NHR-49 is an orphan nuclear hormone receptor of the HNF4 family that serves as a central transcriptional regulator of lipid metabolism in C. elegans, functionally analogous to mammalian PPARalpha. NHR-49 controls two major metabolic branches: (1) fatty acid beta-oxidation, by promoting expression of acs-2, ech-1, cpt-5, and other mitochondrial beta-oxidation genes, and (2) fatty acid desaturation, by activating delta-9 desaturases fat-5 and fat-7 (with modest effects on fat-6). NHR-49 operates through distinct heterodimeric partnerships: NHR-49/NHR-80 regulates desaturation genes, NHR-49/NHR-66 represses sphingolipid and lipid remodeling genes, and NHR-49/NHR-13 also contributes to desaturase regulation. NHR-49 also interacts with the Mediator subunit MDT-15 as a transcriptional coactivator. Loss of nhr-49 causes dramatically shortened lifespan (~41% reduction), increased fat storage, and altered fatty acid composition with elevated stearic-to-oleic acid ratio. NHR-49 is required for LIPL-4/LBP-8-mediated longevity signaling (acting as a cofactor with NHR-80, which is the direct OEA receptor), for germline-loss-mediated longevity (where it is transcriptionally upregulated by DAF-16 and TCER-1), and for hypoxia adaptation in parallel with HIF-1. NHR-49 also participates in transgenerational epigenetic inheritance of lipid accumulation from high-fat diet, functioning as an executor but not a transmitter of heritable memory. NHR-49 is expressed broadly in somatic tissues including intestine, neurons, hypodermis, and muscle, localizing to both nucleus and cytoplasm. It is an orphan receptor with no confirmed endogenous ligand; NHR-49 does not bind oleoylethanolamide (OEA), unlike its partner NHR-80.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005634 nucleus | IBA GO_REF:0000033 | ACCEPT | Summary: NHR-49 is a nuclear hormone receptor with a predicted nuclear localization based on its DNA-binding domain (PROSITE-ProRule:PRU00407). Multiple experimental studies confirm nuclear localization: NHR-49::GFP is visible in nuclei of neurons, muscle, hypodermis, and intestinal cells (PMID:25474470), and nuclear localization is increased upon germline removal. The IBA annotation from phylogenetic inference is fully consistent with these experimental data. Reason: Nuclear localization is a core feature of NHR-49 as a nuclear hormone receptor transcription factor. IDA evidence (PMID:25474470) directly confirms this IBA annotation. NHR-49::GFP localizes to nuclei in multiple somatic tissues. Falcon deep research notes NHR-49 is broadly expressed in multiple tissues including intestine and neurons. Supporting Evidence: PMID:25474470 NHR-49::GFP is visible in the cytoplasm and nuclei of neurons (E), muscle (F), hypodermis (G) and intestinal cells (H). file:worm/nhr-49/nhr-49-deep-research-falcon.md Broadly expressed in multiple tissues, including **intestine** and **neurons** |
| GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding | IBA GO_REF:0000033 | ACCEPT | Summary: NHR-49 contains a conserved zinc-finger DNA-binding domain (HNF4-like, InterPro IPR049636) and functions as a transcription factor that activates target gene promoters including acs-2, fat-5, fat-7, and fmo-2 (PMID:15719061, PMID:22511885, PMID:35285794). The IBA annotation from phylogenetic inference is consistent with NHR-49 being a nuclear receptor that binds DNA in a sequence-specific manner, although direct cis-regulatory binding assays (e.g., ChIP) have not been published specifically for NHR-49. Reason: NHR-49 has a well-characterized zinc-finger DNA-binding domain and controls transcription of specific target genes. The IBA annotation is phylogenetically sound for this HNF4 family member. It is reasonable that NHR-49 binds cis-regulatory regions of its target gene promoters to achieve the highly specific transcriptional effects documented across multiple studies. Falcon deep research describes NHR-49 as a sequence-specific transcription factor that both activates and represses metabolic gene programs. Supporting Evidence: PMID:15719061 Our screen revealed that deletion of nhr-49 significantly altered the expression of 13 genes, including six genes predicted to be involved in fatty acid Ξ²-oxidation, three genes involved in fatty acid desaturation PMID:22511885 We show that NHR-49 regulates distinct subsets of its target genes by partnering with at least two other distinct nuclear receptors file:worm/nhr-49/nhr-49-deep-research-falcon.md NHR-49 acts as a **transcriptional regulator** that can both **activate** and **repress** metabolic gene programs |
| GO:0004879 nuclear receptor activity | IBA GO_REF:0000033 | ACCEPT | Summary: NHR-49 is an established member of the nuclear hormone receptor family, containing both a zinc-finger DNA-binding domain and a ligand-binding domain (NR LBD, PROSITE PRU01189). It is classified as an orphan nuclear receptor, as no endogenous ligand has been confirmed (PMID:25554789 showed NHR-49 does not bind OEA). NHR-49 functions as a ligand-independent or orphan transcription factor that regulates lipid metabolism genes (PMID:15719061, PMID:22511885). Reason: Nuclear receptor activity is a core molecular function of NHR-49. It has the characteristic NHR domain architecture (DBD + LBD) and functions as a transcriptional regulator through DNA binding and partner interactions. The IBA annotation accurately captures this fundamental function. Falcon deep research independently confirms NHR-49 as a sequence-specific nuclear receptor transcription factor functionally comparable to mammalian PPARalpha and HNF4alpha, and notes that despite a functionally important ligand-binding domain, no definitive endogenous ligand is established (orphan receptor). Supporting Evidence: PMID:15719061 deletion of the Caenorhabditis elegans NHR gene nhr-49 yielded worms with elevated fat content and shortened life span PMID:25554789 no binding was detected between NHR-49 and OEA or OEA analogue file:worm/nhr-49/nhr-49-deep-research-falcon.md NHR-49 is a sequence-specific transcription factor of the nuclear receptor superfamily file:worm/nhr-49/nhr-49-deep-research-falcon.md a definitive endogenous ligand for NHR-49 is not established |
| GO:0006357 regulation of transcription by RNA polymerase II | IBA GO_REF:0000033 | ACCEPT | Summary: NHR-49 is a transcription factor that regulates expression of numerous target genes involved in fatty acid beta-oxidation and desaturation (PMID:15719061), sphingolipid processing (PMID:22511885), hypoxia response (PMID:35285794), and autophagy genes. It works with the Mediator subunit MDT-15 as a transcriptional coactivator (PMID:16651656), placing it squarely in the Pol II transcription regulatory machinery. Reason: Regulation of Pol II transcription is a core biological process for NHR-49. Multiple studies demonstrate its role in activating and repressing transcription of specific gene sets through partnerships with other NHRs and with the Mediator complex. The IBA annotation is well supported. Falcon deep research reinforces the central role of MDT-15 (Mediator subunit) as a critical co-regulator across NHR-49 transcriptional outputs in both metabolism and stress programs. Supporting Evidence: PMID:16651656 we report the identification of MDT-15, a subunit of the C. elegans Mediator complex, as an NHR-49-interacting protein and transcriptional coactivator PMID:15719061 nhr-49 is extensively involved in the control of fatty acid metabolism, with a pronounced role in the promotion of mitochondrial Ξ²-oxidation and fatty acid desaturation file:worm/nhr-49/nhr-49-deep-research-falcon.md MDT-15 (Mediator subunit)** as a critical co-regulator for NHR-49-driven transcriptional outputs |
| GO:0030154 cell differentiation | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: There is no direct experimental evidence that NHR-49 plays a role in cell differentiation in C. elegans. The original Van Gilst 2005 study explicitly noted that nhr-49 deletion did not noticeably affect development or fertility (PMID:15719061). NHR-49 is primarily a metabolic regulator. The IBA annotation may reflect a conserved role in HNF4 family members in vertebrates (where HNF4alpha has roles in liver and intestinal differentiation), but this function has not been demonstrated for nhr-49 in C. elegans. Reason: While HNF4 family members in vertebrates play roles in cell differentiation, NHR-49 in C. elegans is characterized as a metabolic regulator with no documented role in cell differentiation. Loss of nhr-49 does not affect development or fertility (PMID:15719061). This IBA annotation likely over-extrapolates from vertebrate HNF4 functions that are not conserved in the nematode lineage. Falcon deep research consistently characterizes NHR-49 as a metabolic and stress-resilience regulator with no documented role in cell differentiation, supporting this over-annotation call. Supporting Evidence: PMID:15719061 Although nhr-49 deletion did not noticeably affect development or fertility, nhr-49(nr2041) worms experienced rapid decline in function beginning around day 3 of adulthood file:worm/nhr-49/nhr-49-deep-research-falcon.md NHR-49 coordinates transcriptional programs that balance lipid catabolism |
| GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding | IEA GO_REF:0000002 | ACCEPT | Summary: This IEA annotation from InterPro domain mapping duplicates the IBA annotation for the same term. NHR-49 contains a HNF4-like DNA-binding domain (InterPro IPR049636) and a nuclear receptor zinc finger (IPR001628), consistent with sequence-specific DNA binding at Pol II cis-regulatory regions. Reason: The InterPro-based IEA annotation is consistent with NHR-49 domain architecture and its demonstrated function as a transcription factor. It is broader than the IBA annotation for the same term, but both are acceptable annotations for the same GO term from different evidence sources. Supporting Evidence: PMID:15719061 Our screen revealed that deletion of nhr-49 significantly altered the expression of 13 genes, including six genes predicted to be involved in fatty acid Ξ²-oxidation, three genes involved in fatty acid desaturation |
| GO:0003700 DNA-binding transcription factor activity | IEA GO_REF:0000002 | ACCEPT | Summary: NHR-49 is a well-established DNA-binding transcription factor that regulates expression of multiple target genes. However, the more specific term GO:0004879 (nuclear receptor activity) is already annotated via IBA and better captures the molecular function. This broader IEA term is not wrong but is less informative than the more specific nuclear receptor activity annotation. Reason: While GO:0004879 (nuclear receptor activity) is more specific and already annotated, this broader IEA annotation from InterPro is not incorrect. It is acceptable to retain both a broader IEA and a more specific IBA annotation for the same gene. Supporting Evidence: PMID:15719061 nhr-49 is extensively involved in the control of fatty acid metabolism, with a pronounced role in the promotion of mitochondrial Ξ²-oxidation and fatty acid desaturation |
| GO:0005634 nucleus | IEA GO_REF:0000044 | ACCEPT | Summary: This IEA annotation from UniProt subcellular location mapping is consistent with NHR-49 nuclear localization confirmed by IDA evidence (PMID:25474470) and IBA. UniProt lists nuclear localization based on PROSITE-ProRule:PRU00407. Reason: The IEA annotation is correct and supported by multiple lines of experimental evidence for nuclear localization. It duplicates the IBA and IDA annotations for the same term but from a different evidence source, which is acceptable. Supporting Evidence: PMID:25474470 NHR-49::GFP is visible in the cytoplasm and nuclei of neurons (E), muscle (F), hypodermis (G) and intestinal cells (H). |
| GO:0006355 regulation of DNA-templated transcription | IEA GO_REF:0000002 | ACCEPT | Summary: This IEA annotation is a broader parent term of GO:0006357 (regulation of transcription by RNA polymerase II), which is annotated via IBA. NHR-49 clearly regulates DNA-templated transcription of numerous target genes (PMID:15719061, PMID:22511885, PMID:16651656). Reason: The annotation is correct. While it is broader than the IBA annotation for Pol II-specific regulation, it is not incorrect to retain both. NHR-49 is fundamentally a transcriptional regulator. Supporting Evidence: PMID:15719061 Our screen revealed that deletion of nhr-49 significantly altered the expression of 13 genes |
| GO:0008270 zinc ion binding | IEA GO_REF:0000002 | ACCEPT | Summary: NHR-49 contains two NR C4-type zinc finger motifs (residues 11-31 and 47-71) within its DNA-binding domain, as annotated in UniProt based on PROSITE-ProRule:PRU00407. Zinc coordination is essential for the structural integrity of the nuclear receptor DNA-binding domain. Reason: The zinc ion binding annotation is correct based on the well-characterized C4-type zinc finger motifs in the NHR-49 DNA-binding domain. This is a structural feature inherent to all nuclear hormone receptors. Supporting Evidence: PMID:15719061 nhr-49(nr2041), which harbors a deletion in the nhr-49 gene encompassing part of the DNA binding domain and more than half of the ligand binding domain |
| GO:0030522 intracellular receptor signaling pathway | IEA GO_REF:0000108 | ACCEPT | Summary: NHR-49 is an intracellular (nuclear) receptor that transduces signals by regulating transcription. Although it is an orphan receptor with no confirmed endogenous ligand, NHR-49 functions as a cofactor with NHR-80 in the LIPL-4/LBP-8/OEA lysosome-to-nucleus signaling pathway (PMID:25554789) and responds to germline signals via DAF-16/TCER-1 upregulation (PMID:25474470). The annotation derived from logical inference based on the nuclear receptor activity annotation is reasonable. Reason: NHR-49 participates in intracellular receptor signaling as a nuclear receptor transcription factor. Even though it is orphan (no direct ligand), it functions within signaling pathways that regulate its activity and target gene expression. The IEA annotation from logical inference is appropriate. Falcon deep research reaffirms NHR-49 as an orphan nuclear receptor whose ligand-binding domain is functionally important but for which no definitive endogenous ligand is established. Supporting Evidence: PMID:25554789 Nuclear hormone receptors nhr-49 and nhr-80, previously demonstrated to physically interact (10), were both required for lipl-4βand lbp-8βmediated longevity PMID:25474470 NHR-49 is transcriptionally up-regulated by DAF-16 and TCER-1 in the soma upon germline removal file:worm/nhr-49/nhr-49-deep-research-falcon.md a definitive endogenous ligand for NHR-49 is not established |
| GO:0043565 sequence-specific DNA binding | IEA GO_REF:0000002 | ACCEPT | Summary: NHR-49 contains a conserved HNF4-like DNA-binding domain with two C4-type zinc fingers. This IEA annotation is a parent of the more specific GO:0000978 (RNA polymerase II cis-regulatory region sequence-specific DNA binding) already annotated. It is correct but less specific. Reason: The annotation is correct. NHR-49 binds DNA in a sequence-specific manner through its zinc finger DNA-binding domain. While more specific annotations exist, the IEA from InterPro is not incorrect. Supporting Evidence: PMID:15719061 nhr-49 is extensively involved in the control of fatty acid metabolism, with a pronounced role in the promotion of mitochondrial Ξ²-oxidation and fatty acid desaturation |
| GO:0005515 protein binding | IPI PMID:14704431 A map of the interactome network of the metazoan C. elegans. | MODIFY | Summary: PMID:14704431 (Li et al. 2004) reports a high-throughput yeast two-hybrid interactome mapping study for C. elegans. NHR-49 was identified as an interactor in this screen. However, the generic term protein binding is uninformative. From subsequent focused studies, NHR-49 has been shown to physically interact with specific partners including NHR-80, NHR-66, NHR-13, and MDT-15 (PMID:22511885, PMID:16651656). A more specific term such as DNA-binding transcription factor binding (GO:0140297) would be more appropriate. Reason: Protein binding is too vague for NHR-49, whose protein interactions are well characterized. The high-throughput Y2H screen identified interactions that are better captured by more specific terms. NHR-49 interacts with other transcription factors (NHR-80, NHR-66, NHR-13) and the Mediator coactivator MDT-15. GO:0140297 (DNA-binding transcription factor binding) better describes these interactions. Proposed replacements: DNA-binding transcription factor binding Supporting Evidence: PMID:22511885 We show that NHR-49 regulates distinct subsets of its target genes by partnering with at least two other distinct nuclear receptors PMID:16651656 we report the identification of MDT-15, a subunit of the C. elegans Mediator complex, as an NHR-49-interacting protein and transcriptional coactivator |
| GO:0005515 protein binding | IPI PMID:16651656 A Mediator subunit, MDT-15, integrates regulation of fatty a... | MODIFY | Summary: PMID:16651656 (Taubert et al. 2006) identified MDT-15, a Mediator subunit, as a physical interacting partner and transcriptional coactivator of NHR-49. The interaction was shown through yeast two-hybrid and functional studies. The generic protein binding term fails to capture this specific and functionally important interaction with the Mediator complex. Reason: The interaction between NHR-49 and MDT-15 (Mediator subunit) represents a transcription factor-coactivator interaction. GO:0140297 (DNA-binding transcription factor binding) is more appropriate, as MDT-15 is itself a transcriptional coregulator. Proposed replacements: DNA-binding transcription factor binding Supporting Evidence: PMID:16651656 we report the identification of MDT-15, a subunit of the C. elegans Mediator complex, as an NHR-49-interacting protein and transcriptional coactivator. Knockdown of mdt-15 by RNA interference (RNAi) prevented fasting-induced mRNA accumulation of NHR-49 targets in vivo |
| GO:0005515 protein binding | IPI PMID:19123269 Empirically controlled mapping of the Caenorhabditis elegans... | MODIFY | Summary: PMID:19123269 (Simonis et al. 2009) is a high-throughput yeast two-hybrid interactome mapping study that provides expanded coverage of C. elegans protein-protein interactions. Similar to PMID:14704431, the generic protein binding term is uninformative for NHR-49, whose specific interaction partners are well characterized. Reason: As with the other protein binding annotations, a more specific term is warranted. NHR-49 interacts with other NHRs and the Mediator complex. GO:0140297 (DNA-binding transcription factor binding) better describes the interactions detected. Proposed replacements: DNA-binding transcription factor binding Supporting Evidence: PMID:22511885 We show that NHR-49 regulates distinct subsets of its target genes by partnering with at least two other distinct nuclear receptors |
| GO:0005515 protein binding | IPI PMID:23791784 Extensive rewiring and complex evolutionary dynamics in a C.... | MODIFY | Summary: PMID:23791784 (Reece-Hoyes et al. 2013) characterized transcription factor network rewiring in C. elegans through systematic Y2H and other interaction assays. The study found that even highly similar TFs often have different interaction partners. For NHR-49, this provides network context but the generic protein binding annotation is too vague. Reason: The protein binding term is too generic for NHR-49. The interactions detected in this TF network study are primarily TF-TF interactions. GO:0140297 (DNA-binding transcription factor binding) is more specific and appropriate. Proposed replacements: DNA-binding transcription factor binding Supporting Evidence: PMID:23791784 we comprehensively characterize such network rewiring for C. elegans transcription factors (TFs) within and across four newly delineated molecular networks |
| GO:0140297 DNA-binding transcription factor binding | IPI PMID:22511885 Coordinate regulation of lipid metabolism by novel nuclear r... | ACCEPT | Summary: PMID:22511885 (Pathare et al. 2012) demonstrated that NHR-49 physically interacts with multiple nuclear hormone receptors including NHR-80, NHR-66, NHR-13, NHR-22, NHR-79, NHR-105, and NHR-256, forming both homodimers and heterodimers. Direct physical interactions were confirmed for NHR-49/NHR-80 and NHR-49/NHR-66 by yeast two-hybrid and functional studies. This term accurately captures NHR-49 binding to other DNA-binding transcription factors. Reason: This annotation accurately describes the well-characterized physical interactions between NHR-49 and other NHRs (NHR-80, NHR-66, NHR-13). The term is specific and informative, directly supported by the referenced study. Falcon deep research independently summarizes the context-dependent NHR partnerships (NHR-80 for desaturase genes, NHR-66 for sphingolipid/lipid remodeling genes). Supporting Evidence: PMID:22511885 We show that NHR-49 regulates distinct subsets of its target genes by partnering with at least two other distinct nuclear receptors PMID:22511885 Gene expression profiles suggest that NHR-49 partners with NHR-66 to regulate sphingolipid and lipid remodeling genes and with NHR-80 to regulate genes involved in fatty acid desaturation file:worm/nhr-49/nhr-49-deep-research-falcon.md NHR-49 was shown to regulate distinct gene subsets via **partnerships with other NHRs** file:worm/nhr-49/nhr-49-deep-research-falcon.md **NHR-80**: linked to regulation of **fatty-acid desaturase** genes. |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IMP PMID:24854345 PKG and NHR-49 signalling co-ordinately regulate short-term ... | ACCEPT | Summary: PMID:24854345 (Huang et al. 2014) showed that NHR-49 acts in the intestine during short-term fasting to regulate lysosomal lipid accumulation, coordinating with PKG/EGL-4 signaling. NHR-49 activates expression of IPLA-2 and other hydrolases in response to fasting. The positive regulation of transcription annotation is consistent with NHR-49 activating target gene expression in this context. Reason: NHR-49 positively regulates transcription of target genes including acs-2, fat-5, fat-7, fmo-2, and genes involved in fasting responses. The IMP evidence from the fasting study supports this annotation, though the annotation captures a general function rather than the specific fasting context. Supporting Evidence: PMID:24854345 NHR-49 acts in intestine to inhibit lipids accumulation via activation of IPLA-2 |
| GO:0008340 determination of adult lifespan | IGI PMID:24107417 TAF-4 is required for the life extension of isp-1, clk-1 and... | ACCEPT | Summary: PMID:24107417 (Khan et al. 2013) identified NHR-49 among transcription factors whose RNAi knockdown affected development, stress response, or fecundity of isp-1 mitochondrial (Mit) mutants. The study examined lifespan in Mit mutants. NHR-49 is listed alongside HIF-1 and other TFs that affect Mit mutant lifespan. This is consistent with NHR-49 having a role in lifespan determination, particularly in the context of mitochondrial function. Reason: NHR-49 has a well-established role in determination of adult lifespan. Loss of nhr-49 causes ~41% reduction in lifespan (PMID:15719061, PMID:16839188), and it is required for longevity mediated by germline loss (PMID:25474470) and LIPL-4 signaling (PMID:25554789). The IGI evidence from the Mit mutant context adds another dimension to this core function. Supporting Evidence: PMID:24107417 Seven of these transcription factors--AHA-1, CEH-18, HIF-1, JUN-1, NHR-27, NHR-49 and the CREB homolog-1 (CRH-1)-interacting protein TAF-4--were also essential for isp-1 life extension. PMID:15719061 nhr-49(nr2041) worms lived only 6β8 d as adults, significantly shorter than the 15 to 18-d life span of N2 wild-type (WT) animals |
| GO:0005634 nucleus | IDA PMID:25474470 Germline signals deploy NHR-49 to modulate fatty-acid Ξ²-oxid... | ACCEPT | Summary: PMID:25474470 (Ratnappan et al. 2014) directly demonstrated NHR-49::GFP localization to both nuclei and cytoplasm in adult somatic tissues, with highest expression in intestinal cells. Nuclear localization was especially prominent upon germline removal. Reason: Direct experimental evidence using NHR-49::GFP fusion protein confirms nuclear localization in multiple tissues. This is a core annotation for a nuclear hormone receptor. Supporting Evidence: PMID:25474470 In adults, it was visible in all somatic tissues (Fig |
| GO:0005737 cytoplasm | IDA PMID:25474470 Germline signals deploy NHR-49 to modulate fatty-acid Ξ²-oxid... | ACCEPT | Summary: PMID:25474470 (Ratnappan et al. 2014) showed NHR-49::GFP localization to both nuclei and cytoplasm in adult somatic tissues. Cytoplasmic localization was evident alongside nuclear localization in neurons, muscle, hypodermis, and intestinal cells. Reason: Direct experimental evidence confirms cytoplasmic localization of NHR-49. This likely reflects the dynamic shuttling of nuclear receptors between cytoplasm and nucleus. The dual localization is common for nuclear hormone receptors. Supporting Evidence: PMID:25474470 In adults, it was visible in all somatic tissues (Fig |
| GO:0005634 nucleus | HDA PMID:21611156 Determining the sub-cellular localization of proteins within... | ACCEPT | Summary: PMID:21611156 (Meissner et al. 2011) is a high-throughput localizome study determining sub-cellular localization of proteins within C. elegans body wall muscle using GFP tagging. NHR-49 was localized to the nucleus in this study. While this is body wall muscle-specific data, it is consistent with the broader expression and localization data from PMID:25474470. Reason: The HDA evidence from the muscle localizome study confirms nuclear localization and is consistent with the IDA evidence from PMID:25474470 and the predicted nuclear localization from domain analysis. Supporting Evidence: PMID:21611156 we have analyzed the expression of about 227 GFP-tagged proteins that show localized expression in the body wall muscle of this nematode |
| GO:0008340 determination of adult lifespan | IMP PMID:15719061 Nuclear hormone receptor NHR-49 controls fat consumption and... | ACCEPT | Summary: PMID:15719061 (Van Gilst et al. 2005) is the seminal study characterizing NHR-49 function. It demonstrated that nhr-49(nr2041) deletion mutants have dramatically shortened lifespan (6-8 days vs. 15-18 days for wild type at 23C), representing approximately 41% reduction in adult lifespan. The authors showed a striking correlation between fatty acid desaturase activity (stearic/oleic acid ratio) and lifespan, suggesting the shortened lifespan results at least in part from impaired fat-7 expression. Reason: Determination of adult lifespan is a core phenotype of nhr-49 loss of function. The ~41% reduction in lifespan is one of the most dramatic effects reported for nhr-49 mutants and has been replicated across multiple studies. Falcon deep research lists shortened lifespan among the core loss-of-function phenotypes of nhr-49. Supporting Evidence: PMID:15719061 nhr-49(nr2041) worms lived only 6β8 d as adults, significantly shorter than the 15 to 18-d life span of N2 wild-type (WT) animals PMID:15719061 nhr-49 function is not required for development or fertility, but is clearly essential for normal longevity file:worm/nhr-49/nhr-49-deep-research-falcon.md Loss of **nhr-49** causes high fat, impaired fasting response, shortened lifespan, altered mitochondrial morphology and function, defective pathogen avoidance, and increased sensitivity to oxidative stress, hypoxia, and infection |
| GO:0019217 regulation of fatty acid metabolic process | IMP PMID:15719061 Nuclear hormone receptor NHR-49 controls fat consumption and... | ACCEPT | Summary: PMID:15719061 (Van Gilst et al. 2005) comprehensively demonstrated that NHR-49 regulates expression of 13 fatty acid metabolism genes, including six in beta-oxidation (acs-2, ech-1, F09F3.9), three delta-9 desaturases (fat-5, fat-7, and to a lesser extent fat-6), and genes in fatty acid binding/transport and the glyoxylate pathway. Loss of nhr-49 results in increased fat storage and altered fatty acid composition with elevated stearic-to-oleic acid ratio. Reason: Regulation of fatty acid metabolism is the most central function of NHR-49. The evidence from PMID:15719061 is comprehensive, showing effects on both beta-oxidation and desaturation pathways, with measurable changes in fat storage and fatty acid composition. Falcon deep research confirms the central role of NHR-49 in activating beta-oxidation targets (acs-2, cpt-5, ech-1) and desaturase genes (fat-5, fat-6, fat-7). Supporting Evidence: PMID:15719061 Our screen revealed that deletion of nhr-49 significantly altered the expression of 13 genes, including six genes predicted to be involved in fatty acid Ξ²-oxidation, three genes involved in fatty acid desaturation PMID:15719061 nhr-49(nr2041) animals stained more brightly with Nile Red than did WT worms file:worm/nhr-49/nhr-49-deep-research-falcon.md It activates gene modules involved in **fatty-acid Ξ²-oxidation** (including canonical targets such as **acs-2, cpt-5, ech-1**) and regulates **fatty-acid desaturation** genes (**fat-5, fat-6, fat-7**) |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IMP PMID:15719061 Nuclear hormone receptor NHR-49 controls fat consumption and... | ACCEPT | Summary: PMID:15719061 (Van Gilst et al. 2005) showed that NHR-49 promotes transcription of target genes including acs-2, fat-5, fat-7, and ech-1. Expression of these genes was dramatically reduced (>30-fold for fat-5 and fat-7) in nhr-49 deletion mutants. NHR-49 also works with Mediator subunit MDT-15 for transcriptional activation (PMID:16651656). Reason: Positive regulation of Pol II transcription is a core molecular function of NHR-49 as a transcription factor that activates expression of fatty acid metabolism genes. The evidence is strong and direct. Supporting Evidence: PMID:15719061 fat-5 (W06D12.3) and fat-7 (F10D2.9) expression was dramatically lowered in nhr-49(nr2041) worms (>30-fold) in all four larval stages PMID:16651656 Knockdown of mdt-15 by RNA interference (RNAi) prevented fasting-induced mRNA accumulation of NHR-49 targets in vivo |
| GO:0008340 determination of adult lifespan | IMP PMID:16839188 Genetic regulation of unsaturated fatty acid composition in ... | ACCEPT | Summary: PMID:16839188 (Brock et al. 2006) characterized nhr-80 and delta-9 desaturase mutants, with nhr-49 as a comparison. The study confirmed that nhr-49 mutants have a 41% reduction in mean lifespan (8.2 days vs 13.9 days at 25C) and importantly showed that nhr-80 mutants, despite similar fatty acid composition changes, have only a modest ~10% lifespan reduction. This demonstrates that the short lifespan of nhr-49 is not solely due to desaturase deficiency but involves additional metabolic functions (e.g., beta-oxidation). Reason: This provides independent replication of the nhr-49 lifespan phenotype and adds the important insight that the lifespan effect is not solely attributable to desaturase regulation. Determination of adult lifespan is a core function of nhr-49. Supporting Evidence: PMID:16839188 These data indicate a 10% decrease in mean lifespan between wild type and nhr-80 mutants, the difference between wild type and nhr-49 mutants is much greater with a 41% reduction in mean lifespan. |
| GO:0019216 regulation of lipid metabolic process | IMP PMID:16839188 Genetic regulation of unsaturated fatty acid composition in ... | ACCEPT | Summary: PMID:16839188 (Brock et al. 2006) confirmed that nhr-49 mutants have altered fatty acid composition similar to nhr-80 mutants (elevated 18:0/18:1 ratio), but additionally showed increased fat storage not seen in nhr-80 mutants. NHR-49 regulates both desaturation (via fat-5, fat-7) and beta-oxidation pathways, having broader lipid regulatory functions than NHR-80 alone. Reason: Regulation of lipid metabolism is a core function of NHR-49. While GO:0019217 (regulation of fatty acid metabolic process) from PMID:15719061 is more specific, this broader term also captures NHR-49 roles in sphingolipid processing and lipid remodeling (PMID:22511885) that go beyond fatty acid metabolism. Falcon deep research describes NHR-49 as coordinating transcriptional programs that balance lipid catabolism, fatty-acid desaturation, and lipid remodeling, including NHR-66-dependent sphingolipid/lipid remodeling programs. Supporting Evidence: PMID:16839188 The nhr-49 mutants have increased levels of the saturated fatty acid 18:0, higher fat accumulation, and a shorter lifespan than wild-type animals PMID:22511885 We show that NHR-49 regulates distinct subsets of its target genes by partnering with at least two other distinct nuclear receptors file:worm/nhr-49/nhr-49-deep-research-falcon.md **NHR-66**: linked to regulation of **sphingolipid/lipid remodeling** genes. |
| GO:0071456 cellular response to hypoxia | IMP PMID:35285794 Nuclear hormone receptor NHR-49 acts in parallel with HIF-1 ... | NEW | Summary: PMID:35285794 (Doering et al. 2022) demonstrated that NHR-49 acts in parallel with HIF-1 to promote hypoxia adaptation. Under 0.5% oxygen, NHR-49 activates expression of acs-2, fmo-2, and autophagy-related genes. Loss of nhr-49 reduces embryonic hypoxia survival from 86% to 25%. Combined loss of nhr-49 and hif-1 is nearly lethal under hypoxia (<2% survival). NHR-49 acts in multiple somatic tissues including intestine, head neurons, and hypodermal seam cells. Reason: This annotation captures the well-documented role of NHR-49 in hypoxia adaptation, which is a distinct biological function from its lipid metabolism role. The evidence from Doering et al. 2022 is strong with clear survival phenotypes and target gene identification. Falcon deep research highlights this as an essential hypoxia survival pathway acting in parallel to HIF-1, with NHR-49 required for hypoxia-induced autophagosome (LGG-1::GFP) formation in seam cells. Supporting Evidence: PMID:35285794 nhr-49 is not only required to induce fmo-2, but controls a broad transcriptional response to hypoxia file:worm/nhr-49/nhr-49-deep-research-falcon.md an **essential hypoxia survival pathway** controlled by NHR-49 that operates **in parallel to HIF-1** file:worm/nhr-49/nhr-49-deep-research-falcon.md NHR-49 being required for hypoxia-induced autophagosome formation (LGG-1::GFP foci) in seam cells |
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