{"gene":"ERH","run_date":"2026-04-28T17:46:03","timeline":{"discoveries":[{"year":2001,"finding":"Xenopus ERH (XERH), a 104 amino acid protein identical to its mammalian homologs, was identified as an interaction partner of DCoH/PCD (dimerization cofactor of HNF1) by yeast two-hybrid assay. When fused to the GAL4 DNA-binding domain, XERH represses a GAL4-responsive reporter in HeLa cells (but not NIH3T3 cells), and inhibits DCoH/PCD co-activation of an HNF1-responsive reporter, establishing ERH as a cell-type-specific transcriptional repressor that interferes with HNF1-dependent gene regulation via DCoH/PCD.","method":"Yeast two-hybrid, GAL4-reporter transcriptional repression assay in HeLa and NIH3T3 cells","journal":"Biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2-3 — yeast two-hybrid plus functional reporter assay, single lab, two orthogonal methods","pmids":["11688721"],"is_preprint":false},{"year":2005,"finding":"The crystal structure of murine ERH was determined at 2.1 Å resolution by MAD phasing, revealing a novel alpha+beta fold (three alpha-helices and four beta-strands) that forms a homodimer through beta-sheet interactions. Analytical ultracentrifugation confirmed dimer formation in solution. Highly conserved residues at the dimer interface and a conserved flexible loop (residues 44–53) were identified as likely functionally important features. Putative phosphorylation sites at Thr18 and Ser24 were noted.","method":"X-ray crystallography (MAD), analytical ultracentrifugation","journal":"Protein science","confidence":"High","confidence_rationale":"Tier 1 — crystal structure with solution validation by analytical ultracentrifugation","pmids":["15937287"],"is_preprint":false},{"year":2007,"finding":"The crystal structure of human HEF2/ERH was determined at 1.55 Å resolution, confirming the novel alpha+beta fold and a pseudo-beta-barrel at the dimer interface with a cavity channel. In silico docking to the partner protein DCOH/PCD suggested that ERH may regulate the oligomeric state of DCOH/PCD. In silico protein-interaction mapping indicated interactions with transcription factors and cell-cycle regulators.","method":"X-ray crystallography, computational protein docking","journal":"Proteins","confidence":"High","confidence_rationale":"Tier 1 — high-resolution crystal structure; docking is computational but structural data is rigorous","pmids":["17444515"],"is_preprint":false},{"year":2012,"finding":"ERH depletion in human cells caused severe chromosome misalignment and weakened kinetochore-microtubule attachment during mitosis, with dissociation of the mitotic kinesin CENP-E from kinetochores. ERH was found to promote chromosome alignment at the metaphase plate by maintaining CENP-E localization at kinetochores.","method":"siRNA knockdown, immunofluorescence microscopy, live-cell imaging","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2-3 — clean KD with defined mitotic phenotype and molecular readout (CENP-E localization), single lab","pmids":["22704934"],"is_preprint":false},{"year":2012,"finding":"ERH interacts with the spliceosome protein SNRPD3 (an Sm complex component) and is required for the mRNA splicing of CENP-E, a mitotic motor protein. Loss of ERH leads to loss of CENP-E protein and chromosome congression defects. Gene expression profiling showed ERH is required for expression of multiple cell cycle genes. ERH depletion caused greater toxicity in KRAS-mutant cancer cells than in KRAS wild-type cells, identifying a non-oncogene addiction relationship.","method":"Co-immunoprecipitation, RNAi knockdown, gene expression profiling, cell viability assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, multiple orthogonal methods (splicing assays, expression profiling, viability assays), strong mechanistic follow-up","pmids":["23236152"],"is_preprint":false},{"year":2013,"finding":"ERH is recruited to nuclear speckles when co-expressed with PDIP46/SKAR, and to replication foci when co-expressed with Ciz1, in HeLa cells. Mutagenesis identified specific amino acid residues critical for each localization: H3A/Q9A mutations (on the beta-sheet surface, monomer interface) reduce recruitment to nuclear speckles, while E37A/T51A mutations (near the loop between alpha1 and alpha2 helices) impair recruitment to replication foci. GST pull-down confirmed loss of interactions with PDIP46/SKAR and/or Ciz1 for respective mutants, showing only ERH monomers interact with PDIP46/SKAR while both monomers and dimers can interact with Ciz1.","method":"Site-directed mutagenesis, immunofluorescence, GST pull-down, co-transfection","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1-2 — mutagenesis combined with localization imaging and in vitro pull-down; multiple orthogonal methods","pmids":["24015320"],"is_preprint":false},{"year":2015,"finding":"RNA-binding protein Musashi-1 (MSI1) directly targets Erh mRNA in mouse spermatogonia, identified by RIP and overexpression studies using a transgenic Msi1 testis-specific overexpression model, establishing Erh as a translational regulatory target of MSI1 during early spermatogenesis.","method":"RNA immunoprecipitation (RIP), transgenic overexpression model, expression studies","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 3 — RIP identifying ERH mRNA as MSI1 target, single lab","pmids":["25782991"],"is_preprint":false},{"year":2016,"finding":"Drosophila ERH binds RPS3, RPL19, and DDIT4 as identified by yeast two-hybrid screens using both human and Drosophila libraries. The first 24 amino acids of ERH are necessary and sufficient for nuclear localization, and the sequences required for interaction with RPS3 and RPL19 map to this same 24-amino-acid region, suggesting ERH may enter the nucleus by binding to ribosomal proteins such as RPS3 or RPL19 that have DNA-binding activity.","method":"Yeast two-hybrid, deletion mutagenesis, nuclear localization assays","journal":"Molecular biology international","confidence":"Medium","confidence_rationale":"Tier 3 — yeast two-hybrid with functional mapping of nuclear localization sequences, single lab","pmids":["27830090"],"is_preprint":false},{"year":2019,"finding":"In fission yeast, the ERH ortholog Erh1 forms a homodimer that interacts with the YTH-family RNA-binding protein Mmi1 in a 2:2 stoichiometry (Erh1-Mmi1 complex, EMC) via a conserved hydrophobic molecular interface, as revealed by the co-crystal structure. Structure-guided mutation of Mmi1 Trp112, required for Erh1 binding, caused defects in facultative heterochromatin assembly and gametogenic gene silencing while leaving Mmi1-mediated transcription termination intact, delineating the specific contribution of EMC to gene silencing.","method":"X-ray co-crystallography, structure-guided mutagenesis, chromatin immunoprecipitation, gene expression assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 — co-crystal structure with structure-guided mutagenesis and functional validation of gene silencing","pmids":["30651569"],"is_preprint":false},{"year":2019,"finding":"ERH knockdown in human bladder urothelial carcinoma T24 and 5637 cells significantly inhibited cell migration and invasion in vitro, and reduced lung metastasis in nude mouse tail-vein transfer assays. Gene expression profiling identified MYC as a downstream target of ERH, and functional experiments confirmed that ERH regulates MYC expression to control metastatic behavior.","method":"shRNA knockdown, wound-healing assay, transwell migration/invasion assays, nude mouse metastasis model, gene expression profiling","journal":"BMC cancer","confidence":"Medium","confidence_rationale":"Tier 2-3 — multiple migration/invasion assays in vitro and in vivo, downstream target identified; single lab","pmids":["30866868"],"is_preprint":false},{"year":2020,"finding":"ERH was identified as a component of the Microprocessor complex, binding to the N-terminus of DGCR8 via its hydrophobic groove in a 2:2 stoichiometry as revealed by crystal structure and biochemical experiments. Knockdown of ERH or deletion of the DGCR8 N-terminus reduced processing of suboptimal pri-miRNAs in polycistronic miRNA clusters, demonstrating that the ERH dimer mediates 'cluster assistance' by enabling Microprocessor to process a poor substrate when loaded via a high-affinity neighboring substrate.","method":"X-ray crystallography, biochemical binding assays, siRNA knockdown, pri-miRNA processing assays","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 — crystal structure combined with KD and functional miRNA processing assays, multiple orthogonal methods","pmids":["33035348"],"is_preprint":false},{"year":2020,"finding":"ERH copurifies with Microprocessor and can dimerize and interact with other proteins that can dimerize, suggesting a model in which one Microprocessor recruits another Microprocessor to assist processing of suboptimal miRNA hairpins in clusters. The cluster assistance phenomenon for miR-451 requires Microprocessor recognition of a helper hairpin, physical linkage of the two hairpins, and ERH; it acts predominantly after helper-hairpin processing and can act reciprocally and non-co-transcriptionally.","method":"Biochemical copurification, miRNA processing assays, genetic dissection with hairpin variants","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal assays with systematic dissection of ERH requirement in cluster assistance","pmids":["32302541"],"is_preprint":false},{"year":2022,"finding":"ERH interacts with EIF2α (encoded by EIF2S1) in human T24 bladder cancer cells, as confirmed by co-immunoprecipitation/mass spectrometry and immunofluorescence colocalization. The binding sites were predicted by ZDOCK docking. ERH overexpression upregulated mRNA levels of ATF4 and CHOP, downstream molecules in the EIF2α/ATF4/CHOP pathway, placing ERH as a regulator of ER stress signaling.","method":"Co-immunoprecipitation, shotgun mass spectrometry, immunofluorescence colocalization, ZDOCK docking, qPCR","journal":"Frontiers in oncology","confidence":"Medium","confidence_rationale":"Tier 3 — Co-IP/MS with colocalization and downstream gene expression confirmation, single lab","pmids":["35774124"],"is_preprint":false},{"year":2022,"finding":"The crystal structure of ERH bound to a CIZ1 fragment was solved, revealing that the ERH dimer binds to two CIZ1 fragments in a 2:2 heterotetramer. CIZ1 forms intermolecular antiparallel beta-strands with ERH, and the CIZ1-binding surface on ERH is distinct from those of other known ERH-binding ligands (DGCR8 and Mmi1). Mutagenesis and binding experiments confirmed the ERH-CIZ1 interface, identifying a new ligand-binding mode for ERH.","method":"X-ray crystallography, GST pull-down, mutagenesis, binding assays","journal":"The FEBS journal","confidence":"High","confidence_rationale":"Tier 1 — crystal structure with mutagenesis validation, multiple orthogonal biochemical methods","pmids":["36047590"],"is_preprint":false}],"current_model":"ERH is a small, evolutionarily conserved homodimeric nuclear protein with a unique alpha+beta fold that acts as a scaffold for multiple RNA-processing complexes: it interacts with the Sm spliceosome component SNRPD3 to regulate pre-mRNA splicing of CENP-E and other cell-cycle genes (required for mitotic chromosome alignment); it associates with the Microprocessor complex by binding DGCR8's N-terminus in a 2:2 stoichiometry to facilitate processing of suboptimal pri-miRNA hairpins in polycistronic clusters; in fission yeast, its ortholog Erh1 forms a 2:2 complex with the YTH-protein Mmi1 to drive facultative heterochromatin assembly and gametogenic gene silencing; ERH also interacts with CIZ1 (directing it to replication foci), PDIP46/SKAR (directing ERH to nuclear speckles), EIF2α, and DCoH/PCD, and functions as a transcriptional repressor in certain cell types, collectively placing ERH at the nexus of mRNA splicing, miRNA biogenesis, heterochromatin formation, and cell cycle progression."},"narrative":{"teleology":[{"year":2001,"claim":"The initial functional context of ERH was established when it was identified as a DCoH/PCD-interacting protein that acts as a cell-type-specific transcriptional repressor, linking this conserved small protein to HNF1-dependent gene regulation.","evidence":"Yeast two-hybrid and GAL4-reporter repression assays in HeLa and NIH3T3 cells","pmids":["11688721"],"confidence":"Medium","gaps":["Interaction with DCoH/PCD not confirmed by reciprocal Co-IP or structural methods","Mechanism of cell-type specificity of repression unexplored","Endogenous target genes of ERH-DCoH/PCD complex not identified"]},{"year":2005,"claim":"Determination of the ERH crystal structure revealed a novel alpha+beta fold forming a homodimer through beta-sheet interactions, providing the first structural framework for understanding how ERH engages binding partners.","evidence":"X-ray crystallography (MAD phasing, 2.1 Å) with analytical ultracentrifugation confirming solution dimer","pmids":["15937287","17444515"],"confidence":"High","gaps":["No partner-bound co-crystal structures yet available","Functional significance of the conserved flexible loop (residues 44–53) unresolved","Putative phosphorylation sites (Thr18, Ser24) not experimentally validated"]},{"year":2012,"claim":"ERH was shown to be required for mitotic chromosome alignment through its interaction with the spliceosome component SNRPD3 and its role in maintaining CENP-E mRNA splicing, establishing a direct mechanistic link between ERH-dependent splicing and cell-cycle progression.","evidence":"Co-immunoprecipitation, siRNA knockdown, live-cell imaging, gene expression profiling, and cell viability assays in human cancer cell lines","pmids":["22704934","23236152"],"confidence":"High","gaps":["Whether ERH directly contacts pre-mRNA or acts solely via SNRPD3 is unclear","Full spectrum of ERH-dependent splicing targets not delineated","Structural basis of ERH–SNRPD3 interaction not determined"]},{"year":2013,"claim":"Mutagenesis revealed that ERH uses distinct surface patches to interact with different partners (PDIP46/SKAR for nuclear speckle recruitment versus CIZ1 for replication foci recruitment), establishing the multi-interface scaffold concept.","evidence":"Site-directed mutagenesis, immunofluorescence colocalization, and GST pull-down in HeLa cells","pmids":["24015320"],"confidence":"High","gaps":["Functional consequence of ERH at replication foci not determined","Whether monomer-only interaction with PDIP46/SKAR reflects a dimer-disruption mechanism is untested","No co-crystal structures with these partners at this time"]},{"year":2019,"claim":"The co-crystal structure of fission yeast Erh1–Mmi1 (EMC) in a 2:2 complex demonstrated that ERH orthologs use a conserved hydrophobic interface to recruit RNA-binding proteins for facultative heterochromatin assembly and gametogenic gene silencing, extending ERH function to chromatin regulation.","evidence":"X-ray co-crystallography, structure-guided Mmi1 W112 mutagenesis, ChIP, gene expression assays in S. pombe","pmids":["30651569"],"confidence":"High","gaps":["Whether mammalian ERH participates in analogous heterochromatin silencing is unknown","How EMC is recruited to specific genomic loci remains unclear","Relationship between EMC-mediated silencing and the RNAi pathway not fully resolved"]},{"year":2020,"claim":"Two studies converged to show that ERH binds DGCR8 in a 2:2 stoichiometry and is essential for Microprocessor-mediated 'cluster assistance,' whereby a high-affinity pri-miRNA hairpin facilitates processing of a neighboring suboptimal hairpin, revealing a new role for ERH in miRNA biogenesis.","evidence":"Crystal structure of ERH–DGCR8 N-terminus complex, siRNA knockdown, pri-miRNA processing assays, biochemical copurification, genetic dissection with hairpin variants","pmids":["33035348","32302541"],"confidence":"High","gaps":["In vivo global impact on miRNA maturation profiles upon ERH loss not comprehensively mapped","Whether ERH-mediated Microprocessor dimerization occurs co-transcriptionally in chromatin context is unresolved","Structural mechanism of how ERH bridges two Microprocessor units at polycistronic loci not fully elucidated"]},{"year":2022,"claim":"The ERH–CIZ1 co-crystal structure revealed a distinct ligand-binding mode (intermolecular antiparallel beta-strands) on a surface separate from DGCR8 and Mmi1 binding sites, establishing that ERH uses at least three non-overlapping interfaces to engage different partners.","evidence":"X-ray crystallography, GST pull-down, mutagenesis, and binding assays","pmids":["36047590"],"confidence":"High","gaps":["Functional role of ERH–CIZ1 complex at replication foci still uncharacterized","Whether simultaneous multi-partner engagement occurs in cells is unknown","No structure of ERH–SNRPD3 complex available to complete the interface map"]},{"year":null,"claim":"Key unresolved questions include the structural basis of ERH–SNRPD3 interaction and its role in splicing regulation, whether mammalian ERH participates in heterochromatin formation analogous to fission yeast EMC, and the full scope of ERH-dependent miRNA and mRNA targets that drive its essentiality in cell-cycle progression.","evidence":"","pmids":[],"confidence":"High","gaps":["No ERH–SNRPD3 co-crystal structure","Comprehensive transcriptome-wide identification of ERH-dependent splicing events lacking","In vivo physiological role of ERH in mammalian development not determined using genetic models"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[5,8,10,11,13]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[1,2,13]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[5,7]},{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[5]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[4,10,11]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[3,4]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[8]}],"complexes":["Microprocessor complex (via DGCR8)","Erh1-Mmi1 complex (EMC; fission yeast)"],"partners":["DGCR8","SNRPD3","CIZ1","PDIP46","PCD","MMI1"],"other_free_text":[]},"mechanistic_narrative":"ERH is a small, evolutionarily conserved homodimeric nuclear protein with a unique alpha+beta fold that functions as a multi-interface scaffold linking pre-mRNA splicing, miRNA biogenesis, heterochromatin formation, and cell-cycle progression [PMID:15937287, PMID:17444515]. Through its interaction with the spliceosome component SNRPD3, ERH promotes correct splicing of cell-cycle transcripts including CENP-E, and its depletion causes chromosome misalignment due to loss of CENP-E from kinetochores [PMID:23236152, PMID:22704934]. ERH binds the N-terminus of DGCR8 in a 2:2 stoichiometry to enable Microprocessor-mediated 'cluster assistance,' whereby suboptimal pri-miRNA hairpins within polycistronic clusters are efficiently processed [PMID:33035348, PMID:32302541]. The ERH dimer engages distinct binding surfaces for different partners—DGCR8, CIZ1, Mmi1 (in fission yeast)—each validated by co-crystal structures and mutagenesis, establishing ERH as a versatile protein-protein interaction hub that uses separate interfaces to coordinate diverse nuclear RNA-processing and chromatin-regulatory functions [PMID:36047590, PMID:30651569, PMID:24015320]."},"prefetch_data":{"uniprot":{"accession":"P84090","full_name":"Enhancer of rudimentary homolog","aliases":[],"length_aa":104,"mass_kda":12.3,"function":"May have a role in the cell cycle","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/P84090/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/ERH","classification":"Common Essential","n_dependent_lines":1207,"n_total_lines":1208,"dependency_fraction":0.9991721854304636},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"RBM39","stoichiometry":10.0},{"gene":"RTCB","stoichiometry":10.0},{"gene":"SF3A2","stoichiometry":10.0},{"gene":"SF3B1","stoichiometry":10.0},{"gene":"SNRPB","stoichiometry":10.0},{"gene":"SNRPC","stoichiometry":10.0},{"gene":"SSRP1","stoichiometry":10.0},{"gene":"TOP1","stoichiometry":10.0},{"gene":"CPSF6","stoichiometry":4.0},{"gene":"DDX21","stoichiometry":4.0}],"url":"https://opencell.sf.czbiohub.org/search/ERH","total_profiled":1310},"omim":[{"mim_id":"601191","title":"ERH mRNA SPLICING AND MITOSIS FACTOR; ERH","url":"https://www.omim.org/entry/601191"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ERH"},"hgnc":{"alias_symbol":["DROER"],"prev_symbol":[]},"alphafold":{"accession":"P84090","domains":[{"cath_id":"3.30.2260.10","chopping":"2-102","consensus_level":"high","plddt":96.4238,"start":2,"end":102}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P84090","model_url":"https://alphafold.ebi.ac.uk/files/AF-P84090-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P84090-F1-predicted_aligned_error_v6.png","plddt_mean":95.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ERH","jax_strain_url":"https://www.jax.org/strain/search?query=ERH"},"sequence":{"accession":"P84090","fasta_url":"https://rest.uniprot.org/uniprotkb/P84090.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P84090/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P84090"}},"corpus_meta":[{"pmid":"31672964","id":"PMC_31672964","title":"Theabrownin from Pu-erh tea attenuates hypercholesterolemia via modulation of gut microbiota and bile acid metabolism.","date":"2019","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/31672964","citation_count":557,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"15656692","id":"PMC_15656692","title":"Comparative studies on the hypolipidemic and growth suppressive effects of oolong, black, pu-erh, and green tea leaves in rats.","date":"2005","source":"Journal of agricultural and food chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15656692","citation_count":121,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"34053553","id":"PMC_34053553","title":"Pu-erh tea ameliorates obesity and modulates gut microbiota in high fat diet fed mice.","date":"2021","source":"Food research international (Ottawa, Ont.)","url":"https://pubmed.ncbi.nlm.nih.gov/34053553","citation_count":120,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"21656777","id":"PMC_21656777","title":"Effects of enzymatic action on the formation of theabrownin during solid state fermentation of Pu-erh tea.","date":"2011","source":"Journal of the science of food and agriculture","url":"https://pubmed.ncbi.nlm.nih.gov/21656777","citation_count":108,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"25820466","id":"PMC_25820466","title":"Pu-erh tea polysaccharides decrease blood sugar by inhibition of α-glucosidase activity in vitro and in mice.","date":"2015","source":"Food & function","url":"https://pubmed.ncbi.nlm.nih.gov/25820466","citation_count":83,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"25974221","id":"PMC_25974221","title":"An Integrated Metagenomics/Metaproteomics Investigation of the Microbial Communities and Enzymes in Solid-state Fermentation of Pu-erh tea.","date":"2015","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/25974221","citation_count":82,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"15612813","id":"PMC_15612813","title":"Effects of pu-erh tea on oxidative damage and nitric oxide scavenging.","date":"2004","source":"Journal of agricultural and food chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15612813","citation_count":74,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"20722930","id":"PMC_20722930","title":"Effects of theabrownin from pu-erh tea on the metabolism of serum lipids in rats: mechanism of action.","date":"2010","source":"Journal of food science","url":"https://pubmed.ncbi.nlm.nih.gov/20722930","citation_count":73,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"34460244","id":"PMC_34460244","title":"Aged Ripe Pu-erh Tea Reduced Oxidative Stress-Mediated Inflammation in Dextran Sulfate Sodium-Induced Colitis Mice by Regulating Intestinal Microbes.","date":"2021","source":"Journal of agricultural and food chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/34460244","citation_count":64,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"22127373","id":"PMC_22127373","title":"Pu-erh tea, green tea, and black tea suppresses hyperlipidemia, hyperleptinemia and fatty acid synthase through activating AMPK in rats fed a high-fructose diet.","date":"2011","source":"Food & function","url":"https://pubmed.ncbi.nlm.nih.gov/22127373","citation_count":63,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"25098399","id":"PMC_25098399","title":"Oolong, black and pu-erh tea suppresses adiposity in mice via activation of AMP-activated protein kinase.","date":"2014","source":"Food & function","url":"https://pubmed.ncbi.nlm.nih.gov/25098399","citation_count":62,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"19916505","id":"PMC_19916505","title":"Application of metabolomics in the analysis of manufacturing type of pu-erh tea and composition changes with different postfermentation year.","date":"2010","source":"Journal of agricultural and food chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/19916505","citation_count":60,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"23236152","id":"PMC_23236152","title":"Evolutionarily conserved protein ERH controls CENP-E mRNA splicing and is required for the survival of KRAS mutant cancer cells.","date":"2012","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/23236152","citation_count":58,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32302541","id":"PMC_32302541","title":"MicroRNA Clustering Assists Processing of Suboptimal MicroRNA Hairpins through the Action of the ERH Protein.","date":"2020","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/32302541","citation_count":58,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"33570405","id":"PMC_33570405","title":"Ripened Pu-erh Tea Extract Promotes Gut Microbiota Resilience against Dextran Sulfate Sodium Induced Colitis.","date":"2021","source":"Journal of agricultural and food chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/33570405","citation_count":55,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"26794005","id":"PMC_26794005","title":"Pu-erh tea extract ameliorates high-fat diet-induced nonalcoholic steatohepatitis and insulin resistance by modulating hepatic IL-6/STAT3 signaling in mice.","date":"2016","source":"Journal of gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/26794005","citation_count":49,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"17032009","id":"PMC_17032009","title":"Free radical scavenging effect of Pu-erh tea extracts and their protective effect on oxidative damage in human fibroblast cells.","date":"2006","source":"Journal of agricultural and food chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/17032009","citation_count":46,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"19459711","id":"PMC_19459711","title":"Pu-erh tea attenuates hyperlipogenesis and induces hepatoma cells growth arrest through activating AMP-activated protein kinase (AMPK) in human HepG2 cells.","date":"2009","source":"Journal of agricultural and food chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/19459711","citation_count":43,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"36461373","id":"PMC_36461373","title":"Pu-erh tea and theabrownin ameliorate metabolic syndrome in mice via potential microbiota-gut-liver-brain interactions.","date":"2022","source":"Food research international (Ottawa, Ont.)","url":"https://pubmed.ncbi.nlm.nih.gov/36461373","citation_count":39,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"34601212","id":"PMC_34601212","title":"Investigation and dynamic profiling of oligopeptides, free amino acids and derivatives during Pu-erh tea fermentation by ultra-high performance liquid chromatography tandem mass spectrometry.","date":"2021","source":"Food chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/34601212","citation_count":37,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"24078386","id":"PMC_24078386","title":"The enigmatic ERH protein: its role in cell cycle, RNA splicing and cancer.","date":"2013","source":"Protein & cell","url":"https://pubmed.ncbi.nlm.nih.gov/24078386","citation_count":37,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"31273522","id":"PMC_31273522","title":"Theabrownin from Pu-erh tea together with swinging exercise synergistically ameliorates obesity and insulin resistance in rats.","date":"2019","source":"European journal of nutrition","url":"https://pubmed.ncbi.nlm.nih.gov/31273522","citation_count":36,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"11688721","id":"PMC_11688721","title":"ERH (enhancer of rudimentary homologue), a conserved factor identical between frog and human, is a transcriptional repressor.","date":"2001","source":"Biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11688721","citation_count":36,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"23211442","id":"PMC_23211442","title":"Studies on the bioactivity of aqueous extract of pu-erh tea and its fractions: in vitro antioxidant activity and α-glycosidase inhibitory property, and their effect on postprandial hyperglycemia in diabetic mice.","date":"2012","source":"Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association","url":"https://pubmed.ncbi.nlm.nih.gov/23211442","citation_count":35,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"35749873","id":"PMC_35749873","title":"Pu-erh tea increases the metabolite Cinnabarinic acid to improve circadian rhythm disorder-induced obesity.","date":"2022","source":"Food chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/35749873","citation_count":34,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30651569","id":"PMC_30651569","title":"A conserved dimer interface connects ERH and YTH family proteins to promote gene silencing.","date":"2019","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/30651569","citation_count":33,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"28620304","id":"PMC_28620304","title":"Pu-erh Tea Extract Ameliorates Ovariectomy-Induced Osteoporosis in Rats and Suppresses Osteoclastogenesis In Vitro.","date":"2017","source":"Frontiers in pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/28620304","citation_count":32,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"21112366","id":"PMC_21112366","title":"Pu-erh black tea supplementation decreases quinocetone-induced ROS generation and oxidative DNA damage in Balb/c mice.","date":"2010","source":"Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association","url":"https://pubmed.ncbi.nlm.nih.gov/21112366","citation_count":32,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"16925113","id":"PMC_16925113","title":"Pu-erh tea supplementation suppresses fatty acid synthase expression in the rat liver through downregulating Akt and JNK signalings as demonstrated in human hepatoma HepG2 cells.","date":"2005","source":"Oncology research","url":"https://pubmed.ncbi.nlm.nih.gov/16925113","citation_count":31,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"33035348","id":"PMC_33035348","title":"ERH facilitates microRNA maturation through the interaction with the N-terminus of DGCR8.","date":"2020","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/33035348","citation_count":31,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30804786","id":"PMC_30804786","title":"Pu-erh Tea Regulates Fatty Acid Metabolism in Mice Under High-Fat Diet.","date":"2019","source":"Frontiers in pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/30804786","citation_count":31,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"15937287","id":"PMC_15937287","title":"Crystal structure of an enhancer of rudimentary homolog (ERH) at 2.1 Angstroms resolution.","date":"2005","source":"Protein science : a publication of the Protein Society","url":"https://pubmed.ncbi.nlm.nih.gov/15937287","citation_count":30,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30610284","id":"PMC_30610284","title":"Aqueous raw and ripe Pu-erh tea extracts alleviate obesity and alter cecal microbiota composition and function in diet-induced obese rats.","date":"2019","source":"Applied microbiology and biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/30610284","citation_count":30,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"24604453","id":"PMC_24604453","title":"Component analysis of Pu-erh and its anti-constipation effects.","date":"2014","source":"Molecular medicine reports","url":"https://pubmed.ncbi.nlm.nih.gov/24604453","citation_count":29,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"23591759","id":"PMC_23591759","title":"Structure and dynamics of the bacterial communities in fermentation of the traditional Chinese post-fermented pu-erh tea revealed by 16S rRNA gene clone library.","date":"2013","source":"World journal of microbiology & biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/23591759","citation_count":29,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"27578019","id":"PMC_27578019","title":"Pu-erh Tea Protects the Nervous System by Inhibiting the Expression of Metabotropic Glutamate Receptor 5.","date":"2016","source":"Molecular neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/27578019","citation_count":28,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30866868","id":"PMC_30866868","title":"The ERH gene regulates migration and invasion in 5637 and T24 bladder cancer cells.","date":"2019","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/30866868","citation_count":28,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"35475616","id":"PMC_35475616","title":"Pu-erh Tea Restored Circadian Rhythm Disruption by Regulating Tryptophan Metabolism.","date":"2022","source":"Journal of agricultural and food chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/35475616","citation_count":28,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"25782991","id":"PMC_25782991","title":"RNA binding protein Musashi-1 directly targets Msi2 and Erh during early testis germ cell development and interacts with IPO5 upon translocation to the nucleus.","date":"2015","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/25782991","citation_count":27,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"22704934","id":"PMC_22704934","title":"Enhancer of rudimentary homolog (ERH) plays an essential role in the progression of mitosis by promoting mitotic chromosome alignment.","date":"2012","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/22704934","citation_count":26,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"28366855","id":"PMC_28366855","title":"Physicochemical properties and cell-based bioactivity of Pu'erh tea polysaccharide conjugates.","date":"2017","source":"International journal of biological macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/28366855","citation_count":25,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"22174618","id":"PMC_22174618","title":"Pu-erh tea inhibits tumor cell growth by down-regulating mutant p53.","date":"2011","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/22174618","citation_count":25,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"25659129","id":"PMC_25659129","title":"Pu-erh tea down-regulates sterol regulatory element-binding protein and stearyol-CoA desaturase to reduce fat storage in Caenorhaditis elegans.","date":"2015","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/25659129","citation_count":25,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"28364190","id":"PMC_28364190","title":"Pu'erh tea extract-mediated protection against hepatosteatosis and insulin resistance in mice with diet-induced obesity is associated with the induction of de novo lipogenesis in visceral adipose tissue.","date":"2017","source":"Journal of gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/28364190","citation_count":24,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"23831194","id":"PMC_23831194","title":"Free radical scavenging and anti-oxidative activities of an ethanol-soluble pigment extract prepared from fermented Zijuan Pu-erh tea.","date":"2013","source":"Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association","url":"https://pubmed.ncbi.nlm.nih.gov/23831194","citation_count":24,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32239008","id":"PMC_32239008","title":"Hot-water extract of ripened Pu-erh tea attenuates DSS-induced colitis through modulation of the NF-κB and HIF-1α signaling pathways in mice.","date":"2020","source":"Food & function","url":"https://pubmed.ncbi.nlm.nih.gov/32239008","citation_count":24,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"33233112","id":"PMC_33233112","title":"Optimizing the extraction of bioactive compounds from pu-erh tea (Camellia sinensis var. assamica) and evaluation of antioxidant, cytotoxic, antimicrobial, antihemolytic, and inhibition of α-amylase and α-glucosidase activities.","date":"2020","source":"Food research international (Ottawa, Ont.)","url":"https://pubmed.ncbi.nlm.nih.gov/33233112","citation_count":24,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"22014163","id":"PMC_22014163","title":"Pu-Erh tea and GABA attenuates oxidative stress in kainic acid-induced status epilepticus.","date":"2011","source":"Journal of biomedical science","url":"https://pubmed.ncbi.nlm.nih.gov/22014163","citation_count":23,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"23832364","id":"PMC_23832364","title":"Pu-erh tea suppresses diet-induced body fat accumulation in C57BL/6J mice by down-regulating SREBP-1c and related molecules.","date":"2013","source":"Bioscience, biotechnology, and biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/23832364","citation_count":22,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"8948440","id":"PMC_8948440","title":"The embryonic RNA helicase gene (ERH): a new member of the DEAD box family of RNA helicases.","date":"1995","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/8948440","citation_count":22,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"18500978","id":"PMC_18500978","title":"Enhancer of the rudimentary gene homologue (ERH) expression pattern in sporadic human breast cancer and normal breast tissue.","date":"2008","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/18500978","citation_count":22,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"22482420","id":"PMC_22482420","title":"Inhibition of advanced glycation end product formation by Pu-erh tea ameliorates progression of experimental diabetic nephropathy.","date":"2012","source":"Journal of agricultural and food chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/22482420","citation_count":21,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"8786099","id":"PMC_8786099","title":"Cloning and mapping of a novel human cDNA homologous to DROER, the enhancer of the Drosophila melanogaster rudimentary gene.","date":"1996","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/8786099","citation_count":20,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"36461293","id":"PMC_36461293","title":"Multi-omics analysis of the metabolism of phenolic compounds in tea leaves by Aspergillus luchuensis during fermentation of pu-erh tea.","date":"2022","source":"Food research international (Ottawa, Ont.)","url":"https://pubmed.ncbi.nlm.nih.gov/36461293","citation_count":20,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"21870867","id":"PMC_21870867","title":"Inhibition of the replication of hepatitis B virus in vitro by pu-erh tea extracts.","date":"2011","source":"Journal of agricultural and food chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21870867","citation_count":20,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"39232541","id":"PMC_39232541","title":"Identification and molecular mechanism of novel hypoglycemic peptide in ripened pu-erh tea: Molecular docking, dynamic simulation, and cell experiments.","date":"2024","source":"Food research international (Ottawa, Ont.)","url":"https://pubmed.ncbi.nlm.nih.gov/39232541","citation_count":20,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"17444515","id":"PMC_17444515","title":"A 1.55 A resolution X-ray crystal structure of HEF2/ERH and insights into its transcriptional and cell-cycle interaction networks.","date":"2007","source":"Proteins","url":"https://pubmed.ncbi.nlm.nih.gov/17444515","citation_count":20,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"37024732","id":"PMC_37024732","title":"Theabrownin of raw and ripened pu-erh tea varies in the alleviation of HFD-induced obesity via the regulation of gut microbiota.","date":"2023","source":"European journal of nutrition","url":"https://pubmed.ncbi.nlm.nih.gov/37024732","citation_count":19,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30699941","id":"PMC_30699941","title":"Ripe and Raw Pu-Erh Tea: LC-MS Profiling, Antioxidant Capacity and Enzyme Inhibition Activities of Aqueous and Hydro-Alcoholic Extracts.","date":"2019","source":"Molecules (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/30699941","citation_count":19,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"35677162","id":"PMC_35677162","title":"ERH Gene and Its Role in Cancer Cells.","date":"2022","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/35677162","citation_count":18,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"28428754","id":"PMC_28428754","title":"Pu-erh Tea Water Extract Mediates Cell Cycle Arrest and Apoptosis in MDA-MB-231 Human Breast Cancer Cells.","date":"2017","source":"Frontiers in pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/28428754","citation_count":18,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"22079314","id":"PMC_22079314","title":"Pu-erh black tea extract supplementation attenuates the oxidative DNA damage and oxidative stress in Sprague-Dawley rats with renal dysfunction induced by subchronic 3-methyl-2-quinoxalin benzenevinylketo-1,4-dioxide exposure.","date":"2011","source":"Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association","url":"https://pubmed.ncbi.nlm.nih.gov/22079314","citation_count":18,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"24804206","id":"PMC_24804206","title":"Pu-erh tea extract induces the degradation of FET family proteins involved in the pathogenesis of amyotrophic lateral sclerosis.","date":"2014","source":"BioMed research international","url":"https://pubmed.ncbi.nlm.nih.gov/24804206","citation_count":18,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32405406","id":"PMC_32405406","title":"Correlation analysis between filamentous fungi and chemical compositions in a pu-erh type tea after a long-term storage.","date":"2020","source":"Food science & nutrition","url":"https://pubmed.ncbi.nlm.nih.gov/32405406","citation_count":17,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"35040129","id":"PMC_35040129","title":"Theabrownin isolated from Pu-erh tea regulates Bacteroidetes to improve metabolic syndrome of rats induced by high-fat, high-sugar and high-salt diet.","date":"2022","source":"Journal of the science of food and agriculture","url":"https://pubmed.ncbi.nlm.nih.gov/35040129","citation_count":17,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"36592713","id":"PMC_36592713","title":"Pu-erh tea alleviated colitis-mediated brain dysfunction by promoting butyric acid production.","date":"2022","source":"Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association","url":"https://pubmed.ncbi.nlm.nih.gov/36592713","citation_count":17,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"39029137","id":"PMC_39029137","title":"Theabrownin from Pu-erh Tea Improves DSS-Induced Colitis via Restoring Gut Homeostasis and Inhibiting TLR2&4 Signaling Pathway.","date":"2024","source":"Phytomedicine : international journal of phytotherapy and phytopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/39029137","citation_count":16,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"35774124","id":"PMC_35774124","title":"ERH Interacts With EIF2α and Regulates the EIF2α/ATF4/CHOP Pathway in Bladder Cancer Cells.","date":"2022","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/35774124","citation_count":15,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"22837686","id":"PMC_22837686","title":"Pu-erh tea reduces nitric oxide levels in rats by inhibiting inducible nitric oxide synthase expression through toll-like receptor 4.","date":"2012","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/22837686","citation_count":15,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"28164196","id":"PMC_28164196","title":"Preventive effect of Silibinin in combination with Pu-erh tea extract on non-alcoholic fatty liver disease in ob/ob mice.","date":"2017","source":"Food & function","url":"https://pubmed.ncbi.nlm.nih.gov/28164196","citation_count":15,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"31558747","id":"PMC_31558747","title":"Isolation, analysis and in vitro assessment of CYP3A4 inhibition by methylxanthines extracted from Pu-erh and Bancha tea leaves.","date":"2019","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/31558747","citation_count":14,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"37048289","id":"PMC_37048289","title":"Theabrownin Isolated from Pu-Erh Tea Enhances the Innate Immune and Anti-Inflammatory Effects of RAW264.7 Macrophages via the TLR2/4-Mediated Signaling Pathway.","date":"2023","source":"Foods (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/37048289","citation_count":14,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"24579782","id":"PMC_24579782","title":"Fermented Pu-erh tea increases in vitro anticancer activities in HT-29 cells and has antiangiogenetic effects on HUVECs.","date":"2013","source":"Journal of environmental pathology, toxicology and oncology : official organ of the International Society for Environmental Toxicology and Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/24579782","citation_count":14,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"33386866","id":"PMC_33386866","title":"Paenibacillus puerhi sp. nov., isolated from the rhizosphere soil of Pu-erh tea plants (Camellia sinensis var. assamica).","date":"2021","source":"Archives of microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/33386866","citation_count":14,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"21858494","id":"PMC_21858494","title":"Antibacterial property and mechanism of a novel Pu-erh tea nanofibrous membrane.","date":"2011","source":"Applied microbiology and biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/21858494","citation_count":13,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"24015320","id":"PMC_24015320","title":"Identification of amino acid residues of ERH required for its recruitment to nuclear speckles and replication foci in HeLa cells.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24015320","citation_count":13,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"38137315","id":"PMC_38137315","title":"The Characteristic Aroma Compounds of GABA Sun-Dried Green Tea and Raw Pu-Erh Tea Determined by Headspace Solid-Phase Microextraction Gas Chromatography-Mass Spectrometry and Relative Odor Activity Value.","date":"2023","source":"Foods (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/38137315","citation_count":12,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"23027678","id":"PMC_23027678","title":"Effects of aqueous extracts of raw pu-erh tea and ripened pu-erh tea on proliferation and differentiation of 3T3-L1 preadipocytes.","date":"2012","source":"Phytotherapy research : PTR","url":"https://pubmed.ncbi.nlm.nih.gov/23027678","citation_count":12,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"35954052","id":"PMC_35954052","title":"Mellow and Thick Taste of Pu-Erh Ripe Tea Based on Chemical Properties by Sensory-Directed Flavor Analysis.","date":"2022","source":"Foods (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/35954052","citation_count":11,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"39069062","id":"PMC_39069062","title":"Metagenomics-based gene exploration and biochemical characterization of novel glucoamylases and α-amylases in Daqu and Pu-erh tea microorganisms.","date":"2024","source":"International journal of biological macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/39069062","citation_count":11,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"23437791","id":"PMC_23437791","title":"Pu-erh tea hot-water extract activates Akt and induces insulin-independent glucose transport in rat skeletal muscle.","date":"2013","source":"Journal of medicinal food","url":"https://pubmed.ncbi.nlm.nih.gov/23437791","citation_count":10,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"20970486","id":"PMC_20970486","title":"Protective effect of a new amide compound from Pu-erh tea on human micro-vascular endothelial cell against cytotoxicity induced by hydrogen peroxide.","date":"2010","source":"Fitoterapia","url":"https://pubmed.ncbi.nlm.nih.gov/20970486","citation_count":10,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"27001463","id":"PMC_27001463","title":"Pu-erh Tea Extract Attenuates Nicotine-Induced Foam Cell Formation in Primary Cultured Monocytes: An in Vitro Mechanistic Study.","date":"2016","source":"Journal of agricultural and food chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/27001463","citation_count":9,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"35540571","id":"PMC_35540571","title":"Guanine deaminase provides evidence of the increased caffeine content during the piling process of pu'erh tea.","date":"2019","source":"RSC advances","url":"https://pubmed.ncbi.nlm.nih.gov/35540571","citation_count":9,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30210650","id":"PMC_30210650","title":"Pu-erh Tea Ameliorates Atherosclerosis Associated with Promoting Macrophage Apoptosis by Reducing NF-κB Activation in ApoE Knockout Mice.","date":"2018","source":"Oxidative medicine and cellular longevity","url":"https://pubmed.ncbi.nlm.nih.gov/30210650","citation_count":9,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32144435","id":"PMC_32144435","title":"ERH proteins: connecting RNA processing to tumorigenesis?","date":"2020","source":"Current genetics","url":"https://pubmed.ncbi.nlm.nih.gov/32144435","citation_count":8,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"27830090","id":"PMC_27830090","title":"Drosophila Enhancer of Rudimentary Homolog, ERH, Is a Binding Partner of RPS3, RPL19, and DDIT4, Suggesting a Mechanism for the Nuclear Localization of ERH.","date":"2016","source":"Molecular biology international","url":"https://pubmed.ncbi.nlm.nih.gov/27830090","citation_count":8,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"38723460","id":"PMC_38723460","title":"Pu-erh tea theabrownin improves the ovarian function and gut microbiota in laying hens.","date":"2024","source":"Poultry science","url":"https://pubmed.ncbi.nlm.nih.gov/38723460","citation_count":7,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"34008989","id":"PMC_34008989","title":"Proteogenomics Study of Blastobotrys adeninivorans TMCC 70007-A Dominant Yeast in the Fermentation Process of Pu-erh Tea.","date":"2021","source":"Journal of proteome research","url":"https://pubmed.ncbi.nlm.nih.gov/34008989","citation_count":7,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"33809701","id":"PMC_33809701","title":"Apoptotic Effects of Anthocyanins from Vitis coignetiae Pulliat Are Enhanced by Augmented Enhancer of the Rudimentary Homolog (ERH) in Human Gastric Carcinoma MKN28 Cells.","date":"2021","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/33809701","citation_count":6,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"16511088","id":"PMC_16511088","title":"Overproduction, purification, crystallization and preliminary X-ray diffraction studies of the human transcription repressor ERH.","date":"2005","source":"Acta crystallographica. Section F, Structural biology and crystallization communications","url":"https://pubmed.ncbi.nlm.nih.gov/16511088","citation_count":6,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"39638201","id":"PMC_39638201","title":"Theabrownin from Pu-erh tea attenuated high-fat diet-induced metabolic syndrome in rat by regulating microRNA and affecting gut microbiota.","date":"2024","source":"International journal of biological macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/39638201","citation_count":6,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"36047590","id":"PMC_36047590","title":"Molecular basis for the recognition of CIZ1 by ERH.","date":"2022","source":"The FEBS journal","url":"https://pubmed.ncbi.nlm.nih.gov/36047590","citation_count":5,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"37887293","id":"PMC_37887293","title":"Thirty Years with ERH: An mRNA Splicing and Mitosis Factor Only or Rather a Novel Genome Integrity Protector?","date":"2023","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/37887293","citation_count":5,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"34499597","id":"PMC_34499597","title":"Massilia puerhi sp. nov., isolated from soil of Pu-erh tea cellar.","date":"2021","source":"International journal of systematic and evolutionary microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/34499597","citation_count":5,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"39521187","id":"PMC_39521187","title":"High lead-tolerant mutant Bacillus tropicus AT31-1 from rhizosphere soil of Pu-erh and its remediation mechanism.","date":"2024","source":"Bioresource technology","url":"https://pubmed.ncbi.nlm.nih.gov/39521187","citation_count":5,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"7330047","id":"PMC_7330047","title":"Defective packing of an unusual DNA in a virulent Erwinia phage, Erh 1.","date":"1981","source":"Progress in clinical and biological research","url":"https://pubmed.ncbi.nlm.nih.gov/7330047","citation_count":5,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"22715783","id":"PMC_22715783","title":"[Spectroscopic and structural characteristics of the main components of Theabrownin in Pu-erh tea].","date":"2012","source":"Guang pu xue yu guang pu fen xi = Guang pu","url":"https://pubmed.ncbi.nlm.nih.gov/22715783","citation_count":5,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"37266757","id":"PMC_37266757","title":"Effects of Pu-erh and Dian Hong tea polyphenols on the gut-liver axis in mice.","date":"2023","source":"AMB Express","url":"https://pubmed.ncbi.nlm.nih.gov/37266757","citation_count":4,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"22855451","id":"PMC_22855451","title":"[The mechanisms of weight-cutting effect and bioactive components in Pu-erh tea].","date":"2012","source":"Dong wu xue yan jiu = Zoological research","url":"https://pubmed.ncbi.nlm.nih.gov/22855451","citation_count":4,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"16169070","id":"PMC_16169070","title":"A human protein-protein interaction network: a resource for annotating the proteome.","date":"2005","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/16169070","citation_count":1704,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"12477932","id":"PMC_12477932","title":"Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences.","date":"2002","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/12477932","citation_count":1479,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"25416956","id":"PMC_25416956","title":"A proteome-scale map of the human interactome network.","date":"2014","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/25416956","citation_count":977,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"22681889","id":"PMC_22681889","title":"The mRNA-bound proteome and its global occupancy profile on protein-coding transcripts.","date":"2012","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/22681889","citation_count":973,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"15635413","id":"PMC_15635413","title":"Nucleolar proteome dynamics.","date":"2005","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/15635413","citation_count":934,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"32296183","id":"PMC_32296183","title":"A reference map of the human binary protein interactome.","date":"2020","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/32296183","citation_count":849,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"19490893","id":"PMC_19490893","title":"A genome-wide RNAi screen identifies multiple synthetic lethal interactions with the Ras oncogene.","date":"2009","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/19490893","citation_count":843,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"17353931","id":"PMC_17353931","title":"Large-scale mapping of human protein-protein interactions by mass spectrometry.","date":"2007","source":"Molecular systems biology","url":"https://pubmed.ncbi.nlm.nih.gov/17353931","citation_count":733,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"33961781","id":"PMC_33961781","title":"Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.","date":"2021","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/33961781","citation_count":705,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"29395067","id":"PMC_29395067","title":"High-Density Proximity Mapping Reveals the Subcellular Organization of mRNA-Associated Granules and Bodies.","date":"2018","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/29395067","citation_count":580,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"28302793","id":"PMC_28302793","title":"Anticancer sulfonamides target splicing by inducing RBM39 degradation via recruitment to DCAF15.","date":"2017","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/28302793","citation_count":533,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"33080218","id":"PMC_33080218","title":"SARS-CoV-2 Disrupts Splicing, Translation, and Protein Trafficking to Suppress Host Defenses.","date":"2020","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/33080218","citation_count":449,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"15489334","id":"PMC_15489334","title":"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).","date":"2004","source":"Genome research","url":"https://pubmed.ncbi.nlm.nih.gov/15489334","citation_count":438,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"35271311","id":"PMC_35271311","title":"OpenCell: Endogenous tagging for the cartography of human cellular organization.","date":"2022","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/35271311","citation_count":432,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"20360068","id":"PMC_20360068","title":"Systematic analysis of human protein complexes identifies chromosome segregation proteins.","date":"2010","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/20360068","citation_count":421,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"15166316","id":"PMC_15166316","title":"Dissection of the mammalian midbody proteome reveals conserved cytokinesis mechanisms.","date":"2004","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/15166316","citation_count":417,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"17620599","id":"PMC_17620599","title":"Functional specialization of beta-arrestin interactions revealed by proteomic analysis.","date":"2007","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/17620599","citation_count":360,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"34079125","id":"PMC_34079125","title":"A proximity-dependent biotinylation map of a human cell.","date":"2021","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/34079125","citation_count":339,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"23084401","id":"PMC_23084401","title":"The cellular EJC interactome reveals higher-order mRNP structure and an EJC-SR protein nexus.","date":"2012","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/23084401","citation_count":272,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21900206","id":"PMC_21900206","title":"A directed protein interaction network for investigating intracellular signal transduction.","date":"2011","source":"Science signaling","url":"https://pubmed.ncbi.nlm.nih.gov/21900206","citation_count":258,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"35031058","id":"PMC_35031058","title":"EWSR1-induced circNEIL3 promotes glioma progression and exosome-mediated macrophage immunosuppressive polarization via stabilizing IGF2BP3.","date":"2022","source":"Molecular cancer","url":"https://pubmed.ncbi.nlm.nih.gov/35031058","citation_count":257,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"35063084","id":"PMC_35063084","title":"Tau interactome maps synaptic and mitochondrial processes associated with neurodegeneration.","date":"2022","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/35063084","citation_count":256,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"30033366","id":"PMC_30033366","title":"Mapping the Genetic Landscape of Human Cells.","date":"2018","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/30033366","citation_count":225,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"19460752","id":"PMC_19460752","title":"A genome-wide short hairpin RNA screening of jurkat T-cells for human proteins contributing to productive HIV-1 replication.","date":"2009","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/19460752","citation_count":211,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"26618866","id":"PMC_26618866","title":"∆F508 CFTR interactome remodelling promotes rescue of cystic fibrosis.","date":"2015","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/26618866","citation_count":209,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21516116","id":"PMC_21516116","title":"Next-generation sequencing to generate interactome datasets.","date":"2011","source":"Nature methods","url":"https://pubmed.ncbi.nlm.nih.gov/21516116","citation_count":200,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"23022380","id":"PMC_23022380","title":"NOTCH1 nuclear interactome reveals key regulators of its transcriptional activity and oncogenic function.","date":"2012","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/23022380","citation_count":174,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"32807901","id":"PMC_32807901","title":"UFMylation maintains tumour suppressor p53 stability by antagonizing its ubiquitination.","date":"2020","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/32807901","citation_count":168,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"30804502","id":"PMC_30804502","title":"H4K20me0 recognition by BRCA1-BARD1 directs homologous recombination to sister chromatids.","date":"2019","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/30804502","citation_count":162,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"30833792","id":"PMC_30833792","title":"A protein-interaction network of interferon-stimulated genes extends the innate immune system landscape.","date":"2019","source":"Nature immunology","url":"https://pubmed.ncbi.nlm.nih.gov/30833792","citation_count":159,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":47050,"output_tokens":3377,"usd":0.095903},"stage2":{"model":"claude-opus-4-6","input_tokens":6802,"output_tokens":2289,"usd":0.136852},"total_usd":0.506068,"stage1_batch_id":"msgbatch_0118RScg3WGaGkaZRtWZbtce","stage2_batch_id":"msgbatch_01Cpfzvtbj42aqp5oYZ5Te2s","note":"batch pricing = 50% of standard","round2_stage1":{"model":"claude-sonnet-4-6","input_tokens":58899,"output_tokens":4731,"usd":0.123831},"round2_rules_fired":"R3","round2_stage2":{"model":"claude-opus-4-6","input_tokens":7446,"output_tokens":2497,"usd":0.149482}},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2012,\n      \"finding\": \"ERH interacts with the spliceosome protein SNRPD3 and is required for mRNA splicing of the mitotic motor protein CENP-E; loss of ERH leads to loss of CENP-E protein and chromosome congression defects in mitosis.\",\n      \"method\": \"RNAi knockdown, Co-IP, gene expression profiling, cell biology (mitosis assays)\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP plus functional KD with defined mitotic phenotype, replicated by independent group (PMID:22704934)\",\n      \"pmids\": [\"23236152\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"ERH depletion causes severe chromosome misalignment, weakened kinetochore-microtubule attachment, and dissociation of CENP-E from kinetochores of mitotic chromosomes, establishing ERH as required for mitotic chromosome alignment.\",\n      \"method\": \"siRNA knockdown, immunofluorescence microscopy, live-cell imaging\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KD with specific mitotic phenotype, independently corroborates PMID:23236152\",\n      \"pmids\": [\"22704934\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ERH is a component of the Microprocessor complex; it uses a hydrophobic groove to bind a conserved region in the N-terminus of DGCR8 in a 2:2 stoichiometry, and facilitates processing of suboptimal pri-miRNAs in polycistronic clusters ('cluster assistance').\",\n      \"method\": \"Crystal structure determination, biochemical binding assays, pri-miRNA processing assays, ERH knockdown/DGCR8 N-terminus deletion\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure plus biochemical reconstitution plus mutagenesis, replicated by independent lab (PMID:32302541)\",\n      \"pmids\": [\"33035348\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ERH copurifies with Microprocessor, can dimerize, and is required for cluster-assisted processing of suboptimal miRNA hairpins (e.g., miR-451 assisted by a neighboring hairpin); ERH is proposed to recruit a second Microprocessor complex via its dimerization.\",\n      \"method\": \"Co-purification, miRNA processing assays, ERH depletion, hairpin order/linker-length swap experiments\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods in a single rigorous study, independently corroborated by PMID:33035348\",\n      \"pmids\": [\"32302541\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In fission yeast, the ERH ortholog Erh1 homodimerizes and interacts with the YTH RNA-binding protein Mmi1 in a 2:2 complex (EMC); co-crystal structure reveals Mmi1-Trp112 contacts a conserved dimer interface on Erh1; EMC is required for facultative heterochromatin assembly and gametogenic gene silencing but not for Mmi1-mediated transcription termination.\",\n      \"method\": \"Co-crystal structure, structure-guided mutagenesis, genetic epistasis, chromatin assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — co-crystal structure plus mutagenesis plus functional genetics in a single study\",\n      \"pmids\": [\"30651569\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Crystal structure of murine ERH at 2.1 Å resolution shows a novel alpha+beta fold (three alpha-helices and four beta-strands); ERH forms a homodimer through beta-sheet interactions, confirmed by analytical ultracentrifugation; conserved residues at the dimer interface and a conserved flexible loop (aa 44–53) are identified as likely functional elements.\",\n      \"method\": \"X-ray crystallography (MAD phasing), analytical ultracentrifugation\",\n      \"journal\": \"Protein science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure with solution-phase dimer confirmation\",\n      \"pmids\": [\"15937287\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Human ERH (HEF2/ERH) crystal structure at 1.55 Å confirms a novel alpha+beta fold forming a pseudo-beta-barrel homodimer with a cavity channel at the dimer interface; structural docking suggests ERH may regulate the oligomeric state of its partner DCoH/PCD.\",\n      \"method\": \"X-ray crystallography, in silico protein-interaction mapping, structural docking\",\n      \"journal\": \"Proteins\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — high-resolution crystal structure of human ERH with structural docking analysis\",\n      \"pmids\": [\"17444515\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Xenopus ERH (XERH), which is identical in sequence to mammalian ERH, acts as a transcriptional repressor when fused to the GAL4 DNA-binding domain in HeLa cells; XERH inhibits DCoH/PCD co-activation of an HNF1-responsive reporter and was identified as a DCoH/PCD interaction partner by yeast two-hybrid.\",\n      \"method\": \"Yeast two-hybrid, GAL4 fusion reporter assay, HNF1-responsive reporter assay in HeLa and NIH3T3 cells\",\n      \"journal\": \"Biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — yeast two-hybrid plus functional reporter assays; single lab, cell-type-specific repression\",\n      \"pmids\": [\"11688721\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"ERH is required for localization of CENP-E at kinetochore regions; ERH-depleted cells exhibit chromosome misalignment and weakened kinetochore-microtubule attachment, positioning ERH upstream of CENP-E in the pathway controlling metaphase chromosome alignment.\",\n      \"method\": \"Genetic epistasis by sequential RNAi, immunofluorescence\",\n      \"journal\": \"Protein & cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — review that synthesizes mechanistic findings from the authors' own prior experimental work (PMID:23236152, 22704934)\",\n      \"pmids\": [\"24078386\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"ERH localizes to nuclear speckles when co-expressed with PDIP46/SKAR, and to replication foci when co-expressed with CIZ1; specific ERH residues (H3, Q9 for speckles; E37, T51 for replication foci) are required for each localization and for binding to the respective partners as shown by GST pull-down.\",\n      \"method\": \"Fluorescence microscopy in HeLa cells, site-directed mutagenesis, GST pull-down\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — mutagenesis combined with localization imaging and in vitro pull-down; single lab\",\n      \"pmids\": [\"24015320\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ERH recognizes CIZ1 via a fragment upstream of CIZ1's first zinc finger; crystal structure of ERH–CIZ1 complex shows an ERH homodimer bound to two CIZ1 fragments in a 2:2 heterotetramer via intermolecular antiparallel beta-strands, at a surface distinct from other known ERH-binding sites; mutagenesis validates the interface.\",\n      \"method\": \"GST pull-down, X-ray crystallography, site-directed mutagenesis, binding assays\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — co-crystal structure plus mutagenesis plus biochemical validation\",\n      \"pmids\": [\"36047590\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ERH knockdown in bladder cancer T24 and 5637 cells inhibits cell migration and invasion in vitro and metastasis in vivo; gene expression profiling identifies MYC as a downstream functional target of ERH in T24 cells.\",\n      \"method\": \"shRNA knockdown, wound-healing assay, transwell migration/invasion, nude mouse tail-vein metastasis assay, gene expression chip, functional rescue experiments\",\n      \"journal\": \"BMC cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KD with multiple in vitro and in vivo assays plus downstream target identification; single lab\",\n      \"pmids\": [\"30866868\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ERH interacts with EIF2α (EIF2S1) in human T24 bladder cancer cells, as shown by co-IP/MS and immunofluorescence co-localization; ERH overexpression upregulates downstream ATF4 and CHOP mRNA, linking ERH to the EIF2α/ATF4/CHOP signaling pathway.\",\n      \"method\": \"Co-immunoprecipitation, shotgun mass spectrometry, immunofluorescence co-localization, ZDOCK structural prediction, RT-PCR\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — Co-IP/MS with partial functional follow-up; single lab, limited mechanistic depth\",\n      \"pmids\": [\"35774124\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"In Drosophila ERH, the first 24 amino acids are necessary and sufficient for nuclear localization; yeast two-hybrid screens identify RPS3, RPL19, and DDIT4 as ERH-binding partners, and the ERH sequences required for RPS3 and RPL19 interactions map to the same 24-amino-acid nuclear-localization region, suggesting ERH enters the nucleus by piggy-backing on these ribosomal proteins.\",\n      \"method\": \"Deletion analysis, yeast two-hybrid, fluorescence localization in Drosophila cells\",\n      \"journal\": \"Molecular biology international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — yeast two-hybrid plus deletion mapping; Drosophila ortholog, consistent with mammalian ERH biology\",\n      \"pmids\": [\"27830090\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"RNA-binding protein Musashi-1 (MSI1) directly targets Erh mRNA in mouse spermatogonia, as shown by RIP (RNA immunoprecipitation); MSI1 overexpression in the testis suppresses ERH protein levels, demonstrating translational regulation of ERH by MSI1 during spermatogenesis.\",\n      \"method\": \"RNA immunoprecipitation, transgenic MSI1 overexpression model, expression studies\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — RIP plus transgenic model; single lab, functional consequence on ERH protein level demonstrated\",\n      \"pmids\": [\"25782991\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ERH is a highly conserved homodimeric nuclear scaffold protein that (1) associates with the SNRPD3/spliceosome to facilitate mRNA splicing of cell-cycle genes including CENP-E, thereby enabling mitotic chromosome alignment; (2) forms a stoichiometric 2:2 complex with DGCR8 via a hydrophobic groove to promote Microprocessor-dependent processing of suboptimal pri-miRNA hairpins in polycistronic clusters; and (3) uses its dimer interface to engage diverse RNA-regulatory partners (Mmi1 in fission yeast for heterochromatin-mediated gene silencing; CIZ1 at replication foci; PDIP46/SKAR at nuclear speckles), while also acting as a transcriptional repressor through interaction with DCoH/PCD and regulating cell migration partly through MYC.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll systematically classify each paper before extracting discoveries.\n\n**Classification:**\n\nThe gene ERH (Enhancer of Rudimentary Homolog) is a small, highly conserved nuclear protein involved in mRNA splicing, miRNA biogenesis, cell cycle, and related processes.\n\n**KEEP papers** (about canonical ERH protein):\n- [13] PMID:23236152 - ERH, KRAS, CENP-E splicing\n- [14] PMID:32302541 - ERH in miRNA clustering/Microprocessor\n- [21] PMID:24078386 - ERH review (cell cycle, RNA splicing)\n- [23] PMID:11688721 - XERH as transcriptional repressor\n- [26] PMID:30651569 - ERH/Erh1 crystal structure, gene silencing\n- [30] PMID:33035348 - ERH-DGCR8 interaction, miRNA maturation\n- [32] PMID:15937287 - Crystal structure of ERH\n- [37] PMID:30866868 - ERH in bladder cancer migration/invasion, MYC\n- [39] PMID:25782991 - MSI1 targets Erh mRNA\n- [40] PMID:22704934 - ERH role in mitosis, CENP-E\n- [50] PMID:8948440 - EXCLUDE: This is a different gene \"ERH\" (embryonic RNA helicase, DEAD box) - SYMBOL COLLISION\n- [51] PMID:18500978 - ERH expression in breast cancer (expression only, no mechanism)\n- [53] PMID:8786099 - Human ERH cDNA cloning/mapping\n- [57] PMID:17444515 - HEF2/ERH crystal structure, interactions\n- [60] PMID:35677162 - ERH review\n- [68] PMID:35774124 - ERH interacts with EIF2α\n- [76] PMID:24015320 - ERH recruitment to nuclear speckles, PDIP46/SKAR, Ciz1\n- [86] PMID:32144435 - ERH review\n- [87] PMID:27830090 - Drosophila ERH binding partners RPS3, RPL19, DDIT4\n- [90] PMID:33809701 - ERH augments apoptosis\n- [91] PMID:16511088 - ERH crystal structure\n- [93] PMID:36047590 - ERH-CIZ1 structure\n- [94] PMID:37887293 - ERH comprehensive review\n- Additional gene2pubmed papers relevant to ERH: [1]PMID:16169070, [7]PMID:19490893, [11]PMID:28302793 (splicing context)\n\n**EXCLUDE** (Pu-erh tea, symbol collision with bacteriophage Erh1, or unrelated):\n- Papers [1]-[12], [15]-[20], [22], [24]-[25], [27]-[29], [31]-[36], [38], [41]-[49], [52], [54]-[56], [58]-[59], [61]-[67], [69]-[75], [77]-[85], [88]-[89], [92], [95]-[100]\n- PMID:8948440 [50] - different gene (DEAD box helicase)\n- PMID:7330047 [97] - bacteriophage Erh 1 - SYMBOL COLLISION\n\nAdditional gene2pubmed papers: Most are large proteomics/interactome screens. I'll include those that directly mention ERH interactions with mechanistic context.\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2001,\n      \"finding\": \"Xenopus ERH (XERH), a 104 amino acid protein identical to its mammalian homologs, was identified as an interaction partner of DCoH/PCD (dimerization cofactor of HNF1) by yeast two-hybrid assay. When fused to the GAL4 DNA-binding domain, XERH represses a GAL4-responsive reporter in HeLa cells (but not NIH3T3 cells), and inhibits DCoH/PCD co-activation of an HNF1-responsive reporter, establishing ERH as a cell-type-specific transcriptional repressor that interferes with HNF1-dependent gene regulation via DCoH/PCD.\",\n      \"method\": \"Yeast two-hybrid, GAL4-reporter transcriptional repression assay in HeLa and NIH3T3 cells\",\n      \"journal\": \"Biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — yeast two-hybrid plus functional reporter assay, single lab, two orthogonal methods\",\n      \"pmids\": [\"11688721\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"The crystal structure of murine ERH was determined at 2.1 Å resolution by MAD phasing, revealing a novel alpha+beta fold (three alpha-helices and four beta-strands) that forms a homodimer through beta-sheet interactions. Analytical ultracentrifugation confirmed dimer formation in solution. Highly conserved residues at the dimer interface and a conserved flexible loop (residues 44–53) were identified as likely functionally important features. Putative phosphorylation sites at Thr18 and Ser24 were noted.\",\n      \"method\": \"X-ray crystallography (MAD), analytical ultracentrifugation\",\n      \"journal\": \"Protein science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure with solution validation by analytical ultracentrifugation\",\n      \"pmids\": [\"15937287\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"The crystal structure of human HEF2/ERH was determined at 1.55 Å resolution, confirming the novel alpha+beta fold and a pseudo-beta-barrel at the dimer interface with a cavity channel. In silico docking to the partner protein DCOH/PCD suggested that ERH may regulate the oligomeric state of DCOH/PCD. In silico protein-interaction mapping indicated interactions with transcription factors and cell-cycle regulators.\",\n      \"method\": \"X-ray crystallography, computational protein docking\",\n      \"journal\": \"Proteins\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — high-resolution crystal structure; docking is computational but structural data is rigorous\",\n      \"pmids\": [\"17444515\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"ERH depletion in human cells caused severe chromosome misalignment and weakened kinetochore-microtubule attachment during mitosis, with dissociation of the mitotic kinesin CENP-E from kinetochores. ERH was found to promote chromosome alignment at the metaphase plate by maintaining CENP-E localization at kinetochores.\",\n      \"method\": \"siRNA knockdown, immunofluorescence microscopy, live-cell imaging\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — clean KD with defined mitotic phenotype and molecular readout (CENP-E localization), single lab\",\n      \"pmids\": [\"22704934\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"ERH interacts with the spliceosome protein SNRPD3 (an Sm complex component) and is required for the mRNA splicing of CENP-E, a mitotic motor protein. Loss of ERH leads to loss of CENP-E protein and chromosome congression defects. Gene expression profiling showed ERH is required for expression of multiple cell cycle genes. ERH depletion caused greater toxicity in KRAS-mutant cancer cells than in KRAS wild-type cells, identifying a non-oncogene addiction relationship.\",\n      \"method\": \"Co-immunoprecipitation, RNAi knockdown, gene expression profiling, cell viability assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, multiple orthogonal methods (splicing assays, expression profiling, viability assays), strong mechanistic follow-up\",\n      \"pmids\": [\"23236152\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"ERH is recruited to nuclear speckles when co-expressed with PDIP46/SKAR, and to replication foci when co-expressed with Ciz1, in HeLa cells. Mutagenesis identified specific amino acid residues critical for each localization: H3A/Q9A mutations (on the beta-sheet surface, monomer interface) reduce recruitment to nuclear speckles, while E37A/T51A mutations (near the loop between alpha1 and alpha2 helices) impair recruitment to replication foci. GST pull-down confirmed loss of interactions with PDIP46/SKAR and/or Ciz1 for respective mutants, showing only ERH monomers interact with PDIP46/SKAR while both monomers and dimers can interact with Ciz1.\",\n      \"method\": \"Site-directed mutagenesis, immunofluorescence, GST pull-down, co-transfection\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — mutagenesis combined with localization imaging and in vitro pull-down; multiple orthogonal methods\",\n      \"pmids\": [\"24015320\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"RNA-binding protein Musashi-1 (MSI1) directly targets Erh mRNA in mouse spermatogonia, identified by RIP and overexpression studies using a transgenic Msi1 testis-specific overexpression model, establishing Erh as a translational regulatory target of MSI1 during early spermatogenesis.\",\n      \"method\": \"RNA immunoprecipitation (RIP), transgenic overexpression model, expression studies\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — RIP identifying ERH mRNA as MSI1 target, single lab\",\n      \"pmids\": [\"25782991\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Drosophila ERH binds RPS3, RPL19, and DDIT4 as identified by yeast two-hybrid screens using both human and Drosophila libraries. The first 24 amino acids of ERH are necessary and sufficient for nuclear localization, and the sequences required for interaction with RPS3 and RPL19 map to this same 24-amino-acid region, suggesting ERH may enter the nucleus by binding to ribosomal proteins such as RPS3 or RPL19 that have DNA-binding activity.\",\n      \"method\": \"Yeast two-hybrid, deletion mutagenesis, nuclear localization assays\",\n      \"journal\": \"Molecular biology international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — yeast two-hybrid with functional mapping of nuclear localization sequences, single lab\",\n      \"pmids\": [\"27830090\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In fission yeast, the ERH ortholog Erh1 forms a homodimer that interacts with the YTH-family RNA-binding protein Mmi1 in a 2:2 stoichiometry (Erh1-Mmi1 complex, EMC) via a conserved hydrophobic molecular interface, as revealed by the co-crystal structure. Structure-guided mutation of Mmi1 Trp112, required for Erh1 binding, caused defects in facultative heterochromatin assembly and gametogenic gene silencing while leaving Mmi1-mediated transcription termination intact, delineating the specific contribution of EMC to gene silencing.\",\n      \"method\": \"X-ray co-crystallography, structure-guided mutagenesis, chromatin immunoprecipitation, gene expression assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — co-crystal structure with structure-guided mutagenesis and functional validation of gene silencing\",\n      \"pmids\": [\"30651569\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ERH knockdown in human bladder urothelial carcinoma T24 and 5637 cells significantly inhibited cell migration and invasion in vitro, and reduced lung metastasis in nude mouse tail-vein transfer assays. Gene expression profiling identified MYC as a downstream target of ERH, and functional experiments confirmed that ERH regulates MYC expression to control metastatic behavior.\",\n      \"method\": \"shRNA knockdown, wound-healing assay, transwell migration/invasion assays, nude mouse metastasis model, gene expression profiling\",\n      \"journal\": \"BMC cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — multiple migration/invasion assays in vitro and in vivo, downstream target identified; single lab\",\n      \"pmids\": [\"30866868\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ERH was identified as a component of the Microprocessor complex, binding to the N-terminus of DGCR8 via its hydrophobic groove in a 2:2 stoichiometry as revealed by crystal structure and biochemical experiments. Knockdown of ERH or deletion of the DGCR8 N-terminus reduced processing of suboptimal pri-miRNAs in polycistronic miRNA clusters, demonstrating that the ERH dimer mediates 'cluster assistance' by enabling Microprocessor to process a poor substrate when loaded via a high-affinity neighboring substrate.\",\n      \"method\": \"X-ray crystallography, biochemical binding assays, siRNA knockdown, pri-miRNA processing assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure combined with KD and functional miRNA processing assays, multiple orthogonal methods\",\n      \"pmids\": [\"33035348\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ERH copurifies with Microprocessor and can dimerize and interact with other proteins that can dimerize, suggesting a model in which one Microprocessor recruits another Microprocessor to assist processing of suboptimal miRNA hairpins in clusters. The cluster assistance phenomenon for miR-451 requires Microprocessor recognition of a helper hairpin, physical linkage of the two hairpins, and ERH; it acts predominantly after helper-hairpin processing and can act reciprocally and non-co-transcriptionally.\",\n      \"method\": \"Biochemical copurification, miRNA processing assays, genetic dissection with hairpin variants\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal assays with systematic dissection of ERH requirement in cluster assistance\",\n      \"pmids\": [\"32302541\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ERH interacts with EIF2α (encoded by EIF2S1) in human T24 bladder cancer cells, as confirmed by co-immunoprecipitation/mass spectrometry and immunofluorescence colocalization. The binding sites were predicted by ZDOCK docking. ERH overexpression upregulated mRNA levels of ATF4 and CHOP, downstream molecules in the EIF2α/ATF4/CHOP pathway, placing ERH as a regulator of ER stress signaling.\",\n      \"method\": \"Co-immunoprecipitation, shotgun mass spectrometry, immunofluorescence colocalization, ZDOCK docking, qPCR\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — Co-IP/MS with colocalization and downstream gene expression confirmation, single lab\",\n      \"pmids\": [\"35774124\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"The crystal structure of ERH bound to a CIZ1 fragment was solved, revealing that the ERH dimer binds to two CIZ1 fragments in a 2:2 heterotetramer. CIZ1 forms intermolecular antiparallel beta-strands with ERH, and the CIZ1-binding surface on ERH is distinct from those of other known ERH-binding ligands (DGCR8 and Mmi1). Mutagenesis and binding experiments confirmed the ERH-CIZ1 interface, identifying a new ligand-binding mode for ERH.\",\n      \"method\": \"X-ray crystallography, GST pull-down, mutagenesis, binding assays\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure with mutagenesis validation, multiple orthogonal biochemical methods\",\n      \"pmids\": [\"36047590\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ERH is a small, evolutionarily conserved homodimeric nuclear protein with a unique alpha+beta fold that acts as a scaffold for multiple RNA-processing complexes: it interacts with the Sm spliceosome component SNRPD3 to regulate pre-mRNA splicing of CENP-E and other cell-cycle genes (required for mitotic chromosome alignment); it associates with the Microprocessor complex by binding DGCR8's N-terminus in a 2:2 stoichiometry to facilitate processing of suboptimal pri-miRNA hairpins in polycistronic clusters; in fission yeast, its ortholog Erh1 forms a 2:2 complex with the YTH-protein Mmi1 to drive facultative heterochromatin assembly and gametogenic gene silencing; ERH also interacts with CIZ1 (directing it to replication foci), PDIP46/SKAR (directing ERH to nuclear speckles), EIF2α, and DCoH/PCD, and functions as a transcriptional repressor in certain cell types, collectively placing ERH at the nexus of mRNA splicing, miRNA biogenesis, heterochromatin formation, and cell cycle progression.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"ERH is a highly conserved homodimeric nuclear scaffold protein that couples mRNA splicing, miRNA biogenesis, and heterochromatin-mediated gene silencing by engaging diverse RNA-regulatory partners through its dimer interface. ERH forms a homodimer with a novel α+β pseudo-β-barrel fold and uses distinct surface patches to bind SNRPD3 for spliceosome-dependent processing of mitotic transcripts such as CENP-E, DGCR8 in a 2:2 complex for Microprocessor-mediated cluster-assisted pri-miRNA processing, and CIZ1 at replication foci via intermolecular antiparallel β-strands [PMID:15937287, PMID:33035348, PMID:36047590, PMID:23236152]. Loss of ERH abolishes CENP-E mRNA splicing and kinetochore localization, producing chromosome congression defects in mitosis [PMID:23236152, PMID:22704934]. In fission yeast the conserved dimer interface engages the YTH protein Mmi1 in a 2:2 EMC complex required for facultative heterochromatin assembly and gametogenic gene silencing, demonstrating an ancient role for ERH dimerization in recruiting effector complexes to RNA targets [PMID:30651569].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"The initial molecular function attributed to ERH was transcriptional repression: ERH was identified as a DCoH/PCD-interacting protein that inhibits HNF1-dependent co-activation, establishing ERH as a nuclear factor with gene-regulatory activity.\",\n      \"evidence\": \"Yeast two-hybrid identification and GAL4-fusion reporter assays in HeLa and NIH3T3 cells\",\n      \"pmids\": [\"11688721\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"DCoH interaction shown only by yeast two-hybrid without reciprocal Co-IP\", \"endogenous transcriptional targets of ERH-DCoH axis not identified\", \"physiological relevance of HNF1 co-repression unclear\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Determination of the murine ERH crystal structure revealed a novel α+β fold forming a homodimer through β-sheet interactions, identifying the dimer interface and a conserved flexible loop as the likely functional elements for partner engagement.\",\n      \"evidence\": \"X-ray crystallography at 2.1 Å with analytical ultracentrifugation confirming solution dimer\",\n      \"pmids\": [\"15937287\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"no binding partner mapped to the dimer surface at this stage\", \"function of the conserved loop (aa 44–53) unresolved\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"The human ERH structure at 1.55 Å confirmed the pseudo-β-barrel homodimer with a cavity channel, and structural docking suggested ERH could modulate DCoH oligomeric state, providing a first structural hypothesis for partner regulation.\",\n      \"evidence\": \"X-ray crystallography and in silico docking\",\n      \"pmids\": [\"17444515\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"DCoH regulation model based solely on docking, not biochemically validated\", \"no in vivo evidence for ERH-DCoH stoichiometric modulation\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Two independent studies established that ERH functions in mitotic chromosome alignment by interacting with the spliceosome component SNRPD3 and being required for CENP-E mRNA splicing and kinetochore localization, linking ERH to cell-cycle progression.\",\n      \"evidence\": \"RNAi knockdown, reciprocal Co-IP, immunofluorescence, live-cell imaging in human cells\",\n      \"pmids\": [\"23236152\", \"22704934\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"mechanism by which ERH promotes CENP-E splicing specificity unknown\", \"whether ERH affects splicing of other mitotic transcripts beyond CENP-E not comprehensively tested\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Mapping of ERH partner-specific interaction surfaces showed that distinct residues direct ERH to nuclear speckles (via PDIP46/SKAR) or replication foci (via CIZ1), demonstrating that the small ERH dimer uses separable surfaces for compartment-specific functions.\",\n      \"evidence\": \"Site-directed mutagenesis, GST pull-down, fluorescence microscopy in HeLa cells\",\n      \"pmids\": [\"24015320\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"functional consequences of ERH at replication foci not determined\", \"PDIP46/SKAR interaction lacks structural validation\", \"single-lab observation\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"The fission yeast ERH ortholog Erh1 was shown to form a 2:2 complex with Mmi1 (EMC) required for facultative heterochromatin assembly and gametogenic gene silencing, revealing an evolutionarily conserved role of the ERH dimer interface in recruiting RNA-regulatory effectors.\",\n      \"evidence\": \"Co-crystal structure, structure-guided mutagenesis, chromatin and genetic assays in S. pombe\",\n      \"pmids\": [\"30651569\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"whether human ERH participates in analogous heterochromatin silencing is unknown\", \"downstream effectors recruited by EMC not fully identified\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Two independent studies demonstrated that ERH is a Microprocessor-associated factor that binds DGCR8 in a 2:2 stoichiometry via a hydrophobic groove and facilitates cluster-assisted processing of suboptimal pri-miRNAs, establishing a second major RNA-processing role for ERH alongside its splicing function.\",\n      \"evidence\": \"Crystal structure of ERH–DGCR8 complex, biochemical reconstitution, pri-miRNA processing assays, ERH depletion\",\n      \"pmids\": [\"33035348\", \"32302541\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"full repertoire of ERH-dependent miRNAs not catalogued\", \"how ERH dimerization recruits a second Microprocessor to adjacent hairpins not structurally resolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"The crystal structure of ERH–CIZ1 revealed a 2:2 heterotetramer using intermolecular antiparallel β-strands at a surface distinct from the DGCR8- and Mmi1-binding sites, demonstrating that ERH engages multiple partners simultaneously through non-overlapping interfaces on its dimer.\",\n      \"evidence\": \"X-ray crystallography, mutagenesis, GST pull-down binding assays\",\n      \"pmids\": [\"36047590\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"functional role of ERH–CIZ1 complex at replication foci still undefined\", \"whether ERH can simultaneously bind CIZ1 and DGCR8 not tested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Open question: how ERH achieves substrate selectivity in splicing (e.g., CENP-E specificity), the full scope of ERH-dependent miRNA targets, and whether ERH's distinct partner-binding surfaces enable formation of higher-order multi-partner assemblies remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"mechanism of ERH-mediated splicing selectivity for specific transcripts unknown\", \"no comprehensive miRNA profiling upon ERH loss in matched systems\", \"structural basis for simultaneous multi-partner engagement not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 2, 3, 4, 10]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [9, 13]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 2, 3]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"complexes\": [\n      \"Microprocessor (ERH-DGCR8)\",\n      \"EMC (Erh1-Mmi1)\"\n    ],\n    \"partners\": [\n      \"DGCR8\",\n      \"SNRPD3\",\n      \"CIZ1\",\n      \"PDIP46\",\n      \"DCoH\",\n      \"Mmi1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"ERH is a small, evolutionarily conserved homodimeric nuclear protein with a unique alpha+beta fold that functions as a multi-interface scaffold linking pre-mRNA splicing, miRNA biogenesis, heterochromatin formation, and cell-cycle progression [PMID:15937287, PMID:17444515]. Through its interaction with the spliceosome component SNRPD3, ERH promotes correct splicing of cell-cycle transcripts including CENP-E, and its depletion causes chromosome misalignment due to loss of CENP-E from kinetochores [PMID:23236152, PMID:22704934]. ERH binds the N-terminus of DGCR8 in a 2:2 stoichiometry to enable Microprocessor-mediated 'cluster assistance,' whereby suboptimal pri-miRNA hairpins within polycistronic clusters are efficiently processed [PMID:33035348, PMID:32302541]. The ERH dimer engages distinct binding surfaces for different partners—DGCR8, CIZ1, Mmi1 (in fission yeast)—each validated by co-crystal structures and mutagenesis, establishing ERH as a versatile protein-protein interaction hub that uses separate interfaces to coordinate diverse nuclear RNA-processing and chromatin-regulatory functions [PMID:36047590, PMID:30651569, PMID:24015320].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"The initial functional context of ERH was established when it was identified as a DCoH/PCD-interacting protein that acts as a cell-type-specific transcriptional repressor, linking this conserved small protein to HNF1-dependent gene regulation.\",\n      \"evidence\": \"Yeast two-hybrid and GAL4-reporter repression assays in HeLa and NIH3T3 cells\",\n      \"pmids\": [\"11688721\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Interaction with DCoH/PCD not confirmed by reciprocal Co-IP or structural methods\",\n        \"Mechanism of cell-type specificity of repression unexplored\",\n        \"Endogenous target genes of ERH-DCoH/PCD complex not identified\"\n      ]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Determination of the ERH crystal structure revealed a novel alpha+beta fold forming a homodimer through beta-sheet interactions, providing the first structural framework for understanding how ERH engages binding partners.\",\n      \"evidence\": \"X-ray crystallography (MAD phasing, 2.1 Å) with analytical ultracentrifugation confirming solution dimer\",\n      \"pmids\": [\"15937287\", \"17444515\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No partner-bound co-crystal structures yet available\",\n        \"Functional significance of the conserved flexible loop (residues 44–53) unresolved\",\n        \"Putative phosphorylation sites (Thr18, Ser24) not experimentally validated\"\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"ERH was shown to be required for mitotic chromosome alignment through its interaction with the spliceosome component SNRPD3 and its role in maintaining CENP-E mRNA splicing, establishing a direct mechanistic link between ERH-dependent splicing and cell-cycle progression.\",\n      \"evidence\": \"Co-immunoprecipitation, siRNA knockdown, live-cell imaging, gene expression profiling, and cell viability assays in human cancer cell lines\",\n      \"pmids\": [\"22704934\", \"23236152\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether ERH directly contacts pre-mRNA or acts solely via SNRPD3 is unclear\",\n        \"Full spectrum of ERH-dependent splicing targets not delineated\",\n        \"Structural basis of ERH–SNRPD3 interaction not determined\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Mutagenesis revealed that ERH uses distinct surface patches to interact with different partners (PDIP46/SKAR for nuclear speckle recruitment versus CIZ1 for replication foci recruitment), establishing the multi-interface scaffold concept.\",\n      \"evidence\": \"Site-directed mutagenesis, immunofluorescence colocalization, and GST pull-down in HeLa cells\",\n      \"pmids\": [\"24015320\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Functional consequence of ERH at replication foci not determined\",\n        \"Whether monomer-only interaction with PDIP46/SKAR reflects a dimer-disruption mechanism is untested\",\n        \"No co-crystal structures with these partners at this time\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"The co-crystal structure of fission yeast Erh1–Mmi1 (EMC) in a 2:2 complex demonstrated that ERH orthologs use a conserved hydrophobic interface to recruit RNA-binding proteins for facultative heterochromatin assembly and gametogenic gene silencing, extending ERH function to chromatin regulation.\",\n      \"evidence\": \"X-ray co-crystallography, structure-guided Mmi1 W112 mutagenesis, ChIP, gene expression assays in S. pombe\",\n      \"pmids\": [\"30651569\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether mammalian ERH participates in analogous heterochromatin silencing is unknown\",\n        \"How EMC is recruited to specific genomic loci remains unclear\",\n        \"Relationship between EMC-mediated silencing and the RNAi pathway not fully resolved\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Two studies converged to show that ERH binds DGCR8 in a 2:2 stoichiometry and is essential for Microprocessor-mediated 'cluster assistance,' whereby a high-affinity pri-miRNA hairpin facilitates processing of a neighboring suboptimal hairpin, revealing a new role for ERH in miRNA biogenesis.\",\n      \"evidence\": \"Crystal structure of ERH–DGCR8 N-terminus complex, siRNA knockdown, pri-miRNA processing assays, biochemical copurification, genetic dissection with hairpin variants\",\n      \"pmids\": [\"33035348\", \"32302541\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"In vivo global impact on miRNA maturation profiles upon ERH loss not comprehensively mapped\",\n        \"Whether ERH-mediated Microprocessor dimerization occurs co-transcriptionally in chromatin context is unresolved\",\n        \"Structural mechanism of how ERH bridges two Microprocessor units at polycistronic loci not fully elucidated\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"The ERH–CIZ1 co-crystal structure revealed a distinct ligand-binding mode (intermolecular antiparallel beta-strands) on a surface separate from DGCR8 and Mmi1 binding sites, establishing that ERH uses at least three non-overlapping interfaces to engage different partners.\",\n      \"evidence\": \"X-ray crystallography, GST pull-down, mutagenesis, and binding assays\",\n      \"pmids\": [\"36047590\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Functional role of ERH–CIZ1 complex at replication foci still uncharacterized\",\n        \"Whether simultaneous multi-partner engagement occurs in cells is unknown\",\n        \"No structure of ERH–SNRPD3 complex available to complete the interface map\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural basis of ERH–SNRPD3 interaction and its role in splicing regulation, whether mammalian ERH participates in heterochromatin formation analogous to fission yeast EMC, and the full scope of ERH-dependent miRNA and mRNA targets that drive its essentiality in cell-cycle progression.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No ERH–SNRPD3 co-crystal structure\",\n        \"Comprehensive transcriptome-wide identification of ERH-dependent splicing events lacking\",\n        \"In vivo physiological role of ERH in mammalian development not determined using genetic models\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [5, 8, 10, 11, 13]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [1, 2, 13]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [5, 7]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [4, 10, 11]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [3, 4]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"complexes\": [\n      \"Microprocessor complex (via DGCR8)\",\n      \"Erh1-Mmi1 complex (EMC; fission yeast)\"\n    ],\n    \"partners\": [\n      \"DGCR8\",\n      \"SNRPD3\",\n      \"CIZ1\",\n      \"PDIP46\",\n      \"PCD\",\n      \"MMI1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}