{"gene":"TNRC6C","run_date":"2026-06-10T10:51:55","timeline":{"discoveries":[{"year":2009,"finding":"The N-terminal GW-repeat-containing region of TNRC6C interacts with all four human Argonaute proteins (AGO1-AGO4), while the C-terminal silencing domain independently mediates silencing of bound mRNAs through translational repression and mRNA destabilization (including deadenylation), independent of AGO interaction.","method":"Tethering assays, deletion analysis, mRNA stability assays, reporter gene assays","journal":"RNA (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal domain mapping with deletion constructs, multiple orthogonal functional assays (reporter repression, mRNA stability, deadenylation), independently replicated across two concurrent studies (PMID:19383768 and PMID:19304925)","pmids":["19383768"],"is_preprint":false},{"year":2009,"finding":"The C-terminal domain of TNRC6C encompassing the RRM RNA-binding motif is the key effector domain mediating translational repression; tethering of TNRC6C to a reporter mRNA causes dramatic inhibition of protein synthesis through combined effects on mRNA levels and translation.","method":"Tethering assays, deletion and mutagenesis analysis of TNRC6C C-terminal domain, reporter gene assays","journal":"RNA (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct mutagenesis and domain deletion with functional readout (translational repression), two orthogonal methods in a single focused study","pmids":["19304925"],"is_preprint":false},{"year":2017,"finding":"TNRC6C is essential for microvascular maturation during distal lung sacculation in vivo; TNRC6c knockout mice die at birth with respiratory failure due to failure of capillary network apposition to surface epithelium, with concurrent downregulation of TGFβ1, TGFβR2, and VEGFR in mutant lungs, demonstrating a non-redundant in vivo function among GW182 paralogs.","method":"Conditional knockout mouse model, immunohistology, qRT-PCR, cell population analysis","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean genetic knockout with specific cellular and molecular phenotypic readout, multiple orthogonal analyses (histology, qRT-PCR, cell kinetics) in a single focused study","pmids":["28811219"],"is_preprint":false},{"year":2021,"finding":"TNRC6C overexpression in papillary thyroid cancer cells inhibits proliferation, migration, and invasion while promoting apoptosis; RNA-sequencing identified downstream target genes (including SCD, CRLF1, APCDD1L, CTHRC1, PTPRU, ALDH1A3, VCAN, TNC, ECE1, COL1A1, and MMP14) that are significantly downregulated upon TNRC6C overexpression.","method":"Gain/loss-of-function in cancer cell lines, RNA-sequencing, functional assays (proliferation, migration, invasion, apoptosis)","journal":"International journal of endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — clean KO/OE with defined cellular phenotype and RNA-seq target identification, but single lab and limited mechanistic follow-up on pathway placement","pmids":["33564303"],"is_preprint":false}],"current_model":"TNRC6C (a vertebrate GW182 paralog) is recruited to miRNA target mRNAs through N-terminal GW-repeat-mediated interaction with AGO1-AGO4, after which its C-terminal domain (containing an RRM motif) independently drives translational repression and mRNA deadenylation/degradation; in vivo, TNRC6C plays a non-redundant role in pulmonary microvascular maturation during sacculation by supporting TGFβ and VEGFR signaling, with its loss causing neonatal lethality in mice."},"narrative":{"mechanistic_narrative":"TNRC6C is a GW182-family effector of miRNA-mediated gene silencing that bridges Argonaute proteins to the mRNA decay and translational repression machinery [PMID:19383768]. Its N-terminal GW-repeat region binds all four human Argonaute proteins (AGO1-AGO4), recruiting TNRC6C to miRNA-targeted transcripts, while its C-terminal silencing domain — which contains an RRM motif — independently drives translational repression and mRNA destabilization including deadenylation, even when uncoupled from AGO binding [PMID:19383768, PMID:19304925]. Tethering of TNRC6C to a reporter mRNA dramatically inhibits protein synthesis through combined effects on mRNA level and translation [PMID:19304925]. In vivo, TNRC6C carries a non-redundant role among GW182 paralogs in pulmonary microvascular maturation: its loss in mice causes failure of capillary apposition to surface epithelium during distal lung sacculation, neonatal respiratory failure, and downregulation of TGFβ1, TGFβR2, and VEGFR [PMID:28811219]. In papillary thyroid cancer cells, TNRC6C overexpression suppresses proliferation, migration, and invasion and promotes apoptosis, accompanied by downregulation of a defined set of target transcripts [PMID:33564303].","teleology":[{"year":2009,"claim":"Established the modular architecture of TNRC6C as a silencing effector, resolving how it both engages the miRNA machinery and executes repression as separable activities.","evidence":"Tethering assays, reciprocal deletion mapping, mRNA stability and deadenylation reporter assays in human cells","pmids":["19383768","19304925"],"confidence":"High","gaps":["Does not define which endogenous mRNAs are regulated","Stoichiometry and structural basis of AGO–GW-repeat binding not resolved","Decay machinery recruited by the C-terminal domain not identified"]},{"year":2009,"claim":"Pinpointed the C-terminal RRM-containing domain as the key effector mediating translational repression, separating mRNA-level effects from translational inhibition.","evidence":"Domain deletion and mutagenesis of the TNRC6C C-terminus with reporter readouts","pmids":["19304925"],"confidence":"High","gaps":["RNA-binding specificity of the RRM motif not characterized","Mechanistic link between the RRM and the translation apparatus unresolved"]},{"year":2017,"claim":"Demonstrated a non-redundant physiological requirement for TNRC6C, showing GW182 paralogs are not functionally interchangeable in vivo.","evidence":"Conditional knockout mouse with lung histology, qRT-PCR, and cell population analysis","pmids":["28811219"],"confidence":"High","gaps":["Whether the lung phenotype reflects loss of miRNA silencing activity specifically is not established","Direct miRNA/mRNA targets driving TGFβ and VEGFR downregulation not identified","Mechanism of paralog non-redundancy unknown"]},{"year":2021,"claim":"Linked TNRC6C dosage to tumor-suppressive cellular behavior and nominated candidate downstream transcripts in a cancer context.","evidence":"Gain/loss-of-function in papillary thyroid cancer cell lines with RNA-sequencing and proliferation/migration/invasion/apoptosis assays","pmids":["33564303"],"confidence":"Medium","gaps":["Single lab without mechanistic pathway placement","Whether identified targets are direct miRNA-pathway targets versus indirect is unclear","No in vivo tumor validation"]},{"year":null,"claim":"How TNRC6C-specific silencing activity connects to its non-redundant developmental role and its tumor-suppressive function remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No endogenous miRNA target network mapped to a phenotype","No structural model of the AGO–TNRC6C interaction","Basis for paralog-specific function among GW182 proteins unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[1]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0]},{"term_id":"GO:0045182","term_label":"translation regulator activity","supporting_discovery_ids":[0,1]}],"localization":[],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,1]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[2]}],"complexes":[],"partners":["AGO1","AGO2","AGO3","AGO4"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9HCJ0","full_name":"Trinucleotide repeat-containing gene 6C protein","aliases":[],"length_aa":1936,"mass_kda":201.8,"function":"Plays a role in RNA-mediated gene silencing by micro-RNAs (miRNAs). Required for miRNA-dependent translational repression of complementary mRNAs by argonaute family proteins. As scaffoldng protein associates with argonaute proteins bound to partially complementary mRNAs and simultaneously can recruit CCR4-NOT and PAN deadenylase complexes","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q9HCJ0/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TNRC6C","classification":"Not Classified","n_dependent_lines":4,"n_total_lines":1208,"dependency_fraction":0.0033112582781456954},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"AGO1","stoichiometry":4.0},{"gene":"AGO2","stoichiometry":0.2},{"gene":"DDOST","stoichiometry":0.2},{"gene":"MIF","stoichiometry":0.2},{"gene":"OST4","stoichiometry":0.2},{"gene":"RACK1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/TNRC6C","total_profiled":1310},"omim":[{"mim_id":"619408","title":"TRIPARTITE MOTIF-CONTAINING PROTEIN 65; TRIM65","url":"https://www.omim.org/entry/619408"},{"mim_id":"610741","title":"TRINUCLEOTIDE REPEAT-CONTAINING GENE 6C; TNRC6C","url":"https://www.omim.org/entry/610741"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"retina","ntpm":22.8}],"url":"https://www.proteinatlas.org/search/TNRC6C"},"hgnc":{"alias_symbol":["KIAA1582","FLJ20015"],"prev_symbol":[]},"alphafold":{"accession":"Q9HCJ0","domains":[{"cath_id":"-","chopping":"1117-1175_1182-1207","consensus_level":"medium","plddt":78.9506,"start":1117,"end":1207},{"cath_id":"3.30.70.330","chopping":"1512-1596","consensus_level":"medium","plddt":91.0931,"start":1512,"end":1596}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9HCJ0","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9HCJ0-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9HCJ0-F1-predicted_aligned_error_v6.png","plddt_mean":40.34},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TNRC6C","jax_strain_url":"https://www.jax.org/strain/search?query=TNRC6C"},"sequence":{"accession":"Q9HCJ0","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9HCJ0.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9HCJ0/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9HCJ0"}},"corpus_meta":[{"pmid":"19383768","id":"PMC_19383768","title":"The C-terminal domains of human TNRC6A, TNRC6B, and TNRC6C silence bound transcripts independently of Argonaute proteins.","date":"2009","source":"RNA (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/19383768","citation_count":119,"is_preprint":false},{"pmid":"19304925","id":"PMC_19304925","title":"Importance of the C-terminal domain of the human GW182 protein TNRC6C for translational repression.","date":"2009","source":"RNA (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/19304925","citation_count":106,"is_preprint":false},{"pmid":"30938030","id":"PMC_30938030","title":"Suppression of long non-coding RNA TNRC6C-AS1 protects against thyroid carcinoma through DNA demethylation of STK4 via the Hippo signalling pathway.","date":"2019","source":"Cell proliferation","url":"https://pubmed.ncbi.nlm.nih.gov/30938030","citation_count":37,"is_preprint":false},{"pmid":"29893424","id":"PMC_29893424","title":"LncRNA TNRC6C-AS1 regulates UNC5B in thyroid cancer to influence cell proliferation, migration, and invasion as a competing endogenous RNA of miR-129-5p.","date":"2018","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/29893424","citation_count":30,"is_preprint":false},{"pmid":"31657132","id":"PMC_31657132","title":"Long non-coding RNA TNRC6C-AS1 promotes methylation of STK4 to inhibit thyroid carcinoma cell apoptosis and autophagy via Hippo signalling pathway.","date":"2019","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/31657132","citation_count":25,"is_preprint":false},{"pmid":"30038597","id":"PMC_30038597","title":"Long Non-coding Antisense RNA TNRC6C-AS1 Is Activated in Papillary Thyroid Cancer and Promotes Cancer Progression by Suppressing TNRC6C Expression.","date":"2018","source":"Frontiers in endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/30038597","citation_count":20,"is_preprint":false},{"pmid":"34393509","id":"PMC_34393509","title":"TNRC6C-AS1 Promotes Thyroid Cancer Progression by Upregulating LPAR5 via miR-513c-5p.","date":"2021","source":"Cancer management and research","url":"https://pubmed.ncbi.nlm.nih.gov/34393509","citation_count":9,"is_preprint":false},{"pmid":"28811219","id":"PMC_28811219","title":"Trinucleotide repeat containing 6c (TNRC6c) is essential for microvascular maturation during distal airspace sacculation in the developing lung.","date":"2017","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/28811219","citation_count":7,"is_preprint":false},{"pmid":"33564303","id":"PMC_33564303","title":"TNRC6C Functions as a Tumor Suppressor and Is Frequently Downregulated in Papillary Thyroid Cancer.","date":"2021","source":"International journal of endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/33564303","citation_count":6,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.11.20.688229","title":"Dynamic Epigenetic Changes During Antidepressant Pharmacotherapy in Major Depressive Disorder","date":"2025-11-20","source":"bioRxiv","url":"https://doi.org/10.1101/2025.11.20.688229","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":7764,"output_tokens":1143,"usd":0.020219,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7699,"output_tokens":1811,"usd":0.041885,"stage2_stop_reason":"end_turn"},"total_usd":0.062104,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2009,\n      \"finding\": \"The N-terminal GW-repeat-containing region of TNRC6C interacts with all four human Argonaute proteins (AGO1-AGO4), while the C-terminal silencing domain independently mediates silencing of bound mRNAs through translational repression and mRNA destabilization (including deadenylation), independent of AGO interaction.\",\n      \"method\": \"Tethering assays, deletion analysis, mRNA stability assays, reporter gene assays\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal domain mapping with deletion constructs, multiple orthogonal functional assays (reporter repression, mRNA stability, deadenylation), independently replicated across two concurrent studies (PMID:19383768 and PMID:19304925)\",\n      \"pmids\": [\"19383768\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"The C-terminal domain of TNRC6C encompassing the RRM RNA-binding motif is the key effector domain mediating translational repression; tethering of TNRC6C to a reporter mRNA causes dramatic inhibition of protein synthesis through combined effects on mRNA levels and translation.\",\n      \"method\": \"Tethering assays, deletion and mutagenesis analysis of TNRC6C C-terminal domain, reporter gene assays\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct mutagenesis and domain deletion with functional readout (translational repression), two orthogonal methods in a single focused study\",\n      \"pmids\": [\"19304925\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TNRC6C is essential for microvascular maturation during distal lung sacculation in vivo; TNRC6c knockout mice die at birth with respiratory failure due to failure of capillary network apposition to surface epithelium, with concurrent downregulation of TGFβ1, TGFβR2, and VEGFR in mutant lungs, demonstrating a non-redundant in vivo function among GW182 paralogs.\",\n      \"method\": \"Conditional knockout mouse model, immunohistology, qRT-PCR, cell population analysis\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean genetic knockout with specific cellular and molecular phenotypic readout, multiple orthogonal analyses (histology, qRT-PCR, cell kinetics) in a single focused study\",\n      \"pmids\": [\"28811219\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TNRC6C overexpression in papillary thyroid cancer cells inhibits proliferation, migration, and invasion while promoting apoptosis; RNA-sequencing identified downstream target genes (including SCD, CRLF1, APCDD1L, CTHRC1, PTPRU, ALDH1A3, VCAN, TNC, ECE1, COL1A1, and MMP14) that are significantly downregulated upon TNRC6C overexpression.\",\n      \"method\": \"Gain/loss-of-function in cancer cell lines, RNA-sequencing, functional assays (proliferation, migration, invasion, apoptosis)\",\n      \"journal\": \"International journal of endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — clean KO/OE with defined cellular phenotype and RNA-seq target identification, but single lab and limited mechanistic follow-up on pathway placement\",\n      \"pmids\": [\"33564303\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TNRC6C (a vertebrate GW182 paralog) is recruited to miRNA target mRNAs through N-terminal GW-repeat-mediated interaction with AGO1-AGO4, after which its C-terminal domain (containing an RRM motif) independently drives translational repression and mRNA deadenylation/degradation; in vivo, TNRC6C plays a non-redundant role in pulmonary microvascular maturation during sacculation by supporting TGFβ and VEGFR signaling, with its loss causing neonatal lethality in mice.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TNRC6C is a GW182-family effector of miRNA-mediated gene silencing that bridges Argonaute proteins to the mRNA decay and translational repression machinery [#0]. Its N-terminal GW-repeat region binds all four human Argonaute proteins (AGO1-AGO4), recruiting TNRC6C to miRNA-targeted transcripts, while its C-terminal silencing domain — which contains an RRM motif — independently drives translational repression and mRNA destabilization including deadenylation, even when uncoupled from AGO binding [#0, #1]. Tethering of TNRC6C to a reporter mRNA dramatically inhibits protein synthesis through combined effects on mRNA level and translation [#1]. In vivo, TNRC6C carries a non-redundant role among GW182 paralogs in pulmonary microvascular maturation: its loss in mice causes failure of capillary apposition to surface epithelium during distal lung sacculation, neonatal respiratory failure, and downregulation of TGFβ1, TGFβR2, and VEGFR [#2]. In papillary thyroid cancer cells, TNRC6C overexpression suppresses proliferation, migration, and invasion and promotes apoptosis, accompanied by downregulation of a defined set of target transcripts [#3].\",\n  \"teleology\": [\n    {\n      \"year\": 2009,\n      \"claim\": \"Established the modular architecture of TNRC6C as a silencing effector, resolving how it both engages the miRNA machinery and executes repression as separable activities.\",\n      \"evidence\": \"Tethering assays, reciprocal deletion mapping, mRNA stability and deadenylation reporter assays in human cells\",\n      \"pmids\": [\"19383768\", \"19304925\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not define which endogenous mRNAs are regulated\", \"Stoichiometry and structural basis of AGO–GW-repeat binding not resolved\", \"Decay machinery recruited by the C-terminal domain not identified\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Pinpointed the C-terminal RRM-containing domain as the key effector mediating translational repression, separating mRNA-level effects from translational inhibition.\",\n      \"evidence\": \"Domain deletion and mutagenesis of the TNRC6C C-terminus with reporter readouts\",\n      \"pmids\": [\"19304925\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"RNA-binding specificity of the RRM motif not characterized\", \"Mechanistic link between the RRM and the translation apparatus unresolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrated a non-redundant physiological requirement for TNRC6C, showing GW182 paralogs are not functionally interchangeable in vivo.\",\n      \"evidence\": \"Conditional knockout mouse with lung histology, qRT-PCR, and cell population analysis\",\n      \"pmids\": [\"28811219\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the lung phenotype reflects loss of miRNA silencing activity specifically is not established\", \"Direct miRNA/mRNA targets driving TGFβ and VEGFR downregulation not identified\", \"Mechanism of paralog non-redundancy unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Linked TNRC6C dosage to tumor-suppressive cellular behavior and nominated candidate downstream transcripts in a cancer context.\",\n      \"evidence\": \"Gain/loss-of-function in papillary thyroid cancer cell lines with RNA-sequencing and proliferation/migration/invasion/apoptosis assays\",\n      \"pmids\": [\"33564303\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab without mechanistic pathway placement\", \"Whether identified targets are direct miRNA-pathway targets versus indirect is unclear\", \"No in vivo tumor validation\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How TNRC6C-specific silencing activity connects to its non-redundant developmental role and its tumor-suppressive function remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No endogenous miRNA target network mapped to a phenotype\", \"No structural model of the AGO–TNRC6C interaction\", \"Basis for paralog-specific function among GW182 proteins unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0045182\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"AGO1\", \"AGO2\", \"AGO3\", \"AGO4\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}