nhr-47 (C24G6.4) is one of the ~280 nuclear hormone receptors (NHRs) of Caenorhabditis elegans, the great majority of which arose by a nematode-specific expansion of an ancestral HNF4-like orphan receptor and are termed supplementary nuclear receptors (supnrs). The 579-residue protein has the canonical nuclear-receptor architecture: an N-terminal DNA-binding domain built from two C4-type (Cys4) zinc-finger motifs that coordinate zinc, and a C-terminal ligand-binding domain. On the basis of this diagnostic domain organization and phylogenetic placement, NHR-47 is a zinc-dependent, sequence-specific DNA-binding transcription factor of the nuclear-receptor superfamily that acts in the nucleus to regulate RNA polymerase II transcription. It is annotated as an orphan receptor: no endogenous ligand has been identified. NHR-47 is expressed in head and tail neurons, the ventral nerve cord, the spermatheca, the pharynx and the intestine, and it physically interacts with another nuclear receptor, NHR-17. The only reported loss-of-function phenotypes are in the germline: knockdown modulates susceptibility to environmental toxicants (polystyrene nanoparticles and 6-PPD-quinone), where NHR-47 acts as a positive mediator of reproductive and transgenerational toxicity and lies upstream of insulin, Ephrin and Wnt ligand-gene expression. nhr-47 transcription is also induced by exposure to the vertebrate steroid estradiol. Its endogenous physiological role, its ligand (if any), and its direct transcriptional targets remain undetermined.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005634 nucleus | IBA GO_REF:0000033 | ACCEPT | Summary: NHR-47 is a nuclear-receptor transcription factor and acts in the nucleus. Supported by the canonical NR DNA-binding domain and UniProt subcellular location. Reason: Nuclear localization is expected for a functional nuclear-receptor transcription factor and is independently annotated from UniProt SubCell mapping. This is a core cellular-component assignment. |
| GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding | IBA GO_REF:0000033 | ACCEPT | Summary: Sequence-specific DNA binding at Pol II cis-regulatory regions is the diagnostic molecular function of the NR DNA-binding domain (two C4 zinc fingers) that NHR-47 possesses. Reason: Consistent with the conserved NR DBD architecture and phylogenetic placement in the HNF4-like DNA-binding-domain class. A core molecular function. |
| GO:0004879 nuclear receptor activity | IBA GO_REF:0000033 | ACCEPT | Summary: NHR-47 is a member of the nuclear-receptor superfamily with a canonical DBD and ligand-binding domain; nuclear receptor activity (ligand-modulated sequence-specific DNA-binding TF activity) is its family-level molecular function. Reason: Well supported by domain architecture and family membership. Note that NHR-47 is an orphan receptor: no ligand is known, so the ligand-modulated aspect of this term is inferred, not demonstrated (see knowledge_gaps). Retained as a core MF. |
| GO:0006357 regulation of transcription by RNA polymerase II | IBA GO_REF:0000033 | ACCEPT | Summary: As a sequence-specific DNA-binding TF of the NR family, NHR-47 regulates Pol II transcription. This is the core biological process for the molecular function. Reason: Directly follows from the nuclear-receptor / DNA-binding-TF molecular function and nuclear localization. Core process. |
| GO:0030154 cell differentiation | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: A generic biological process propagated across the nuclear-receptor family by phylogenetic inference. No nhr-47-specific evidence links it to a differentiation program. Reason: This is a broad pan-family IBA propagation. NHR-47 has no reported role in cell differentiation; its only experimental phenotypes are germline toxicant responses. Retain (family inference is not contradicted) but mark non-core rather than core. |
| GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro2GO assignment (IPR049636, HNF4-like DBD) of the same sequence-specific Pol II DNA-binding function, in agreement with the IBA annotation above. Reason: Independent InterPro domain-based support for the core sequence-specific DNA-binding molecular function. Consistent with the phylogenetic annotation. |
| GO:0003700 DNA-binding transcription factor activity | IEA GO_REF:0000002 | ACCEPT | Summary: General DNA-binding transcription factor activity assigned from the nuclear-receptor zinc-finger domain (IPR001628). NHR-47 is a bona fide DNA-binding TF. Reason: Correct parent molecular function for a nuclear-receptor TF; supported by the C4 zinc-finger DBD. Core MF (the RNA Pol II-specific children above are the more precise forms). |
| GO:0005634 nucleus | IEA GO_REF:0000044 | ACCEPT | Summary: Nuclear localization from UniProt Swiss-Prot subcellular-location mapping (SL-0191), consistent with the IBA nucleus annotation. Reason: Independent support for nuclear localization of this transcription factor. Core CC. |
| GO:0006355 regulation of DNA-templated transcription | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: General (DNA-templated) transcription-regulation term from InterPro. This is the broad parent of the RNA Pol II-specific regulation term. Reason: Not wrong, but less informative than the RNA polymerase II-specific regulation term (GO:0006357) already accepted as core. Retain as a non-core general annotation. |
| GO:0008270 zinc ion binding | IEA GO_REF:0000002 | ACCEPT | Summary: The two C4-type (Cys4) zinc-finger motifs of the NR DNA-binding domain coordinate zinc; zinc binding is a structural molecular function underpinning DNA binding. Reason: Directly supported by the diagnostic C4 zinc-finger DBD (ZN_FING 11-31 and 47-71 in UniProt Q17370). Structural MF that enables the core DNA-binding function. |
| GO:0030522 intracellular receptor signaling pathway | IEA GO_REF:0000108 | KEEP AS NON CORE | Summary: Auto-inferred by inter-ontology logic from nuclear receptor activity (GO:0004879). For an orphan receptor with no known ligand, the signaling-pathway aspect is unproven. Reason: A logically-derived (GO_REF:0000108) consequence of the nuclear-receptor MF, not direct evidence. Because NHR-47 is an orphan receptor with no demonstrated ligand-activated signaling, retain as non-core rather than core. |
| GO:0043565 sequence-specific DNA binding | IEA GO_REF:0000002 | ACCEPT | Summary: Sequence-specific DNA binding assigned from the NR zinc-finger domain (IPR001628); the general parent of the Pol II cis-regulatory DNA-binding term. Reason: Supported by the conserved C4 zinc-finger DBD. Core MF (parent of GO:0000978). |
| GO:0005515 protein binding | IPI PMID:19123269 Empirically controlled mapping of the Caenorhabditis elegans... | KEEP AS NON CORE | Summary: Experimental yeast two-hybrid interaction captured in the worm interactome; the partner is the nuclear receptor NHR-17 (UniProtKB:Q17589). "Protein binding" is an uninformative molecular-function term. Reason: A real, curated physical interaction (NHR-47<->NHR-17), so it should not be removed. However GO:0005515 conveys no specific molecular function, and a single Y2H edge does not justify a more informative MF (e.g. nuclear receptor binding) as a core function. Retain as non-core. |
| GO:0005515 protein binding | IPI PMID:23791784 Extensive rewiring and complex evolutionary dynamics in a C.... | KEEP AS NON CORE | Summary: Second experimental interaction annotation (C. elegans multiparameter TF network), again with NHR-17 (UniProtKB:Q17589). Uninformative "protein binding" term. Reason: Corroborates the NHR-47<->NHR-17 interaction from an independent dataset. Keep (real interaction) but non-core; GO:0005515 does not describe a specific molecular function. |
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Download this section (compressed HTML)Q: Is NHR-47 a ligand-regulated receptor, and if so what endogenous metabolite or lipid binds its ligand-binding domain, or is it a constitutive/orphan transcriptional regulator?
Suggested experts: Nuclear-receptor biochemists, C. elegans NHR-family biologists
Q: What are the direct genomic binding sites and target genes of NHR-47, and does it act as a transcriptional activator or repressor?
Suggested experts: Transcription / gene-regulatory-network biologists
Q: What is the endogenous (non-toxicant) physiological role of nhr-47, given its expression in neurons, the ventral nerve cord, spermatheca, pharynx and intestine and its germline role in toxicant responses?
Suggested experts: C. elegans developmental / germline biologists
Experiment: Determine the direct NHR-47 regulon by ChIP-seq or CUT&RUN with an endogenously tagged NHR-47, combined with RNA-seq of a null mutant, to identify direct target genes and the DNA response element and to establish activator vs repressor behavior.
Type: Genome-wide binding assay
Experiment: Express and purify the NHR-47 ligand-binding domain and screen for bound endogenous lipids/metabolites (e.g. by lipidomics of co-purified ligands or reporter-based ligand-sensing assays) to test whether NHR-47 is ligand-regulated or a true orphan.
Type: Ligand identification
Experiment: Generate and characterize a null allele (CRISPR) across development, metabolism, reproduction, stress and innate-immune assays to define the baseline endogenous function, and test genetic interaction with the interacting receptor nhr-17.
Type: Loss-of-function phenotyping
What is not known — curated, literature-grounded statements of the open unknowns (the inverse of core functions).
Gap: Whether NHR-47 binds an endogenous small-molecule ligand — and, if so, its chemical identity — is unknown. It is classified as an orphan receptor, and as a member of the HNF4-derived supplementary nuclear receptors it may have lost or substantially altered ligand-dependent regulation.
OPEN BIOLOGY MF_DARK
What is known: NHR-47 has a canonical nuclear-receptor ligand-binding domain (UniProt NR LBD, residues 164-553), but UniProt annotates it as an orphan nuclear receptor and no ligand has been reported. nhr-47 transcription is induced by estradiol exposure, but transcriptional induction is not evidence that estradiol (or any specific molecule) is a direct NHR-47 ligand.
Significance: Knowing whether NHR-47 is ligand-regulated (and by what) would determine whether it is a sensor of a metabolite/hormone or a constitutive/orphan transcriptional regulator, and would shape any pharmacological or genetic strategy to control its activity.
Provenance (the field's own admissions):
Gap: The direct transcriptional targets and the DNA response element bound by NHR-47 in vivo are undetermined, and it is unknown whether NHR-47 acts as an activator or a repressor. No ChIP, reporter, or motif data define its regulon; the downstream genes that change on nhr-47 knockdown in toxicant assays (e.g. ins-3, daf-28, efn-3) are whole-organism readouts, not demonstrated direct targets.
OPEN BIOLOGYCURATION MF_DARK
What is known: NHR-47 is a sequence-specific DNA-binding transcription factor and participates in the C. elegans transcription-factor interaction network, and knockdown alters downstream secreted-ligand gene expression, but no bona fide direct target has been established.
Significance: Identifying direct targets and the response element would convert NHR-47 from a predicted TF into a defined regulator and reveal the pathway(s) it controls.
Provenance (the field's own admissions):
Gap: The endogenous physiological role and definitive loss-of-function phenotype of nhr-47 are unresolved. Its only reported phenotypes are germline RNAi effects that modulate susceptibility to environmental toxicants (polystyrene nanoparticles and 6-PPD-quinone); no baseline developmental, metabolic, or immune phenotype, and no characterized null mutant, has been reported.
OPEN BIOLOGY BP_DARK
What is known: nhr-47 is expressed in neurons, ventral nerve cord, spermatheca, pharynx and intestine, and germline knockdown modulates transgenerational/reproductive toxicant responses, but a stand-alone required function under normal conditions has not been defined.
Significance: A defined loss-of-function phenotype would anchor NHR-47's biological process annotation, which is currently only family-propagated (IBA) or inferred from a toxicant-stress context.
Provenance (the field's own admissions):
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