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.
|
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 โ curated, literature-grounded statements of the open unknowns (the inverse of core functions).
Gap: Whether NHR-47 binds an endogenous small-molecule ligand โ and, if so, its chemical identity โ 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):
The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.
You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.
We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.
We are interested in where in or outside the cell the gene product carries out its function.
We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.
Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.
NHR-47 (UniProt: Q17370) is a nuclear hormone receptor encoded by the gene nhr-47 (systematic/ORF name C24G6.4) on chromosome II of Caenorhabditis elegans. The gene carries an older synonym, csr-1, which must not be confused with the well-characterized CSR-1 Argonaute protein involved in small RNA pathwaysโa completely distinct gene product. NHR-47 contains an HNF4-like DNA-binding domain (IPR049636) and a nuclear hormone receptor ligand-binding domain (IPR000536), consistent with its classification as a member of the nuclear hormone receptor superfamily (Nuclear_hrmn_rcpt, IPR001723; Nuclear_hormone_rcpt_NR2, IPR050274).
The following table summarizes verified properties and available experimental data for NHR-47:
| Category | NHR-47 summary |
|---|---|
| Gene / protein identifiers | Gene name: nhr-47; Systematic name / ORF: C24G6.4; UniProt accession: Q17370; Reported synonym: csr-1 (must not be confused with the unrelated CSR-1 Argonaute gene) (novillo2005changesinnuclear pages 3-4) |
| Organism | Caenorhabditis elegans (novillo2005changesinnuclear pages 3-4) |
| Protein family | Nuclear hormone receptor (NHR); HNF4-like supplementary NHR within the nematode-expanded receptor family (taubert2011nuclearhormonereceptors pages 2-4, taubert2011nuclearhormonereceptors pages 1-2) |
| Core domains | HNF4-like DNA-binding domain and nuclear receptor ligand-binding domain; domain architecture is consistent with a canonical ligand-regulated transcription factor in the NHR superfamily (taubert2011nuclearhormonereceptors pages 2-4, taubert2011nuclearhormonereceptors pages 1-2) |
| Predicted molecular function | Putative ligand-dependent transcription factor / transcriptional regulator responding to lipophilic small molecules, inferred from its NHR family membership and HNF4-like architecture (taubert2011nuclearhormonereceptors pages 2-4, taubert2011nuclearhormonereceptors pages 1-2) |
| Direct experimental evidence: steroid responsiveness | Estradiol-induced upregulation: 10 ฮผM estradiol increased nhr-47 expression 3.4-fold in microarray analysis, identifying it as an estradiol-responsive NHR (novillo2005changesinnuclear pages 3-4) |
| Direct experimental evidence: C. elegans phenotype | Published RNAi experiments in C. elegans reported no observable phenotype for nhr-47, indicating either redundancy, condition-specific function, or weak effect under standard assay conditions (reported in Ciche et al. summarizing prior RNAi studies) (ciche2007postembryonicrnaiin pages 6-8) |
| Cross-species ortholog evidence | RNAi of the Heterorhabditis bacteriophora ortholog Hba-nhr-47 usually caused no obvious phenotype, with only 3โ12% sterility in some trials, supporting a subtle or context-dependent role (ciche2007postembryonicrnaiin pages 4-6, ciche2007postembryonicrnaiin pages 6-8) |
| Putative biological processes | Likely part of an estrogen-sensitive gene network associated with vitellogenesis, lipid availability, and broader metabolic/endocrine responses; however, no direct downstream targets have been established for nhr-47 itself (novillo2005changesinnuclear pages 3-4) |
| Predicted subcellular localization | Nucleus (inferred), because NHR-47 contains an HNF4-like DNA-binding domain and belongs to a family of nuclear transcription factors; no nhr-47-specific localization study was found (taubert2011nuclearhormonereceptors pages 2-4, taubert2011nuclearhormonereceptors pages 1-2) |
| Evolutionary context | Member of the nematode-specific expansion of HNF4-related receptors: C. elegans has 284 NHRs overall, including 269 supplementary NHRs (supnrs) derived from an ancient HNF4-like ancestor; this expansion is far larger than in humans or flies (arda2010functionalmodularityof pages 2-3, taubert2011nuclearhormonereceptors pages 2-4, taubert2011nuclearhormonereceptors pages 1-2, arda2010functionalmodularityof pages 9-10) |
| Broader functional context of family | HNF4-like C. elegans NHRs commonly regulate metabolism, fat storage/catabolism, xenobiotic responses, and physiological adaptation, often in modular gene-regulatory networks; nhr-47 is therefore plausibly metabolic/endocrine, though not directly characterized (arda2010functionalmodularityof pages 2-3, taubert2011nuclearhormonereceptors pages 2-4, arda2010functionalmodularityof pages 3-4) |
| Characterization status | Poorly characterized / orphan receptor. The literature provides direct evidence for steroid-responsive expression but little mechanistic information on ligands, tissue expression, target genes, or physiological necessity under standard conditions (novillo2005changesinnuclear pages 3-4, ciche2007postembryonicrnaiin pages 6-8) |
Table: This table consolidates verified identifiers, family/domain assignment, and the limited direct experimental evidence available for C. elegans NHR-47. It is useful as a high-confidence quick reference because the gene is sparsely characterized and easily confused with unrelated genes sharing similar names.
To understand NHR-47, it is essential to place it within the broader evolutionary and functional context of the massively expanded nuclear hormone receptor family in C. elegans. While the human genome encodes 48 NHRs and Drosophila has 18, the C. elegans genome encodes approximately 284 NHR genesโroughly six times the human complement (taubert2011nuclearhormonereceptors pages 1-2). Of these, only 15 are "conserved" NHRs belonging to five of the six metazoan NHR subfamilies (NR1, NR2, NR4, NR5, and NR6), while the remaining 269 are "supplementary NHRs" (supnrs) that appear to have derived from a single ancient HNF4-like ancestor through lineage-specific gene duplication events (taubert2011nuclearhormonereceptors pages 2-4). This expansion is one of the most dramatic in any metazoan transcription factor family, and the resulting supnrs show rapid evolutionary divergenceโapproximately 50% of NHRs in related nematode species such as C. briggsae and C. remanei are species-specific, indicating that NHRs evolve more rapidly than other transcription factor classes (arda2010functionalmodularityof pages 9-10).
NHR-47 belongs to this expanded HNF4-derived supplementary NHR class. Despite the large number of supnrs, only about 50 NHRs in C. elegans have known functions or detectable phenotypes when mutated or depleted (taubert2011nuclearhormonereceptors pages 1-2). NHR-47 is among the majority of these supplementary receptors that remain functionally uncharacterized.
As a canonical nuclear hormone receptor, NHR-47 is predicted to function as a ligand-dependent transcription factor. Nuclear hormone receptors typically bind small lipophilic molecules (ligands) through their C-terminal ligand-binding domain, undergo conformational changes, and regulate transcription of target genes by binding specific DNA response elements through their N-terminal zinc-finger DNA-binding domain. For NHR-47 specifically, no endogenous ligand has been identified, classifying it as an orphan receptor.
The HNF4-like domain architecture of NHR-47 places it in the NR2A class of nuclear receptors. In vertebrates, the HNF4 receptors (HNF4ฮฑ and HNF4ฮณ) play central roles in cholesterol, amino acid, carbohydrate, lipid, and xenobiotic metabolism, as well as liver-specific gene expression (novillo2005changesinnuclear pages 4-5). In C. elegans, where the intestine performs many of the metabolic functions of the vertebrate liver, HNF4-type NHRs have been shown to regulate fat storage and catabolism, xenobiotic detoxification, and physiological adaptation to environmental and nutritional cues (arda2010functionalmodularityof pages 2-3, arda2010functionalmodularityof pages 3-4). By extension, NHR-47 is plausibly involved in metabolic regulation, though direct evidence for this remains lacking.
The most direct functional data for nhr-47 comes from a microarray study by Novillo et al. (2005), which examined changes in nuclear receptor gene expression in C. elegans exposed to vertebrate steroids and cholesterol. This study demonstrated that 10 ฮผM estradiol induced a 3.4-fold upregulation of nhr-47 expression (novillo2005changesinnuclear pages 3-4). Importantly, each steroid tested (progesterone, estradiol, cholesterol) activated or inhibited entirely distinct subsets of NR genes, with no overlap between treatments, and estradiol specifically regulated 11 of 25 NRs identified as steroid-responsive (novillo2005changesinnuclear pages 1-1). The authors suggested that estradiol-responsive genes, including nhr-47, may constitute an estrogen-sensitive gene network related to vitellogenesis, since vitellogenin production depends on lipid availability to gastrointestinal cells involved in yolk protein synthesis (novillo2005changesinnuclear pages 3-4). This is biologically plausible given that the C. elegans intestine is the primary site of vitellogenin synthesis and that NHRs are known to respond to cholesterol-derived lipophilic signals in nematodes (novillo2005changesinnuclear pages 1-3, novillo2005changesinnuclear pages 5-6).
Published RNAi experiments of nhr-47 in C. elegans have reported no observable phenotype under standard laboratory conditions (ciche2007postembryonicrnaiin pages 6-8). This finding was noted across multiple independent genome-wide RNAi screens. In the related insect-parasitic nematode Heterorhabditis bacteriophora, RNAi of the ortholog Hba-nhr-47 also generally resulted in no observable defect, although very low-penetrance sterility (3โ12%) was noted in some experimental trials (ciche2007postembryonicrnaiin pages 4-6, ciche2007postembryonicrnaiin pages 6-8). The absence of a strong loss-of-function phenotype is consistent with three possible explanations: (1) functional redundancy among the many HNF4-derived supplementary NHRs, (2) a context- or condition-dependent role that is not revealed under standard culture conditions, or (3) a subtle function below the detection threshold of typical phenotypic screens.
A study of selfish toxin-antidote elements in Caenorhabditis species noted that the SLOW-1 protein, a toxin component in C. tropicalis that is homologous to nuclear hormone receptors, shares sequence similarity with C. elegans NHR-47 (17.9% identity) (bendavid2021ubiquitousselfishtoxinantidote pages 9-11). SLOW-1 retains an NHR ligand-binding domain but lacks the canonical DNA-binding domain and instead possesses transmembrane domains, suggesting it may function as a dominant-negative element that sequesters NHR ligands. While this does not directly inform NHR-47 function, it highlights the evolutionary versatility of the HNF4-derived NHR ligand-binding domain in nematodes and the potential for NHR-47-like proteins to interact with lipophilic signaling molecules.
No direct localization study has been performed for NHR-47. However, as a nuclear hormone receptor containing a zinc-finger DNA-binding domain, NHR-47 is predicted to localize to the nucleus, where it would function as a transcription factor. Well-characterized family members such as NHR-86 have been confirmed to localize predominantly to the nuclei of intestinal, excretory gland, and neuronal cells (arda2010functionalmodularityof pages 6-7), and NHR-49 functions in the nucleus to regulate target gene expression (motola2006identificationofligands pages 39-43). By analogy, NHR-47 is expected to occupy a similar nuclear compartment in metabolically active tissues.
The metabolic gene regulatory network (GRN) of C. elegans was experimentally mapped by Arda et al. (2010) using yeast one-hybrid assays, revealing that NHRs are significantly enriched as regulators of metabolic gene promotersโover one quarter of all transcription factors in the metabolic GRN are NHRs (arda2010functionalmodularityof pages 2-3). The metabolic GRN is highly modular, with approximately 60% of NHRs organized into two dominant modules that predominantly regulate genes involved in fat storage and catabolism (arda2010functionalmodularityof pages 3-4). RNAi of most NHRs in these modules resulted in increased lipid staining by Nile Red and Oil-Red-O, indicating roles in lipid metabolism (arda2010functionalmodularityof pages 3-4). These findings suggest that the expansion of the HNF4 family in nematodes has been functionally linked to metabolic regulation, with multiple supplementary NHRs sharing fat-regulatory roles after duplication and divergence.
Furthermore, the Mediator subunit MDT-15 has been identified as a key cofactor that preferentially interacts with metabolic NHRs, and several NHRs form regulatory cascades in which one NHR controls the expression of another (arda2010functionalmodularityof pages 5-6). These inter-NHR regulatory circuits are proposed to enable rapid and adaptive responses to environmental and physiological changes such as nutrient availability (arda2010functionalmodularityof pages 9-10).
NHR-47 remains a poorly characterized orphan nuclear hormone receptor. The available evidence establishes it as an estradiol-responsive member of the massively expanded HNF4-derived supplementary NHR family in C. elegans, but no endogenous ligand, specific target genes, tissue-specific expression pattern, or robust loss-of-function phenotype has been reported. Its function may be obscured by redundancy with other supplementary NHRs, or it may act under specific environmental, nutritional, or developmental conditions not routinely tested in laboratory screens. The protein's function can be inferred from its domain and family architecture: NHR-47 is most likely a ligand-dependent nuclear transcription factor involved in metabolic gene regulation, potentially participating in steroid/lipid-responsive signaling pathways related to vitellogenesis and lipid homeostasis. Future studies employing targeted knockouts, condition-specific screens (e.g., steroid exposure, dietary stress), and tissue-specific expression reporters will be needed to elucidate the precise biological role of this receptor.
References
(novillo2005changesinnuclear pages 3-4): A. Novillo, S. Won, Christine Li, and I. Callard. Changes in nuclear receptor and vitellogenin gene expression in response to steroids and heavy metal in caenorhabditis elegans1. Integrative and Comparative Biology, 45:61-71, Jan 2005. URL: https://doi.org/10.1093/icb/45.1.61, doi:10.1093/icb/45.1.61. This article has 59 citations and is from a peer-reviewed journal.
(taubert2011nuclearhormonereceptors pages 2-4): Stefan Taubert, Jordan D. Ward, and Keith R. Yamamoto. Nuclear hormone receptors in nematodes: evolution and function. Molecular and Cellular Endocrinology, 334:49-55, Mar 2011. URL: https://doi.org/10.1016/j.mce.2010.04.021, doi:10.1016/j.mce.2010.04.021. This article has 136 citations and is from a peer-reviewed journal.
(taubert2011nuclearhormonereceptors pages 1-2): Stefan Taubert, Jordan D. Ward, and Keith R. Yamamoto. Nuclear hormone receptors in nematodes: evolution and function. Molecular and Cellular Endocrinology, 334:49-55, Mar 2011. URL: https://doi.org/10.1016/j.mce.2010.04.021, doi:10.1016/j.mce.2010.04.021. This article has 136 citations and is from a peer-reviewed journal.
(ciche2007postembryonicrnaiin pages 6-8): Todd A Ciche and Paul W Sternberg. Postembryonic rnai in heterorhabditis bacteriophora: a nematode insect parasite and host for insect pathogenic symbionts. BMC Developmental Biology, 7:101-101, Sep 2007. URL: https://doi.org/10.1186/1471-213x-7-101, doi:10.1186/1471-213x-7-101. This article has 78 citations and is from a peer-reviewed journal.
(ciche2007postembryonicrnaiin pages 4-6): Todd A Ciche and Paul W Sternberg. Postembryonic rnai in heterorhabditis bacteriophora: a nematode insect parasite and host for insect pathogenic symbionts. BMC Developmental Biology, 7:101-101, Sep 2007. URL: https://doi.org/10.1186/1471-213x-7-101, doi:10.1186/1471-213x-7-101. This article has 78 citations and is from a peer-reviewed journal.
(arda2010functionalmodularityof pages 2-3): H Efsun Arda, Stefan Taubert, Lesley T MacNeil, Colin C Conine, Ben Tsuda, Marc Van Gilst, Reynaldo Sequerra, Lynn DoucetteโStamm, Keith R Yamamoto, and Albertha J M Walhout. Functional modularity of nuclear hormone receptors in a caenorhabditis elegans metabolic gene regulatory network. Molecular Systems Biology, 6:367-367, May 2010. URL: https://doi.org/10.1038/msb.2010.23, doi:10.1038/msb.2010.23. This article has 148 citations and is from a highest quality peer-reviewed journal.
(arda2010functionalmodularityof pages 9-10): H Efsun Arda, Stefan Taubert, Lesley T MacNeil, Colin C Conine, Ben Tsuda, Marc Van Gilst, Reynaldo Sequerra, Lynn DoucetteโStamm, Keith R Yamamoto, and Albertha J M Walhout. Functional modularity of nuclear hormone receptors in a caenorhabditis elegans metabolic gene regulatory network. Molecular Systems Biology, 6:367-367, May 2010. URL: https://doi.org/10.1038/msb.2010.23, doi:10.1038/msb.2010.23. This article has 148 citations and is from a highest quality peer-reviewed journal.
(arda2010functionalmodularityof pages 3-4): H Efsun Arda, Stefan Taubert, Lesley T MacNeil, Colin C Conine, Ben Tsuda, Marc Van Gilst, Reynaldo Sequerra, Lynn DoucetteโStamm, Keith R Yamamoto, and Albertha J M Walhout. Functional modularity of nuclear hormone receptors in a caenorhabditis elegans metabolic gene regulatory network. Molecular Systems Biology, 6:367-367, May 2010. URL: https://doi.org/10.1038/msb.2010.23, doi:10.1038/msb.2010.23. This article has 148 citations and is from a highest quality peer-reviewed journal.
(novillo2005changesinnuclear pages 4-5): A. Novillo, S. Won, Christine Li, and I. Callard. Changes in nuclear receptor and vitellogenin gene expression in response to steroids and heavy metal in caenorhabditis elegans1. Integrative and Comparative Biology, 45:61-71, Jan 2005. URL: https://doi.org/10.1093/icb/45.1.61, doi:10.1093/icb/45.1.61. This article has 59 citations and is from a peer-reviewed journal.
(novillo2005changesinnuclear pages 1-1): A. Novillo, S. Won, Christine Li, and I. Callard. Changes in nuclear receptor and vitellogenin gene expression in response to steroids and heavy metal in caenorhabditis elegans1. Integrative and Comparative Biology, 45:61-71, Jan 2005. URL: https://doi.org/10.1093/icb/45.1.61, doi:10.1093/icb/45.1.61. This article has 59 citations and is from a peer-reviewed journal.
(novillo2005changesinnuclear pages 1-3): A. Novillo, S. Won, Christine Li, and I. Callard. Changes in nuclear receptor and vitellogenin gene expression in response to steroids and heavy metal in caenorhabditis elegans1. Integrative and Comparative Biology, 45:61-71, Jan 2005. URL: https://doi.org/10.1093/icb/45.1.61, doi:10.1093/icb/45.1.61. This article has 59 citations and is from a peer-reviewed journal.
(novillo2005changesinnuclear pages 5-6): A. Novillo, S. Won, Christine Li, and I. Callard. Changes in nuclear receptor and vitellogenin gene expression in response to steroids and heavy metal in caenorhabditis elegans1. Integrative and Comparative Biology, 45:61-71, Jan 2005. URL: https://doi.org/10.1093/icb/45.1.61, doi:10.1093/icb/45.1.61. This article has 59 citations and is from a peer-reviewed journal.
(bendavid2021ubiquitousselfishtoxinantidote pages 9-11): Eyal Ben-David, Pinelopi Pliota, Sonya A. Widen, Alevtina Koreshova, Tzitziki Lemus-Vergara, Philipp Verpukhovskiy, Sridhar Mandali, Christian Braendle, Alejandro Burga, and Leonid Kruglyak. Ubiquitous selfish toxin-antidote elements in caenorhabditis species. Current Biology, 31:990-1001.e5, Mar 2021. URL: https://doi.org/10.1016/j.cub.2020.12.013, doi:10.1016/j.cub.2020.12.013. This article has 61 citations and is from a highest quality peer-reviewed journal.
(arda2010functionalmodularityof pages 6-7): H Efsun Arda, Stefan Taubert, Lesley T MacNeil, Colin C Conine, Ben Tsuda, Marc Van Gilst, Reynaldo Sequerra, Lynn DoucetteโStamm, Keith R Yamamoto, and Albertha J M Walhout. Functional modularity of nuclear hormone receptors in a caenorhabditis elegans metabolic gene regulatory network. Molecular Systems Biology, 6:367-367, May 2010. URL: https://doi.org/10.1038/msb.2010.23, doi:10.1038/msb.2010.23. This article has 148 citations and is from a highest quality peer-reviewed journal.
(motola2006identificationofligands pages 39-43): Daniel L. Motola, Carolyn L. Cummins, Veerle Rottiers, Kamalesh K. Sharma, Tingting Li, Yong Li, Kelly Suino-Powell, H. Eric Xu, Richard J. Auchus, Adam Antebi, and David J. Mangelsdorf. Identification of ligands for daf-12 that govern dauer formation and reproduction in c. elegans. Cell, 124:1209-1223, Mar 2006. URL: https://doi.org/10.1016/j.cell.2006.01.037, doi:10.1016/j.cell.2006.01.037. This article has 590 citations and is from a highest quality peer-reviewed journal.
(arda2010functionalmodularityof pages 5-6): H Efsun Arda, Stefan Taubert, Lesley T MacNeil, Colin C Conine, Ben Tsuda, Marc Van Gilst, Reynaldo Sequerra, Lynn DoucetteโStamm, Keith R Yamamoto, and Albertha J M Walhout. Functional modularity of nuclear hormone receptors in a caenorhabditis elegans metabolic gene regulatory network. Molecular Systems Biology, 6:367-367, May 2010. URL: https://doi.org/10.1038/msb.2010.23, doi:10.1038/msb.2010.23. This article has 148 citations and is from a highest quality peer-reviewed journal.
Gene: nhr-47 / sequence name C24G6.4 / WormBase WBGene00003637 / UniProt Q17370 (NHR47_CAEEL).
Locus: Chromosome V. Protein: 579 aa nuclear hormone receptor.
Inline provenance uses [PMID:xxxxx "verbatim quote"]. WormBase/Alliance-curated statements
(no direct primary PMID to hand) are marked [WormBase/AGR] and are NOT used as verbatim
supporting_text in the review; only cached-publication PMID quotes are used for that.
nhr-47 is one of the ~280 nuclear hormone receptors (NHRs) of C. elegans, the great majority of
which arose by a nematode-specific expansion of an ancestral HNF4-like orphan receptor and remain
functionally uncharacterized ("supplementary nuclear receptors", supnrs)
PMID:15983867. Its DNA-binding domain is HNF4-like (CDD cd06960 NR_DBD_HNF4A;
InterPro IPR049636 HNF4-like_DBD).
Alliance/WormBase automated + MOD-provided descriptions for WBGene00003637:
- Expressed in head neurons, tail neurons, ventral nerve cord, spermatheca, intestine, and pharynx.
- "gene expression of nhr-47 appears to be induced upon exposure of worm cultures to estradiol"
(WormBase MOD-provided gene description; primary microarray reference not located in cache โ recorded
here as curated context only, not used as review supporting_text).
Two toxicology studies from one group (Southeast University / Dayong Wang lab) are the only primary
papers that assign nhr-47 a phenotype, both in the germline and in an environmental-toxicant
context:
Under exposure, nhr-47 RNAi changes downstream secreted-ligand gene expression
PMID:38922100
(ins-3/ins-39/daf-28 = insulin ligands; efn-3 = Ephrin) โ i.e. nhr-47 sits upstream of insulin/Ephrin
signalling in this stress context. These are downstream/indirect readouts, NOT demonstrated direct targets.
6-PPD-quinone, reproductive toxicity PMID:40482507:
Consistent theme: in the germline, nhr-47 acts (with daf-12/nhr-14) as a positive mediator of
toxicant-induced reproductive/transgenerational toxicity; knocking it down is protective.
KNOWN:
- Molecular identity: zinc-finger, sequence-specific DNA-binding transcription factor of the
nuclear-receptor (HNF4-derived supnr) family; nuclear localization; binds zinc.
- Physically interacts with nhr-17.
- Expressed in neurons, ventral nerve cord, spermatheca, pharynx, intestine.
- Germline knockdown modulates susceptibility to two environmental toxicants (nanoplastics, 6-PPDQ),
positioning it upstream of insulin/Ephrin/Wnt ligand-gene expression in that stress context.
NOT KNOWN (knowledge gaps):
- Ligand: whether nhr-47 has any endogenous small-molecule ligand, and its identity โ it is an orphan
receptor, and supnrs may have altered/lost ligand-dependence
PMID:15983867.
- Direct target genes / response element: no ChIP, reporter, or motif defines the nhr-47 regulon;
it is unknown whether it is an activator or repressor, and whether the toxicant-context downstream
genes (ins-3, daf-28, efn-3, โฆ) are direct or indirect targets.
- Definitive loss-of-function role: no baseline null-mutant developmental/metabolic/immune phenotype;
the only phenotypes are germline RNAi effects in toxicant-challenge assays.
Genuine Edison "deep research" report (23-min run, 22 citations). Key points, each attributed
to the falcon-cited primary source (NOT independently full-text-verified here unless noted):
Synonyms=csr-1 for nhr-47 is an OLD locus synonym andNet effect on review: falcon corroborates the orphan/dark framing, the estradiol angle, and the
absence of a robust loss-of-function phenotype; it did not surface any definitive ligand, direct
target, or physiological role. No core-function or knowledge-gap conclusion was changed by it.
id: Q17370
gene_symbol: nhr-47
product_type: PROTEIN
status: COMPLETE
taxon:
id: NCBITaxon:6239
label: Caenorhabditis elegans
description: >-
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.
references:
- id: GO_REF:0000002
title: Gene Ontology annotation through association of InterPro records with GO
terms
findings: []
- id: GO_REF:0000033
title: Annotation inferences using phylogenetic trees
findings: []
- id: GO_REF:0000044
title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
vocabulary mapping, accompanied by conservative changes to GO terms applied by
UniProt
findings: []
- id: GO_REF:0000108
title: Automatic assignment of GO terms using logical inference, based on on inter-ontology
links
findings: []
- id: PMID:19123269
title: Empirically controlled mapping of the Caenorhabditis elegans protein-protein
interactome network.
findings: []
reference_review:
relevance: MEDIUM
correctness: VERIFIED
review_notes: >-
High-throughput yeast two-hybrid interactome (Worm Interactome / WI8). Underlies
one of the two GOA IPI protein-binding annotations for nhr-47. The specific
NHR-47<->NHR-17 edge is recorded in IntAct/UniProt (with_from UniProtKB:Q17589);
the paper text itself reports the network methodology rather than naming nhr-47,
so no gene-specific verbatim quote is available from the cached full text.
- id: PMID:23791784
title: Extensive rewiring and complex evolutionary dynamics in a C. elegans multiparameter
transcription factor network.
findings: []
reference_review:
relevance: MEDIUM
correctness: VERIFIED
review_notes: >-
C. elegans multiparameter transcription-factor network (protein-DNA, protein-protein,
TF-TF). Underlies the second GOA IPI protein-binding annotation for nhr-47 (again
with NHR-17, UniProtKB:Q17589). Abstract-only in cache; the interaction is captured
in IntAct rather than quoted verbatim in the available text.
- id: PMID:15983867
title: Explosive lineage-specific expansion of the orphan nuclear receptor HNF4 in
nematodes.
findings: []
reference_review:
relevance: HIGH
correctness: VERIFIED
review_notes: >-
Establishes the phylogenetic context for nhr-47: the C. elegans supplementary
nuclear receptors (supnrs), including the HNF4-like DBD class to which nhr-47
belongs, arose from an explosive HNF4 duplication and are predominantly orphan
receptors with uncertain ligand-dependence. Cited in the UniProt entry for Q17370.
- id: PMID:38922100
title: Transgenerational Response of Germline Nuclear Hormone Receptor Genes to Nanoplastics
at Predicted Environmental Doses in Caenorhabditis elegans.
findings: []
reference_review:
relevance: HIGH
correctness: VERIFIED
review_notes: >-
Primary functional study naming nhr-47: germline-expressed, up-regulated by
polystyrene nanoparticles, and germline RNAi confers resistance to transgenerational
nanoplastic toxicity, with downstream effects on insulin/Ephrin ligand-gene
expression. One of only two primary papers reporting an nhr-47 phenotype. Full text
is MDPI-hosted and not downloadable by the validator, so supporting_text quotes are
taken from the abstract only.
- id: PMID:40482507
title: 6-PPD quinone induces response of nuclear hormone receptors in the germline
associated with formation of reproductive toxicity in Caenorhabditis elegans.
findings: []
reference_review:
relevance: HIGH
correctness: VERIFIED
review_notes: >-
Second primary functional study naming nhr-47: knockdown suppresses 6-PPD-quinone
reproductive toxicity, and nhr-47 expression is modulated by DNA-damage-checkpoint
and ferroptosis-related signals. Abstract-only in cache but the nhr-47 result is
explicit in the abstract.
- id: PMID:21676746
title: Changes in Nuclear Receptor and Vitellogenin Gene Expression in Response to
Steroids and Heavy Metal in Caenorhabditis elegans.
findings: []
reference_review:
relevance: MEDIUM
correctness: VERIFIED
review_notes: >-
DNA-microarray study of steroid-responsive nuclear-receptor gene expression in
C. elegans; it is the primary source of the WormBase-curated statement that nhr-47
is induced by estradiol (full text reports ~3.4-fold induction by 10 uM estradiol).
The cached PubMed abstract does not name nhr-47 (the per-gene value is in the full
text / supplementary data), so no gene-specific verbatim supporting_text is attached
to this reference; it is cited as the estradiol-responsiveness source only.
existing_annotations:
- term:
id: GO:0005634
label: nucleus
evidence_type: IBA
original_reference_id: GO_REF:0000033
qualifier: is_active_in
review:
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.
action: ACCEPT
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.
- term:
id: GO:0000978
label: RNA polymerase II cis-regulatory region sequence-specific DNA binding
evidence_type: IBA
original_reference_id: GO_REF:0000033
qualifier: enables
review:
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.
action: ACCEPT
reason: >-
Consistent with the conserved NR DBD architecture and phylogenetic placement in
the HNF4-like DNA-binding-domain class. A core molecular function.
- term:
id: GO:0004879
label: nuclear receptor activity
evidence_type: IBA
original_reference_id: GO_REF:0000033
qualifier: enables
review:
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.
action: ACCEPT
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.
- term:
id: GO:0006357
label: regulation of transcription by RNA polymerase II
evidence_type: IBA
original_reference_id: GO_REF:0000033
qualifier: involved_in
review:
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.
action: ACCEPT
reason: >-
Directly follows from the nuclear-receptor / DNA-binding-TF molecular function and
nuclear localization. Core process.
- term:
id: GO:0030154
label: cell differentiation
evidence_type: IBA
original_reference_id: GO_REF:0000033
qualifier: involved_in
review:
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.
action: KEEP_AS_NON_CORE
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.
- term:
id: GO:0000978
label: RNA polymerase II cis-regulatory region sequence-specific DNA binding
evidence_type: IEA
original_reference_id: GO_REF:0000002
qualifier: enables
review:
summary: >-
InterPro2GO assignment (IPR049636, HNF4-like DBD) of the same sequence-specific
Pol II DNA-binding function, in agreement with the IBA annotation above.
action: ACCEPT
reason: >-
Independent InterPro domain-based support for the core sequence-specific DNA-binding
molecular function. Consistent with the phylogenetic annotation.
- term:
id: GO:0003700
label: DNA-binding transcription factor activity
evidence_type: IEA
original_reference_id: GO_REF:0000002
qualifier: enables
review:
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.
action: ACCEPT
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).
- term:
id: GO:0005634
label: nucleus
evidence_type: IEA
original_reference_id: GO_REF:0000044
qualifier: located_in
review:
summary: >-
Nuclear localization from UniProt Swiss-Prot subcellular-location mapping (SL-0191),
consistent with the IBA nucleus annotation.
action: ACCEPT
reason: >-
Independent support for nuclear localization of this transcription factor. Core CC.
- term:
id: GO:0006355
label: regulation of DNA-templated transcription
evidence_type: IEA
original_reference_id: GO_REF:0000002
qualifier: involved_in
review:
summary: >-
General (DNA-templated) transcription-regulation term from InterPro. This is the
broad parent of the RNA Pol II-specific regulation term.
action: KEEP_AS_NON_CORE
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.
- term:
id: GO:0008270
label: zinc ion binding
evidence_type: IEA
original_reference_id: GO_REF:0000002
qualifier: enables
review:
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.
action: ACCEPT
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.
- term:
id: GO:0030522
label: intracellular receptor signaling pathway
evidence_type: IEA
original_reference_id: GO_REF:0000108
qualifier: involved_in
review:
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.
action: KEEP_AS_NON_CORE
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.
- term:
id: GO:0043565
label: sequence-specific DNA binding
evidence_type: IEA
original_reference_id: GO_REF:0000002
qualifier: enables
review:
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.
action: ACCEPT
reason: >-
Supported by the conserved C4 zinc-finger DBD. Core MF (parent of GO:0000978).
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:19123269
qualifier: enables
review:
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.
action: KEEP_AS_NON_CORE
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.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:23791784
qualifier: enables
review:
summary: >-
Second experimental interaction annotation (C. elegans multiparameter TF network),
again with NHR-17 (UniProtKB:Q17589). Uninformative "protein binding" term.
action: KEEP_AS_NON_CORE
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.
core_functions:
- description: >-
Sequence-specific DNA-binding transcription factor of the nuclear-receptor
superfamily. NHR-47 carries the diagnostic nuclear-receptor DNA-binding domain
formed by two C4-type (Cys4) zinc-finger motifs that coordinate zinc, together with
a C-terminal ligand-binding domain. Acting in the nucleus, it binds RNA polymerase
II cis-regulatory regions in a sequence-specific manner to regulate transcription.
It is an orphan receptor (no ligand identified), belonging to the HNF4-derived
supplementary nuclear receptor class of C. elegans.
molecular_function:
id: GO:0004879
label: nuclear receptor activity
directly_involved_in:
- id: GO:0006357
label: regulation of transcription by RNA polymerase II
locations:
- id: GO:0005634
label: nucleus
supported_by:
- reference_id: PMID:15983867
- description: >-
Zinc-dependent, sequence-specific DNA binding. The two C4 zinc fingers of the NR
DNA-binding domain coordinate zinc and mediate recognition of specific DNA
response elements, providing the biochemical basis for NHR-47 transcription-factor
activity.
molecular_function:
id: GO:0043565
label: sequence-specific DNA binding
locations:
- id: GO:0005634
label: nucleus
supported_by:
- reference_id: PMID:15983867
knowledge_gaps:
- gap_statement: >-
Whether NHR-47 binds an endogenous small-molecule ligand โ and, if so, its
chemical identity โ 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.
boundary: >-
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.
gap_kind:
- BIOLOGY
dark_aspect: MF_DARK
status: OPEN
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:
- reference_id: PMID:15983867
supporting_text: >-
This origin has specific implications for the role of ligand binding in the
function and evolution of the nematode supplementary nuclear receptors.
- gap_statement: >-
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.
boundary: >-
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.
gap_kind:
- BIOLOGY
- CURATION
dark_aspect: MF_DARK
status: OPEN
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:
- reference_id: PMID:38922100
supporting_text: >-
expressions of ins-3, daf-28, and ins-39 encoding insulin ligands, efn-3 encoding
Ephrin ligand, and lin-44 encoding Wnt ligand, as well as expressions of their
receptor genes (daf-2, vab-1, and/or mig-1), were dysregulated by the RNAi of
daf-12, nhr-14, nhr-47, and nhr-12
- gap_statement: >-
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.
boundary: >-
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.
gap_kind:
- BIOLOGY
dark_aspect: BP_DARK
status: OPEN
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:
- reference_id: PMID:38922100
supporting_text: >-
RNAi of daf-12, nhr-14, and nhr-47 caused resistance, whereas RNAi of nhr-12
conferred susceptibility to transgenerational PS-NP toxicity
- reference_id: PMID:40482507
supporting_text: >-
6-PPDQ reproductive toxicity was suppressed by nhr-47, nhr-14, daf-12, and nhr-249
RNAi and accelerated by nhr-12, nhr-145, and nhr-171 RNAi
suggested_questions:
- question: >-
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?
experts:
- Nuclear-receptor biochemists
- C. elegans NHR-family biologists
- question: >-
What are the direct genomic binding sites and target genes of NHR-47, and does it act
as a transcriptional activator or repressor?
experts:
- Transcription / gene-regulatory-network biologists
- question: >-
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?
experts:
- C. elegans developmental / germline biologists
suggested_experiments:
- experiment_type: Genome-wide binding assay
description: >-
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.
- experiment_type: Ligand identification
description: >-
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.
- experiment_type: Loss-of-function phenotyping
description: >-
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.