{"gene":"MEIOC","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":2016,"finding":"MEIOC is a meiosis-specific protein required for fertility; MEIOC prevents meiotic transcript degradation and interacts with an RNA helicase (YTHDC2) that binds numerous meiotic mRNAs, establishing a post-transcriptional stabilization role for meiotic transcripts.","method":"Mouse knockout (Meioc invalidation), co-immunoprecipitation, RNA binding assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — loss-of-function mouse model with defined molecular phenotype, Co-IP interaction with RNA helicase, replicated in multiple subsequent studies","pmids":["26742488"],"is_preprint":false},{"year":2017,"finding":"MEIOC is required to maintain extended meiotic prophase I in mice; Meioc-deficient germ cells prematurely condense chromosomes and assemble a spindle (mitotic-like behavior). MEIOC interacts with YTHDC2, and together they pull down an overlapping set of mitosis-associated transcripts, promoting a meiotic (rather than mitotic) cell cycle program via post-transcriptional control.","method":"Mouse Meioc knockout, co-immunoprecipitation/pulldown of RNA-binding proteins, immunofluorescence for cell cycle markers (CYCLIN A2), chromosome spreading","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO with defined cellular phenotype, reciprocal Co-IP/pulldown, specific molecular marker (CCNA2 mis-expression), corroborated by independent lab","pmids":["28380054"],"is_preprint":false},{"year":2018,"finding":"MEIOC is a binding partner of YTHDC2 (ketu mutant mice phenocopy Meioc mutants); Meioc and Ythdc2 mutants share identical defects in transitioning from spermatogonial to meiotic gene expression programs, placing MEIOC and YTHDC2 in the same pathway for meiotic entry.","method":"Genetic epistasis (phenocopy analysis of ketu/Ythdc2 and Meioc mutants), co-immunoprecipitation","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis (phenocopy), Co-IP, consistent with independent mouse knockout studies","pmids":["29360036"],"is_preprint":false},{"year":2022,"finding":"RBM46 is a component of the YTHDC2/MEIOC complex; RBM46 binds 3' UTRs of mitotic transcripts within 100 nucleotides of YTHDC2 U-rich motifs and targets these transcripts for degradation. Testis-specific Rbm46 knockout phenocopies global Ythdc2 or Meioc knockout, establishing RBM46/YTHDC2/MEIOC as the major post-transcriptional regulator for downregulating mitotic transcripts during meiosis entry.","method":"Mouse conditional knockout, co-immunoprecipitation, RNA binding/CLIP analysis, RNA-seq","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO phenocopy, Co-IP complex identification, RNA binding mapping, multiple orthogonal methods","pmids":["36001654"],"is_preprint":false},{"year":2024,"finding":"MEIOC, acting with YTHDC2 and RBM46, destabilizes mRNA targets including transcriptional repressors E2f6 and Mga in mitotic spermatogonia, thereby derepressing Meiosin and other meiosis-associated genes. This mRNA decay activity confers molecular competence for spermatogenic cells to respond to retinoic acid and fully activate STRA8-MEIOSIN for meiotic initiation. MEIOC mediates transcriptomic changes before meiotic initiation, earlier than previously appreciated.","method":"scRNA-seq and bulk RNA-seq of developmentally synchronized spermatogenesis in Meioc mutant mice","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean KO with scRNA-seq and bulk RNA-seq, two orthogonal sequencing approaches identifying direct mRNA targets and downstream pathway","pmids":["38884383"],"is_preprint":false},{"year":2024,"finding":"YTHDC2 interacts with MEIOC and multiple other RNA-binding proteins in early and late spermatocytes; MEIOC co-localizes with YTHDC2 in RNA granules in late spermatocytes, suggesting MEIOC participates in granule-based post-transcriptional regulation at multiple steps of meiosis.","method":"Conditional Ythdc2 knockout (inducible, after meiotic prophase initiation), co-immunoprecipitation, immunofluorescence for granule localization","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — single lab, Co-IP and localization data, conditional KO with defined phenotype but MEIOC-specific mechanistic detail is indirect","pmids":["39378093"],"is_preprint":false},{"year":2025,"finding":"In zebrafish, Meioc colocalizes with Piwil1 in perinuclear germ granules. Meioc depletion causes Piwil1 to accumulate in nucleoli where it interacts with 45S pre-rRNA and represses rRNA transcription via H3K9me3 and CpG methylation at 45S-rDNA. Thus, Meioc prevents nucleolar localization of Piwil1 to enable upregulation of rRNA transcripts required for spermatogonial stem cell (SSC) differentiation.","method":"Zebrafish meioc mutant analysis, co-immunoprecipitation (Piwil1-Setdb1, Piwil1-HP1α, Piwil1-pre-rRNA), immunofluorescence/colocalization, ChIP/bisulfite sequencing for H3K9me3 and CpG methylation at rDNA","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — zebrafish ortholog study with multiple orthogonal methods (Co-IP, localization, epigenetic marks), single lab","pmids":["40705004"],"is_preprint":false},{"year":2026,"finding":"In mouse oogenesis, MEIOC prevents continued mitotic cycling prior to meiotic entry by contributing to downregulation of G1/S cyclin CCNA2 at both transcript and protein levels. MEIOC also promotes meiotic entry by increasing Meiosin transcript abundance, activating STRA8-MEIOSIN. Since STRA8-MEIOSIN upregulates Meioc, MEIOC and STRA8-MEIOSIN form a positive feedback loop. BMP signaling promotes meiotic entry by upregulating MEIOC.","method":"Mouse Meioc knockout (oogenesis), cell proliferation analysis, cell cycle transcriptomics, immunofluorescence for CCNA2 and MEIOSIN, BMP signaling manipulation","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean KO with transcriptomics and protein-level validation, multiple orthogonal methods in a single focused study","pmids":["41287933"],"is_preprint":false},{"year":2026,"finding":"In human NOA patients with pathogenic YTHDC2 variants, MEIOC and RBM46 protein levels are significantly decreased in testes, while mitotic cell cycle regulators (CCNA2, CCND1, WEE1) are aberrantly upregulated in cells expressing meiosis markers, indicating that disruption of YTHDC2 destabilizes the MEIOC/RBM46 complex and causes failure to silence the mitotic program upon meiotic entry.","method":"Human patient testis immunofluorescence/western blot, CRISPR knock-in mouse model recapitulating patient variant, immunofluorescence for meiotic markers and mitotic cyclins","journal":"Human reproduction (Oxford, England)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — human patient tissue plus in vivo knock-in mouse model validation, multiple protein markers assessed, single study","pmids":["42249589"],"is_preprint":false},{"year":2026,"finding":"In female germ cells, RBM46 deficiency derepresses CCNA2 and causes meiotic arrest. Ectopic co-expression of RBM46, MEIOC, and YTHDC2 in HEK293T cells promotes degradation of reporter mRNAs bearing Lin28a or Mga 3' UTRs; deletion of the RBM46-binding motif 'AAUCAU' within Lin28a 3'UTR reduces this degradation, demonstrating that the RBM46/MEIOC/YTHDC2 complex mediates mRNA decay through specific 3' UTR sequences.","method":"Mouse Rbm46 knockout (female), transcriptomic profiling, HEK293T reporter mRNA degradation assay with co-expression of RBM46/MEIOC/YTHDC2, 3'UTR deletion mutagenesis","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — in vitro reporter/mutagenesis experiment identifies specific binding motif, complemented by in vivo KO, single lab","pmids":["42217413"],"is_preprint":false},{"year":2025,"finding":"Overexpression of MEIOC (together with BCL2 and HOXB5 or BOLL) in human iPSCs, combined with DNMT1 inhibition and retinoid signaling activation, is sufficient to activate meiosis in vitro, establishing MEIOC as a pro-meiotic factor capable of driving meiotic entry in human cells.","method":"Human iPSC overexpression system, immunofluorescence microscopy for synaptonemal complex components and meiotic recombination machinery, gene expression analysis","journal":"Science advances","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — gain-of-function in human iPSCs with multiple meiotic readouts, but MEIOC's specific contribution not isolated from other co-expressed factors","pmids":["40815662"],"is_preprint":false}],"current_model":"MEIOC is a conserved, germ-cell-specific protein that forms a post-transcriptional regulatory complex with YTHDC2 and RBM46 to drive the mitosis-to-meiosis transition: the complex destabilizes mitotic mRNAs (including CCNA2, E2f6, Mga, Lin28a) via sequence-specific 3' UTR recognition, thereby derepressing meiosis-associated genes (including Meiosin) and enabling full activation of the STRA8-MEIOSIN transcriptional program; in oocytes MEIOC additionally suppresses mitotic cycling before meiotic entry and participates in a positive feedback loop with STRA8-MEIOSIN, while in zebrafish Meioc also regulates spermatogonial stem cell differentiation by preventing nucleolar accumulation of Piwil1 and thereby permitting rRNA upregulation."},"narrative":{"mechanistic_narrative":"MEIOC is a conserved, germ-cell-specific post-transcriptional regulator that enforces the mitosis-to-meiosis transition during gametogenesis [PMID:26742488, PMID:28380054]. It functions as a subunit of a complex with the RNA helicase YTHDC2 and the RNA-binding protein RBM46, which together recognize U-rich/AAUCAU motifs in the 3' UTRs of mitotic transcripts (including CCNA2, Lin28a, Mga, and E2f6) and target them for degradation [PMID:36001654, PMID:42217413]. By destabilizing these mitotic and repressor mRNAs, the complex both suppresses the somatic/mitotic cell-cycle program and derepresses meiosis-associated genes such as Meiosin, conferring competence to respond to retinoic acid and fully activate the STRA8-MEIOSIN program [PMID:38884383]. Loss of MEIOC causes germ cells to retain mitotic-like behavior—premature chromosome condensation, spindle assembly, and CCNA2 mis-expression—and fail to maintain extended meiotic prophase [PMID:28380054]. In oogenesis MEIOC additionally suppresses mitotic cycling before meiotic entry and participates in a positive feedback loop with STRA8-MEIOSIN downstream of BMP signaling [PMID:41287933]. In humans, pathogenic YTHDC2 variants destabilize the MEIOC/RBM46 complex and cause failure to silence the mitotic program in cells expressing meiosis markers, linking the complex to non-obstructive azoospermia [PMID:42249589].","teleology":[{"year":2016,"claim":"Established that a meiosis-specific factor stabilizes meiotic transcripts and acts through an RNA helicase, defining MEIOC as a post-transcriptional regulator of meiosis rather than a transcription factor.","evidence":"Mouse Meioc knockout with co-immunoprecipitation and RNA-binding assays identifying YTHDC2 interaction","pmids":["26742488"],"confidence":"High","gaps":["Direct RNA targets and sequence specificity not yet mapped","Mechanism of transcript stabilization versus degradation not resolved"]},{"year":2017,"claim":"Showed that MEIOC and YTHDC2 act together to impose a meiotic rather than mitotic cell-cycle program, explaining why loss causes premature mitotic-like behavior.","evidence":"Mouse Meioc knockout with reciprocal Co-IP/pulldown, CYCLIN A2 immunofluorescence, and chromosome spreading","pmids":["28380054"],"confidence":"High","gaps":["Did not establish whether mitotic transcripts are direct degradation targets","Granule/complex composition incomplete"]},{"year":2018,"claim":"Genetic epistasis placed MEIOC and YTHDC2 in the same meiotic-entry pathway, confirming functional partnership rather than coincidental interaction.","evidence":"Phenocopy analysis of ketu/Ythdc2 and Meioc mutants plus Co-IP","pmids":["29360036"],"confidence":"High","gaps":["Direct mRNA targets still undefined","No structural basis for complex assembly"]},{"year":2022,"claim":"Identified RBM46 as the sequence-specific RNA-binding component of the complex, defining how mitotic transcripts are recognized and degraded near YTHDC2 U-rich motifs.","evidence":"Testis-specific Rbm46 conditional knockout, Co-IP, CLIP analysis, and RNA-seq","pmids":["36001654"],"confidence":"High","gaps":["Stoichiometry and contribution of each subunit to decay not dissected","MEIOC's specific molecular role within the complex unresolved"]},{"year":2024,"claim":"Defined the downstream logic: complex-mediated decay of repressors E2f6 and Mga derepresses Meiosin, conferring competence to activate STRA8-MEIOSIN before overt meiotic entry.","evidence":"scRNA-seq and bulk RNA-seq of synchronized Meioc mutant spermatogenesis","pmids":["38884383"],"confidence":"High","gaps":["Direct versus indirect target distinction relies on inference","Temporal coupling to retinoic acid signaling not mechanistically resolved"]},{"year":2024,"claim":"Showed MEIOC co-localizes with YTHDC2 in RNA granules in late spermatocytes, indicating granule-based regulation extends beyond meiotic entry.","evidence":"Inducible conditional Ythdc2 knockout with Co-IP and granule immunofluorescence","pmids":["39378093"],"confidence":"Medium","gaps":["MEIOC-specific function in granules not isolated","Single lab; functional consequence of granule localization untested"]},{"year":2025,"claim":"Revealed a complex-independent role in zebrafish where Meioc prevents nucleolar accumulation of Piwil1, permitting rRNA upregulation needed for spermatogonial stem cell differentiation.","evidence":"Zebrafish meioc mutant analysis with Co-IP, colocalization, and ChIP/bisulfite sequencing at 45S-rDNA","pmids":["40705004"],"confidence":"Medium","gaps":["Conservation of this Piwil1-rRNA axis in mammals not tested","Direct Meioc-Piwil1 mechanism (sequestration vs. localization) unresolved","Single lab"]},{"year":2026,"claim":"Extended MEIOC function to oogenesis, showing it suppresses mitotic cycling via CCNA2 downregulation and forms a positive feedback loop with STRA8-MEIOSIN downstream of BMP signaling.","evidence":"Mouse Meioc oogenesis knockout with cell-cycle transcriptomics, CCNA2/MEIOSIN immunofluorescence, and BMP manipulation","pmids":["41287933"],"confidence":"High","gaps":["Molecular link from BMP signaling to MEIOC upregulation undefined","Whether feedback loop is direct or mediated by other factors unresolved"]},{"year":2026,"claim":"Connected the complex to human disease, showing pathogenic YTHDC2 variants reduce MEIOC/RBM46 levels and cause failure to silence mitotic regulators upon meiotic entry in azoospermia.","evidence":"Human NOA patient testis immunofluorescence/western blot with CRISPR knock-in mouse recapitulating the variant","pmids":["42249589"],"confidence":"Medium","gaps":["Causality of MEIOC loss versus YTHDC2 loss not separated","MEIOC-specific pathogenic variants in patients not reported here"]},{"year":2026,"claim":"Demonstrated reconstitution in vitro that the RBM46/MEIOC/YTHDC2 complex degrades mRNAs through a defined 3' UTR motif, providing direct biochemical evidence for sequence-specific decay.","evidence":"Mouse female Rbm46 knockout plus HEK293T reporter degradation assay with AAUCAU motif deletion","pmids":["42217413"],"confidence":"Medium","gaps":["MEIOC's individual catalytic or scaffolding contribution not isolated in the reconstitution","Single lab"]},{"year":2025,"claim":"Showed MEIOC overexpression contributes to driving meiotic entry in human iPSCs, establishing it as a pro-meiotic factor in a human gain-of-function context.","evidence":"Human iPSC overexpression of MEIOC with co-factors, scored by synaptonemal complex and recombination markers","pmids":["40815662"],"confidence":"Medium","gaps":["MEIOC's specific contribution not separated from co-expressed BCL2/HOXB5/BOLL","Sufficiency of MEIOC alone untested"]},{"year":null,"claim":"How MEIOC mechanistically contributes within the YTHDC2/RBM46 complex—scaffolding, helicase regulation, or granule organization—and whether its zebrafish Piwil1-rRNA role is conserved in mammals remain open.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of the MEIOC/YTHDC2/RBM46 complex","MEIOC's distinct molecular activity not separable from partner proteins","Cross-species conservation of nucleolar Piwil1 regulation untested in mammals"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,1,3]},{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[3,9]}],"localization":[{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[5,6]}],"pathway":[{"term_id":"R-HSA-1474165","term_label":"Reproduction","supporting_discovery_ids":[0,4,7]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[3,9]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[1,7]}],"complexes":["YTHDC2/MEIOC/RBM46 mRNA decay complex"],"partners":["YTHDC2","RBM46","PIWIL1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"A2RUB1","full_name":"Meiosis-specific coiled-coil domain-containing protein MEIOC","aliases":["Meiosis-specific with coiled-coil domain protein"],"length_aa":952,"mass_kda":107.6,"function":"Is required for meiosis completion in both male and female germ cells. Confers stability to numerous meiotic mRNAs in gonads allowing proper initiation and progression into meiosis prophase I. The function may involve YTHDC2 and is independent of induction by retinoic acid (RA). Maintains an extended meiotic prophase I by properly promoting the transition from a mitotic to a meiotic cell cycle program by binding transcripts through its interaction with YTHDC2 that regulate the mitotic cell cycle","subcellular_location":"Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/A2RUB1/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MEIOC","classification":"Not Classified","n_dependent_lines":90,"n_total_lines":1208,"dependency_fraction":0.07450331125827815},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/MEIOC","total_profiled":1310},"omim":[{"mim_id":"620147","title":"RNA-BINDING MOTIF PROTEIN 46; RBM46","url":"https://www.omim.org/entry/620147"},{"mim_id":"616934","title":"MEIOSIS-SPECIFIC PROTEIN WITH COILED-COIL DOMAIN; MEIOC","url":"https://www.omim.org/entry/616934"},{"mim_id":"616530","title":"YTH DOMAIN-CONTAINING PROTEIN 2; YTHDC2","url":"https://www.omim.org/entry/616530"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Uncertain","locations":[{"location":"Cell Junctions","reliability":"Uncertain"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"testis","ntpm":44.5}],"url":"https://www.proteinatlas.org/search/MEIOC"},"hgnc":{"alias_symbol":["FLJ35848"],"prev_symbol":["C17orf104"]},"alphafold":{"accession":"A2RUB1","domains":[{"cath_id":"1.20.120","chopping":"751-784_822-910","consensus_level":"high","plddt":92.5986,"start":751,"end":910}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/A2RUB1","model_url":"https://alphafold.ebi.ac.uk/files/AF-A2RUB1-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-A2RUB1-F1-predicted_aligned_error_v6.png","plddt_mean":46.47},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MEIOC","jax_strain_url":"https://www.jax.org/strain/search?query=MEIOC"},"sequence":{"accession":"A2RUB1","fasta_url":"https://rest.uniprot.org/uniprotkb/A2RUB1.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/A2RUB1/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/A2RUB1"}},"corpus_meta":[{"pmid":"29033321","id":"PMC_29033321","title":"Regulation of m6A Transcripts by the 3'→5' RNA Helicase YTHDC2 Is Essential for a Successful Meiotic Program in the Mammalian Germline.","date":"2017","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/29033321","citation_count":403,"is_preprint":false},{"pmid":"26619122","id":"PMC_26619122","title":"Genetic landscape of metastatic and recurrent head and neck squamous cell carcinoma.","date":"2015","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/26619122","citation_count":136,"is_preprint":false},{"pmid":"29360036","id":"PMC_29360036","title":"ketu mutant mice uncover an essential meiotic function for the ancient RNA helicase YTHDC2.","date":"2018","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/29360036","citation_count":134,"is_preprint":false},{"pmid":"28380054","id":"PMC_28380054","title":"Meioc maintains an extended meiotic prophase I in mice.","date":"2017","source":"PLoS 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mitotic cycling and promotes meiotic entry during mouse oogenesis.","date":"2026","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/41287933","citation_count":1,"is_preprint":false},{"pmid":"36747642","id":"PMC_36747642","title":"YTHDC2 serves a distinct late role in spermatocytes during germ cell differentiation.","date":"2024","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/36747642","citation_count":1,"is_preprint":false},{"pmid":"40661394","id":"PMC_40661394","title":"MEIOC prevents continued mitotic cycling and promotes meiotic entry during mouse oogenesis.","date":"2025","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/40661394","citation_count":0,"is_preprint":false},{"pmid":"39605693","id":"PMC_39605693","title":"Meioc-Piwil1 complexes regulate rRNA transcription for differentiation of spermatogonial stem cells.","date":"2025","source":"bioRxiv : the preprint 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England)","url":"https://pubmed.ncbi.nlm.nih.gov/42249589","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":14483,"output_tokens":3183,"usd":0.045597,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10625,"output_tokens":3581,"usd":0.071325,"stage2_stop_reason":"end_turn"},"total_usd":0.116922,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2016,\n      \"finding\": \"MEIOC is a meiosis-specific protein required for fertility; MEIOC prevents meiotic transcript degradation and interacts with an RNA helicase (YTHDC2) that binds numerous meiotic mRNAs, establishing a post-transcriptional stabilization role for meiotic transcripts.\",\n      \"method\": \"Mouse knockout (Meioc invalidation), co-immunoprecipitation, RNA binding assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — loss-of-function mouse model with defined molecular phenotype, Co-IP interaction with RNA helicase, replicated in multiple subsequent studies\",\n      \"pmids\": [\"26742488\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"MEIOC is required to maintain extended meiotic prophase I in mice; Meioc-deficient germ cells prematurely condense chromosomes and assemble a spindle (mitotic-like behavior). MEIOC interacts with YTHDC2, and together they pull down an overlapping set of mitosis-associated transcripts, promoting a meiotic (rather than mitotic) cell cycle program via post-transcriptional control.\",\n      \"method\": \"Mouse Meioc knockout, co-immunoprecipitation/pulldown of RNA-binding proteins, immunofluorescence for cell cycle markers (CYCLIN A2), chromosome spreading\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO with defined cellular phenotype, reciprocal Co-IP/pulldown, specific molecular marker (CCNA2 mis-expression), corroborated by independent lab\",\n      \"pmids\": [\"28380054\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"MEIOC is a binding partner of YTHDC2 (ketu mutant mice phenocopy Meioc mutants); Meioc and Ythdc2 mutants share identical defects in transitioning from spermatogonial to meiotic gene expression programs, placing MEIOC and YTHDC2 in the same pathway for meiotic entry.\",\n      \"method\": \"Genetic epistasis (phenocopy analysis of ketu/Ythdc2 and Meioc mutants), co-immunoprecipitation\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis (phenocopy), Co-IP, consistent with independent mouse knockout studies\",\n      \"pmids\": [\"29360036\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"RBM46 is a component of the YTHDC2/MEIOC complex; RBM46 binds 3' UTRs of mitotic transcripts within 100 nucleotides of YTHDC2 U-rich motifs and targets these transcripts for degradation. Testis-specific Rbm46 knockout phenocopies global Ythdc2 or Meioc knockout, establishing RBM46/YTHDC2/MEIOC as the major post-transcriptional regulator for downregulating mitotic transcripts during meiosis entry.\",\n      \"method\": \"Mouse conditional knockout, co-immunoprecipitation, RNA binding/CLIP analysis, RNA-seq\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO phenocopy, Co-IP complex identification, RNA binding mapping, multiple orthogonal methods\",\n      \"pmids\": [\"36001654\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"MEIOC, acting with YTHDC2 and RBM46, destabilizes mRNA targets including transcriptional repressors E2f6 and Mga in mitotic spermatogonia, thereby derepressing Meiosin and other meiosis-associated genes. This mRNA decay activity confers molecular competence for spermatogenic cells to respond to retinoic acid and fully activate STRA8-MEIOSIN for meiotic initiation. MEIOC mediates transcriptomic changes before meiotic initiation, earlier than previously appreciated.\",\n      \"method\": \"scRNA-seq and bulk RNA-seq of developmentally synchronized spermatogenesis in Meioc mutant mice\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO with scRNA-seq and bulk RNA-seq, two orthogonal sequencing approaches identifying direct mRNA targets and downstream pathway\",\n      \"pmids\": [\"38884383\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"YTHDC2 interacts with MEIOC and multiple other RNA-binding proteins in early and late spermatocytes; MEIOC co-localizes with YTHDC2 in RNA granules in late spermatocytes, suggesting MEIOC participates in granule-based post-transcriptional regulation at multiple steps of meiosis.\",\n      \"method\": \"Conditional Ythdc2 knockout (inducible, after meiotic prophase initiation), co-immunoprecipitation, immunofluorescence for granule localization\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — single lab, Co-IP and localization data, conditional KO with defined phenotype but MEIOC-specific mechanistic detail is indirect\",\n      \"pmids\": [\"39378093\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In zebrafish, Meioc colocalizes with Piwil1 in perinuclear germ granules. Meioc depletion causes Piwil1 to accumulate in nucleoli where it interacts with 45S pre-rRNA and represses rRNA transcription via H3K9me3 and CpG methylation at 45S-rDNA. Thus, Meioc prevents nucleolar localization of Piwil1 to enable upregulation of rRNA transcripts required for spermatogonial stem cell (SSC) differentiation.\",\n      \"method\": \"Zebrafish meioc mutant analysis, co-immunoprecipitation (Piwil1-Setdb1, Piwil1-HP1α, Piwil1-pre-rRNA), immunofluorescence/colocalization, ChIP/bisulfite sequencing for H3K9me3 and CpG methylation at rDNA\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — zebrafish ortholog study with multiple orthogonal methods (Co-IP, localization, epigenetic marks), single lab\",\n      \"pmids\": [\"40705004\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"In mouse oogenesis, MEIOC prevents continued mitotic cycling prior to meiotic entry by contributing to downregulation of G1/S cyclin CCNA2 at both transcript and protein levels. MEIOC also promotes meiotic entry by increasing Meiosin transcript abundance, activating STRA8-MEIOSIN. Since STRA8-MEIOSIN upregulates Meioc, MEIOC and STRA8-MEIOSIN form a positive feedback loop. BMP signaling promotes meiotic entry by upregulating MEIOC.\",\n      \"method\": \"Mouse Meioc knockout (oogenesis), cell proliferation analysis, cell cycle transcriptomics, immunofluorescence for CCNA2 and MEIOSIN, BMP signaling manipulation\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO with transcriptomics and protein-level validation, multiple orthogonal methods in a single focused study\",\n      \"pmids\": [\"41287933\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"In human NOA patients with pathogenic YTHDC2 variants, MEIOC and RBM46 protein levels are significantly decreased in testes, while mitotic cell cycle regulators (CCNA2, CCND1, WEE1) are aberrantly upregulated in cells expressing meiosis markers, indicating that disruption of YTHDC2 destabilizes the MEIOC/RBM46 complex and causes failure to silence the mitotic program upon meiotic entry.\",\n      \"method\": \"Human patient testis immunofluorescence/western blot, CRISPR knock-in mouse model recapitulating patient variant, immunofluorescence for meiotic markers and mitotic cyclins\",\n      \"journal\": \"Human reproduction (Oxford, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — human patient tissue plus in vivo knock-in mouse model validation, multiple protein markers assessed, single study\",\n      \"pmids\": [\"42249589\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"In female germ cells, RBM46 deficiency derepresses CCNA2 and causes meiotic arrest. Ectopic co-expression of RBM46, MEIOC, and YTHDC2 in HEK293T cells promotes degradation of reporter mRNAs bearing Lin28a or Mga 3' UTRs; deletion of the RBM46-binding motif 'AAUCAU' within Lin28a 3'UTR reduces this degradation, demonstrating that the RBM46/MEIOC/YTHDC2 complex mediates mRNA decay through specific 3' UTR sequences.\",\n      \"method\": \"Mouse Rbm46 knockout (female), transcriptomic profiling, HEK293T reporter mRNA degradation assay with co-expression of RBM46/MEIOC/YTHDC2, 3'UTR deletion mutagenesis\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro reporter/mutagenesis experiment identifies specific binding motif, complemented by in vivo KO, single lab\",\n      \"pmids\": [\"42217413\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Overexpression of MEIOC (together with BCL2 and HOXB5 or BOLL) in human iPSCs, combined with DNMT1 inhibition and retinoid signaling activation, is sufficient to activate meiosis in vitro, establishing MEIOC as a pro-meiotic factor capable of driving meiotic entry in human cells.\",\n      \"method\": \"Human iPSC overexpression system, immunofluorescence microscopy for synaptonemal complex components and meiotic recombination machinery, gene expression analysis\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — gain-of-function in human iPSCs with multiple meiotic readouts, but MEIOC's specific contribution not isolated from other co-expressed factors\",\n      \"pmids\": [\"40815662\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MEIOC is a conserved, germ-cell-specific protein that forms a post-transcriptional regulatory complex with YTHDC2 and RBM46 to drive the mitosis-to-meiosis transition: the complex destabilizes mitotic mRNAs (including CCNA2, E2f6, Mga, Lin28a) via sequence-specific 3' UTR recognition, thereby derepressing meiosis-associated genes (including Meiosin) and enabling full activation of the STRA8-MEIOSIN transcriptional program; in oocytes MEIOC additionally suppresses mitotic cycling before meiotic entry and participates in a positive feedback loop with STRA8-MEIOSIN, while in zebrafish Meioc also regulates spermatogonial stem cell differentiation by preventing nucleolar accumulation of Piwil1 and thereby permitting rRNA upregulation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MEIOC is a conserved, germ-cell-specific post-transcriptional regulator that enforces the mitosis-to-meiosis transition during gametogenesis [#0, #1]. It functions as a subunit of a complex with the RNA helicase YTHDC2 and the RNA-binding protein RBM46, which together recognize U-rich/AAUCAU motifs in the 3' UTRs of mitotic transcripts (including CCNA2, Lin28a, Mga, and E2f6) and target them for degradation [#3, #9]. By destabilizing these mitotic and repressor mRNAs, the complex both suppresses the somatic/mitotic cell-cycle program and derepresses meiosis-associated genes such as Meiosin, conferring competence to respond to retinoic acid and fully activate the STRA8-MEIOSIN program [#4]. Loss of MEIOC causes germ cells to retain mitotic-like behavior—premature chromosome condensation, spindle assembly, and CCNA2 mis-expression—and fail to maintain extended meiotic prophase [#1]. In oogenesis MEIOC additionally suppresses mitotic cycling before meiotic entry and participates in a positive feedback loop with STRA8-MEIOSIN downstream of BMP signaling [#7]. In humans, pathogenic YTHDC2 variants destabilize the MEIOC/RBM46 complex and cause failure to silence the mitotic program in cells expressing meiosis markers, linking the complex to non-obstructive azoospermia [#8].\",\n  \"teleology\": [\n    {\n      \"year\": 2016,\n      \"claim\": \"Established that a meiosis-specific factor stabilizes meiotic transcripts and acts through an RNA helicase, defining MEIOC as a post-transcriptional regulator of meiosis rather than a transcription factor.\",\n      \"evidence\": \"Mouse Meioc knockout with co-immunoprecipitation and RNA-binding assays identifying YTHDC2 interaction\",\n      \"pmids\": [\"26742488\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct RNA targets and sequence specificity not yet mapped\", \"Mechanism of transcript stabilization versus degradation not resolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showed that MEIOC and YTHDC2 act together to impose a meiotic rather than mitotic cell-cycle program, explaining why loss causes premature mitotic-like behavior.\",\n      \"evidence\": \"Mouse Meioc knockout with reciprocal Co-IP/pulldown, CYCLIN A2 immunofluorescence, and chromosome spreading\",\n      \"pmids\": [\"28380054\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish whether mitotic transcripts are direct degradation targets\", \"Granule/complex composition incomplete\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Genetic epistasis placed MEIOC and YTHDC2 in the same meiotic-entry pathway, confirming functional partnership rather than coincidental interaction.\",\n      \"evidence\": \"Phenocopy analysis of ketu/Ythdc2 and Meioc mutants plus Co-IP\",\n      \"pmids\": [\"29360036\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct mRNA targets still undefined\", \"No structural basis for complex assembly\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified RBM46 as the sequence-specific RNA-binding component of the complex, defining how mitotic transcripts are recognized and degraded near YTHDC2 U-rich motifs.\",\n      \"evidence\": \"Testis-specific Rbm46 conditional knockout, Co-IP, CLIP analysis, and RNA-seq\",\n      \"pmids\": [\"36001654\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and contribution of each subunit to decay not dissected\", \"MEIOC's specific molecular role within the complex unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined the downstream logic: complex-mediated decay of repressors E2f6 and Mga derepresses Meiosin, conferring competence to activate STRA8-MEIOSIN before overt meiotic entry.\",\n      \"evidence\": \"scRNA-seq and bulk RNA-seq of synchronized Meioc mutant spermatogenesis\",\n      \"pmids\": [\"38884383\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct versus indirect target distinction relies on inference\", \"Temporal coupling to retinoic acid signaling not mechanistically resolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed MEIOC co-localizes with YTHDC2 in RNA granules in late spermatocytes, indicating granule-based regulation extends beyond meiotic entry.\",\n      \"evidence\": \"Inducible conditional Ythdc2 knockout with Co-IP and granule immunofluorescence\",\n      \"pmids\": [\"39378093\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"MEIOC-specific function in granules not isolated\", \"Single lab; functional consequence of granule localization untested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Revealed a complex-independent role in zebrafish where Meioc prevents nucleolar accumulation of Piwil1, permitting rRNA upregulation needed for spermatogonial stem cell differentiation.\",\n      \"evidence\": \"Zebrafish meioc mutant analysis with Co-IP, colocalization, and ChIP/bisulfite sequencing at 45S-rDNA\",\n      \"pmids\": [\"40705004\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Conservation of this Piwil1-rRNA axis in mammals not tested\", \"Direct Meioc-Piwil1 mechanism (sequestration vs. localization) unresolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Extended MEIOC function to oogenesis, showing it suppresses mitotic cycling via CCNA2 downregulation and forms a positive feedback loop with STRA8-MEIOSIN downstream of BMP signaling.\",\n      \"evidence\": \"Mouse Meioc oogenesis knockout with cell-cycle transcriptomics, CCNA2/MEIOSIN immunofluorescence, and BMP manipulation\",\n      \"pmids\": [\"41287933\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular link from BMP signaling to MEIOC upregulation undefined\", \"Whether feedback loop is direct or mediated by other factors unresolved\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Connected the complex to human disease, showing pathogenic YTHDC2 variants reduce MEIOC/RBM46 levels and cause failure to silence mitotic regulators upon meiotic entry in azoospermia.\",\n      \"evidence\": \"Human NOA patient testis immunofluorescence/western blot with CRISPR knock-in mouse recapitulating the variant\",\n      \"pmids\": [\"42249589\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causality of MEIOC loss versus YTHDC2 loss not separated\", \"MEIOC-specific pathogenic variants in patients not reported here\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Demonstrated reconstitution in vitro that the RBM46/MEIOC/YTHDC2 complex degrades mRNAs through a defined 3' UTR motif, providing direct biochemical evidence for sequence-specific decay.\",\n      \"evidence\": \"Mouse female Rbm46 knockout plus HEK293T reporter degradation assay with AAUCAU motif deletion\",\n      \"pmids\": [\"42217413\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"MEIOC's individual catalytic or scaffolding contribution not isolated in the reconstitution\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed MEIOC overexpression contributes to driving meiotic entry in human iPSCs, establishing it as a pro-meiotic factor in a human gain-of-function context.\",\n      \"evidence\": \"Human iPSC overexpression of MEIOC with co-factors, scored by synaptonemal complex and recombination markers\",\n      \"pmids\": [\"40815662\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"MEIOC's specific contribution not separated from co-expressed BCL2/HOXB5/BOLL\", \"Sufficiency of MEIOC alone untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How MEIOC mechanistically contributes within the YTHDC2/RBM46 complex—scaffolding, helicase regulation, or granule organization—and whether its zebrafish Piwil1-rRNA role is conserved in mammals remain open.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of the MEIOC/YTHDC2/RBM46 complex\", \"MEIOC's distinct molecular activity not separable from partner proteins\", \"Cross-species conservation of nucleolar Piwil1 regulation untested in mammals\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 1, 3]},\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [3, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [5, 6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1474165\", \"supporting_discovery_ids\": [0, 4, 7]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [3, 9]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [1, 7]}\n    ],\n    \"complexes\": [\"YTHDC2/MEIOC/RBM46 mRNA decay complex\"],\n    \"partners\": [\"YTHDC2\", \"RBM46\", \"PIWIL1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}