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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 pathways—a 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 μM 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 3–12% 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 genes—roughly 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 divergence—approximately 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 (HNF4α and HNF4γ) 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 μM 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 (3–12%) 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 promoters—over 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 Doucette‐Stamm, 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 Doucette‐Stamm, 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 Doucette‐Stamm, 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.
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(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 Doucette‐Stamm, 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.