleoplasm through nuclear-receptor set 376224. This is the participant compartment, not an inference from the reaction label.

Proposed replacements: nucleoplasm

Summary: Refine the ortholog-supported nuclear location to nucleoplasm.

Reason: The mouse source includes PMID:18662995 nuclear-extract/ChIP experiments. The separate PMID:18472334 main experiments were not inspected; their precise assay is not claimed as verified. Independent human evidence resolves the compartment. The current HPA record for human ESRRB has supported nucleoplasm and additional cytosol localization in K-562 cells with HPA074772. Its antigen maps to residues 36–65 shared by all three products, so the antibody does not resolve them. The actual XML and selected blue/red/green image were inspected; no new image quantification or universal tissue distribution is claimed. Both current human Reactome routes explicitly reach ESRRB entity 446173 (O95718, residues 1–433) in nucleoplasm through nuclear-receptor set 376224. This is the participant compartment, not an inference from the reaction label.

Proposed replacements: nucleoplasm

Summary: Retain supported human nucleoplasm localization.

Reason: The current HPA record for human ESRRB has supported nucleoplasm and additional cytosol localization in K-562 cells with HPA074772. Its antigen maps to residues 36–65 shared by all three products, so the antibody does not resolve them. The actual XML and selected blue/red/green image were inspected; no new image quantification or universal tissue distribution is claimed. Both current human Reactome routes explicitly reach ESRRB entity 446173 (O95718, residues 1–433) in nucleoplasm through nuclear-receptor set 376224. This is the participant compartment, not an inference from the reaction label.

Summary: Retain the explicitly modeled human nucleoplasm location.

Reason: Actual Reactome R-HSA-376419 links input nuclear-receptor set 376224 and output complex 376420, which retains that set. Its member 446173 is human ESRRB, referenceEntity O95718, residues 1–433, with nucleoplasm as its own compartment. The MED1-associated event has no catalystActivity to assign to ESRRB. This supports localization, without treating family-set membership as a direct biochemical assay of every receptor–cofactor interaction or assigning ligand specificity. The current HPA record for human ESRRB has supported nucleoplasm and additional cytosol localization in K-562 cells with HPA074772. Its antigen maps to residues 36–65 shared by all three products, so the antibody does not resolve them. The actual XML and selected blue/red/green image were inspected; no new image quantification or universal tissue distribution is claimed.

Summary: Retain the explicitly modeled human nucleoplasm location.

Reason: Actual Reactome R-HSA-382096 links input nuclear-receptor set 376224 and output complex 382093, which retains that set. Its member 446173 is human ESRRB, referenceEntity O95718, residues 1–433, with nucleoplasm as its own compartment. The NCOR-associated event has no catalystActivity to assign to ESRRB. This supports localization, without treating family-set membership as a direct biochemical assay of every receptor–cofactor interaction or assigning ligand specificity. The current HPA record for human ESRRB has supported nucleoplasm and additional cytosol localization in K-562 cells with HPA074772. Its antigen maps to residues 36–65 shared by all three products, so the antibody does not resolve them. The actual XML and selected blue/red/green image were inspected; no new image quantification or universal tissue distribution is claimed.

Summary: Specify the experimentally supported condensed-chromosome context.

Reason: SL-0468 maps to chromosome and preserves a real broad location. The more specific GO:0000793 already present in row 2 is supported by actual ortholog microscopy. PMID:27723719 Results, Figure 1 and Methods show mouse Esrrb on condensed mitotic chromosomes using ectopic GFP, an endogenous TdTomato knock-in and antibody labeling, with Dox-withdrawal controls. Mouse embryonic stem cells and injected mouse embryos are distinguished from human ESRRB. The conserved DNA-binding domain supports the transfer, without assigning every human product an identical mitotic distribution.

Proposed replacements: condensed chromosome

Summary: Specify the mitotic condensed-chromosome location in the donor evidence.

Reason: The actual Q61539 donor assertion points to PMID:27723719. PMID:27723719 Results, Figure 1 and Methods show mouse Esrrb on condensed mitotic chromosomes using ectopic GFP, an endogenous TdTomato knock-in and antibody labeling, with Dox-withdrawal controls. Mouse embryonic stem cells and injected mouse embryos are distinguished from human ESRRB. The conserved DNA-binding domain supports the transfer, without assigning every human product an identical mitotic distribution. The replacement retains this defined context rather than asserting residence on every chromosomal region.

Proposed replacements: condensed chromosome

Summary: Refine the broad cytoplasmic location to cytosol.

Reason: SL-0086 genuinely maps to cytoplasm. Independent target-specific HPA evidence supplies the narrower cytosol location. The current HPA record for human ESRRB has supported nucleoplasm and additional cytosol localization in K-562 cells with HPA074772. Its antigen maps to residues 36–65 shared by all three products, so the antibody does not resolve them. The actual XML and selected blue/red/green image were inspected; no new image quantification or universal tissue distribution is claimed. Cytosolic staining does not establish a cytosolic transcriptional activity or equal localization of every product.

Proposed replacements: cytosol

Summary: Refine cytoplasmic localization using independent human evidence.

Reason: The mouse donor PMID:18472334 original Methods/Results were not recovered; its reported cytoplasmic localization is not rejected. Independent human data support the more precise compartment. The current HPA record for human ESRRB has supported nucleoplasm and additional cytosol localization in K-562 cells with HPA074772. Its antigen maps to residues 36–65 shared by all three products, so the antibody does not resolve them. The actual XML and selected blue/red/green image were inspected; no new image quantification or universal tissue distribution is claimed. This refinement does not claim that the unread mouse experiment itself resolved cytosol.

Proposed replacements: cytosol

Summary: Refine transcription regulation to positive regulation of RNA-polymerase-II transcription using independently measured human ERRbeta activity.

Reason: PMID:23836911 (doi:10.1074/jbc.M113.489674), Experimental Procedures and Figure 1B, shows FLAG-ERRbeta-dependent Perm1 mRNA induction in mouse C2C12 myotubes, but the inspected Methods do not identify the insert accession/species/product, and its ERRE ChIP tests ERRalpha and FLAG-PGC-1alpha rather than ERRbeta. Independent PMID:36646760, main Results on conserved ERR-family mechanisms, Methods construct preparation/protein purification/in-vitro transcription and Supplementary Figure S5b/j/k (with S5l testing p52 competition), directly resolves the human function. Purified FLAG-human ERRbeta-L and ERRbeta-S activate transcription from an ERRE-containing template in a system containing RNA polymerase II, with transcript bands measured; DNA-binding and interface mutants and p52 competition distinguish the tested mechanisms. The chromatin S5b assay additionally contains trace HeLa nuclear extract, explicitly disclosed in its caption. The printed supplemental cDNA Table S4 names NP_004443 and AAS15571; their recovered current sequences correspond to the 508- and 433-residue products, but the unversioned table does not independently authenticate every historical plasmid base. No activity is assigned to the third, 500-residue product. This positive human transcription experiment supports the more precise current GO:0045944, while leaving the original 2013 construct and ChIP limitations intact. No native PERM1-promoter occupancy or universal transcriptional activation is inferred.

Proposed replacements: positive regulation of transcription by RNA polymerase II

Summary: Specify regulation of transcription by RNA polymerase II.

Reason: ARBA00028138 has the exact target-matching condition set 24 (IPR013088, IPR050200 and Catarrhini), and the listed InterPro mappings really emit transcription regulation. The supported substrate system is polymerase II, already represented by the valid IBA row 30. PMID:36646760 Supplementary Figure S5j/k directly couples human ERRβ-L/S DNA binding to polymerase-II transcript output. The source guide and reference review retain the full tested-product and separate chromatin-assay scope.

Proposed replacements: regulation of transcription by RNA polymerase II

Summary: Retain inherited regulation of polymerase-II transcription.

Reason: The verified PTHR48092 target path and exact 433-residue alignment support this IBD inheritance; the complete dated donor and absence-of-NOT audit is in the source guide. The actual GO:0006357 IBD is PTN001182563. PMID:36646760 Supplementary Figure S5j/k directly supports human ERRβ-L/S regulation of polymerase-II transcription. Its tested-product correspondence and separate trace-extract chromatin reaction are bounded in the source guide and reference review.

Summary: Retain zinc binding by the conserved nuclear-receptor DNA-binding domain.

Reason: The actual IPR001628, IPR013088 and IPR024178 mappings support zinc-binding nuclear-receptor domains. Current human sequence features place two C4 zinc fingers at residues 103–123 and 139–163 within the DNA-binding domain shared by the three products. The actual human DNA-binding fragment in PMID:28473536 maps to residues 85–193 and retains this region. This is structural metal binding, not zinc-dependent enzymatic catalysis, and does not imply equivalent downstream regulation by the three different tails.

Summary: Retain the contextual contribution to self-renewing stem-cell divisions.

Reason: Actual mouse Q61539 donor studies PMID:23040478 and PMID:26206133 combine clonal self-renewal/proliferation, stem-cell markers, genetic depletion and rescue. Esrrb contributes transcriptional regulation of the state that permits self-renewing divisions; it is not assigned spindle or cytokinetic machinery. In PMID:23040478 the requirement depends on LIF/GSK3 culture conditions, and in PMID:26206133 trophoblast-stem-cell identity and proliferation are coupled. Retain this contextual process rather than generalize it to all human stem cells.

Summary: Retain the conserved, context-dependent transcriptional contribution to stem-cell population maintenance.

Reason: PMID:25522312, main Methods and Results/Figures 3–4, shows that pCAG-Flag-Esrrb expression rescues prolonged growth, alkaline-phosphatase-positive colonies and pluripotency-associated expression in nucleostemin-depleted mouse ESCs. Supplemental Vector construction does not identify the insert species/accession, and the human iPSC experiment depletes nucleostemin rather than tests ESRRB rescue; EpiSCs also respond differently. Those limits remain unresolved for the exact original assay. Independently inspected mouse PMID:34397088 Results/Figures 1–3 couples Esrrb regulatory-site occupancy to gene expression and maintenance of undifferentiated colonies, with Nr5a2 redundancy; PMID:23040478 Results/Figures 3–4 establishes culture-dependent self-renewal and Esrrb loss/rescue. Together with independently demonstrated human transcriptional activity (PMID:36646760), this supports a conserved contextual regulatory role, as already retained for the more specific stem-cell terms. KEEP_AS_NON_CORE is a gene-level synthesis that retains the experimental curator’s positive assertion; it does not relabel the mouse-cell rescue as a verified human assay or imply equal activity of all three products or universal stem-cell dependence. No source defect is established merely by the missing historical construct identifier.

Summary: Steroid-initiated receptor signaling is unresolved.

Reason: This electronic row derives from GO:0003707, whose steroid-specific premise remains unresolved in row 13. The current GO:0030518 definition specifically requires initiation by steroid binding. The current InterPro mappings from IPR024178 and IPR027289 really do supply this steroid-specific claim; the family labels are not a ligand assay. Current GO definitions require steroid-dependent receptor activity or steroid binding as appropriate. The available ERRβ reporter pharmacology in PMID:20534447 does not identify a steroid ligand, and the verified PMID:24315836 abstract positively reports marine 4-methylenesterol antagonists. Its partial human LBD/GAL4 preview does not expose the complete reporter or direct binding experiments, so steroid modulation cannot be excluded or fully adjudicated. Orphan-receptor nomenclature is not evidence against pharmacological modulation. Retain uncertainty about the steroid-specific assertion rather than assert that ESRRB cannot bind a ligand.

Summary: Retain contextual intracellular receptor signaling without specifying a steroid.

Reason: This term is propagated from the supported general nuclear-receptor activity, not from the disputed steroid-specific mapping. PMID:20534447 Results and Figure 1K show ERRβ-dependent rhodopsin-promoter reporter activation enhanced by DY131 and inhibited by 4-hydroxytamoxifen; mutating the response elements reduces activation. The reporter host is 293T, but the inspected main text does not map the receptor insert to a human accession. Mouse retinal genetics, rescue and pharmacology are separate experiments. PMID:24315836 exposes a human ERRβ-LBD/GAL4 construction and partial reporter Methods in the publisher preview, but complete Results and direct binding measurements were unavailable. These support pharmacologically responsive receptor function without establishing a physiological endogenous ligand, measured steroid binding, or equal responsiveness of all three human products. The annotation is retained for the ligand-responsive transcriptional context, without a newly asserted physiological hormone pathway.

Summary: Retain the donor-supported association with Integrator in a defined cell context.

Reason: PMID:26206133 Results and Figure 5 identify four Integrator components in FLAG-Esrrb mouse trophoblast-stem-cell nuclear proteomics and validate INTS1/INTS9 association by co-immunoprecipitation. Methods distinguish high-salt nuclear extraction, Benzonase treatment and two biological replicates. This supports a contextual association; it does not show that ESRRB is a universal stoichiometric Integrator subunit, that ESRRB catalyzes snRNA cleavage, or that the proposed recruitment mechanism was established. The source is retained without inventing those stronger claims.

Summary: Retain inherited estrogen-response-element binding, distinct from estrogen binding.

Reason: The verified PTHR48092 target path and exact 433-residue alignment support this IBD inheritance; the complete dated donor and absence-of-NOT audit is in the source guide. The exact GO:0034056 IBD is PTN001182563. The term describes binding a DNA regulatory sequence, not binding estrogen as a ligand. The verified human PMID:16332939 abstract reports different ERE-reporter activities among three products; its full Methods were unavailable, so it is corroborative rather than a newly verified direct binding assay. Human DNA-binding data in PMID:28473536 and PMID:36646760 support conserved sequence-specific recognition but are not relabeled as a complete palindromic-ERE affinity series. No target-specific loss of the inherited binding function is established.

Summary: Retain the contextual stem-cell maintenance role.

Reason: The actual mouse donor PMID:34397088 tests Esrrb and Nr5a2 single and combined perturbations in embryonic stem cells, with clonal growth, alkaline-phosphatase colonies, marker expression and chromatin occupancy. Its Results distinguish redundancy and culture dependence; loss of proliferative capacity follows altered cell state. These experiments support a transcriptional contribution to maintaining the stem-cell population, without universal human-tissue or natural-product equivalence.

Summary: Refine the established sequence-specific DNA-binding activity to sequence-specific double-stranded DNA binding.

Reason: PMID:12654265 (doi:10.1016/S0022-2836(03)00183-9) has an independently inspected primary deposition, PDB 1LO1: a human ESRRB DNA-binding fragment associated with complementary DNA strands in a solution-NMR complex. The deposited protein corresponds to current residues 97–194 and includes C163A designated as engineered; the S193N sequence difference is separately marked SEE REMARK 999. The article Methods remain inaccessible, so no full-paper or coordinate-contact analysis is claimed. Independent PMID:28473536 (doi:10.1126/science.aaj2239), Methods HT-SELEX plus original Supplementary Tables S1 row 562 and S2 rows 6418–6427, directly tests the human ESRRB extended DNA-binding domain and reports sequence-selective motifs from double-stranded ligands. The table sequence exactly matches current residues 85–193 without substitution and is common to all three source-described products, but the experiment does not test their full-length functional equivalence. GO:1990837 is the current is_a child of the imported GO:0043565 that captures the tested DNA substrate; it already exists elsewhere among this gene’s imported assertions, so this is a refinement, not a new annotation.

Proposed replacements: sequence-specific double-stranded DNA binding

Summary: Specify sequence-specific double-stranded DNA binding.

Reason: IPR001628 genuinely maps the nuclear-receptor DNA-binding domain to sequence-specific DNA binding. The actual human HT-SELEX fragment/motifs in PMID:28473536 and human ERRβ-L/S assays in PMID:36646760 resolve double-stranded DNA as the substrate. The specific term already exists in rows 49/50; this refinement does not add a new activity.

Proposed replacements: sequence-specific double-stranded DNA binding

Summary: Retain experimentally induced cellular reprogramming as a contextual role.

Reason: PMID:23040477 Results and Figures 3–5 show mouse Esrrb expression promoting EpiSC reversion and somatic pre-iPSC reprogramming, with stable pluripotency markers, transgene silencing and developmental contribution. Methods identify mouse cellular systems and inducible constructs. Esrrb supplies transcriptional regulatory activity during reprogramming; this is more than an expression correlation, but it does not establish routine dedifferentiation in human tissues.

Summary: Retain the conserved retinal photoreceptor-maintenance role with mouse scope.

Reason: PMID:20534447 Results and Figures 2–5 combine conditional mouse Errβ loss, delayed rod degeneration/electroretinographic changes, transcriptional changes preceding cell loss and receptor-expression rescue. These positively support a regulatory role in rod maintenance, while distinguishing early rod effects from later or indirect cone changes. They are not a direct assay of every human product or a claim that ERRβ specifies rod fate.

Summary: Specify positive regulation of polymerase-II transcription.

Reason: The actual mouse sources include rhodopsin-promoter activation in PMID:20534447 and Esrrb/Ncoa3-dependent regulatory assays in PMID:23019124. Independent human assays establish the polymerase-specific positive effect. Human ERRβ-L/S increases polymerase-II transcript output in PMID:36646760 Supplementary Figure S5k, with DNA binding measured separately in S5j. The source guide and reference review retain the construct and preparation limits.

Proposed replacements: positive regulation of transcription by RNA polymerase II

Summary: Retain positive regulation of polymerase-II transcription.

Reason: The donor Q61539 chain includes direct promoter and chromatin experiments, including PMID:18662995 and PMID:27723719. PMID:36646760 Supplementary Figure S5k directly measures positive human ERRβ-L/S regulation of polymerase-II transcription, with S5j testing DNA binding. Full tested-product and separate chromatin-reaction limits are retained in the source guide and reference review.

Summary: Human DFNB35 establishes an auditory role, while the precise developmental transfer remains unresolved.

Reason: PMID:18179891, Methods and Results/Figures 1–3/Table 2, establishes cosegregating biallelic ESRRB variants in five families with severe-to-profound early hearing loss. Its human fetal-cochlear RT-PCR (Figure 5), mouse embryonic expression (Figure 6) and P4 rat localization (Figure 7) support auditory relevance; predicted variant effects are structural models, not measured loss of transcription. GO:0048839 concerns progression from inner-ear formation to the mature structure. Human hearing loss and expression therefore bear on the annotation, but do not independently distinguish a transcriptional contribution to developmental formation from maintenance or ion homeostasis in the functioning ear. The verified mouse PMID:17765677 abstract positively reports marginal-cell fate and ion-transport regulation, but its operative Methods/Results remain unread. Retain UNDECIDED for this precise transferred developmental claim, without disputing DFNB35, treating expression as sufficient process evidence, or assuming that a regulatory protein must be structural machinery to participate.

Summary: Retain the specific transcription-factor association with its complex boundary.

Reason: PMID:18662995 Figures 1–2 and Methods show mouse Esrrb–Oct4 association in embryonic-stem-cell nuclear extracts, including reciprocal co-immunoprecipitation and DNA-disruption controls. GST-Oct4 experiments use Esrrb-containing extracts and do not constitute a homogeneous purified binary assay. This supports the specific polymerase-II transcription-factor binding class, without implying that every contact is direct or that it proves the human products have identical partner selectivity.

Summary: The specific contribution to morula formation remains unresolved.

Reason: The actual mouse primary PMID:39361745, Results and Figures 3–4 plus Methods, separately tests Esrrb, Nr5a2 and double maternal/zygotic deletions. Esrrb loss has a measurable earlier transcriptional contribution but minor effects at the eight-cell stage, whereas Nr5a2 loss recapitulates the major morula-stage phenotype. Normal development after Esrrb loss is not by itself proof of no participation, and the paper’s Nr5a2-focused title is not a target-exclusion argument. The inspected experiments do not resolve how the transferred ESRRB activity specifically contributes to formation of the initial morula mass, as required by the current term definition, rather than broader preimplantation transcription.

Summary: Retain positive regulation of stem-cell population maintenance.

Reason: Actual mouse studies PMID:23040477/23040478 show Esrrb-dependent or Esrrb-induced clonal self-renewal, transgene rescue and culture-dependent maintenance of pluripotency; PMID:26206133 additionally measures trophoblast stem-cell markers, proliferation and rescue with Esrrb. These establish a regulatory role in the studied stem-cell populations, with LIF/GSK3 and lineage context explicit, rather than universal necessity in every stem-cell state.

Summary: The original ESRRB-specific HT-SELEX records establish sequence-specific double-stranded DNA binding by its extended DNA-binding domain.

Reason: PMID:28473536 (doi:10.1126/science.aaj2239), Methods protein production and HT-SELEX, selects randomized double-stranded DNA ligands using expressed human transcription-factor constructs. The actual original Supplementary Table S1 row 562 identifies ESRRB and gives a 109-residue eDBD sequence that exactly matches current O95718 residues 85–193. Supplementary Table S2 rows 6418–6427 contains the corresponding methyl-HT-SELEX and ordinary HT-SELEX motif matrices, including the selected extended half-site motif. These target-specific experimental records, rather than the paper title or a generic list of transcription factors, support GO:1990837. The fragment is shared by O95718-3, O95718-1 and O95718-2; no full-length product equivalence, ligand-response property or particular methylation preference is inferred here. Table cells and Methods were inspected, without claiming microscopy or structural figure-pixel analysis.

Summary: Retain the rule-supported sequence-specific double-stranded DNA-binding activity.

Reason: ARBA00028376 set 1 genuinely matches the target through IPR000536, IPR050200 and Catarrhini. Independent human HT-SELEX in PMID:28473536 and human ERRβ-L/S DNA-binding assays in PMID:36646760 support the same activity. The matching rule is not used to infer an untested steroid ligand or functional equivalence among the three products.

Summary: Retain regulation of self-renewing divisions in the tested stem-cell systems.

Reason: PMID:23019124 shows Esrrb/Ncoa3-dependent self-renewal and transcriptional complexes, while PMID:23040477 tests clonal maintenance and induced reprogramming with Esrrb. This supports regulation of stem-cell division through transcriptional control of the stem state; it does not assign ESRRB a mitotic motor or cytokinetic role. Retain the conditional mouse-derived process as non-core without equating all human products or culture conditions.

Summary: Retain context-dependent restraint of stem-cell differentiation.

Reason: PMID:26206133 combines mouse trophoblast-stem-cell Esrrb depletion, rescue, differentiation markers/morphology and direct binding/activation of stem-state regulators. These experiments establish an active transcriptional contribution to opposing differentiation in this lineage, not simply a necessity phenotype. The downstream process is retained as contextual rather than a universal property of all human tissues or products.