{"gene":"CDAN1","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":2012,"finding":"Codanin-1 (CDAN1) was identified as a direct binding partner of the histone chaperone ASF1 (Anti-Silencing Function 1) via a conserved B-domain, forming part of a cytosolic Asf1-H3.1-H4-Importin-4 complex. This interaction is mutually exclusive with ASF1 binding to CAF-1 and HIRA. Codanin-1 acts as a negative regulator of ASF1 function by sequestering ASF1 in the cytoplasm and blocking histone delivery during DNA replication. Depletion of Codanin-1 accelerates DNA replication and increases chromatin-bound ASF1, while ectopic Codanin-1 expression arrests S-phase progression. Two CDAI disease-causing mutations impair complex formation with ASF1.","method":"Co-immunoprecipitation, pulldown assays, cell fractionation, DNA replication assays, ectopic overexpression, siRNA depletion, mutagenesis of disease-causing alleles","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (Co-IP, in-cell fractionation, functional replication assays, mutagenesis), findings replicated in subsequent independent studies","pmids":["22407294"],"is_preprint":false},{"year":2009,"finding":"Codanin-1 localizes to heterochromatin in interphase cells and undergoes phosphorylation at mitosis, coinciding with its exclusion from condensed chromosomes. Codanin-1 protein levels peak during S phase. The CDAN1 promoter contains E2F binding sites and is a direct transcriptional target of E2F1, as shown by chromatin immunoprecipitation and luciferase reporter assays.","method":"Immunofluorescence, immune electron microscopy, cell synchronization, chromatin immunoprecipitation (ChIP), luciferase reporter assay, E2F1-inducible cell line","journal":"Haematologica","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (immunofluorescence, ChIP, reporter assay) in a single lab","pmids":["19336738"],"is_preprint":false},{"year":2020,"finding":"C15ORF41 (CDIN1) forms a tight, near-stoichiometric heterodimeric complex with the C-terminal region of Codanin-1 in human cells and in vitro. Codanin-1 sequesters C15ORF41 in the cytoplasm, analogous to its sequestration of ASF1. C15ORF41 protein stability depends on Codanin-1.","method":"Immunoprecipitation, in vitro biochemical reconstitution, western blotting, immunofluorescence, cell fractionation","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — reciprocal Co-IP plus in vitro reconstitution and multiple orthogonal methods in single study, independently corroborated by Olijnik et al. 2020","pmids":["32239177"],"is_preprint":false},{"year":2020,"finding":"Both Codanin-1 and C15ORF41 are enriched in the nucleolus. C15ORF41 stability depends on Codanin-1, and both proteins interact to form an obligate complex. Many CDA-I missense and in-frame mutations in Codanin-1 do not destabilize the entire protein but impair specific protein interactions.","method":"Immunoprecipitation, western blotting, immunofluorescence (nucleolar enrichment), patient mutation analysis","journal":"Journal of medical genetics","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — reciprocal immunoprecipitation and immunofluorescence, corroborated by Shroff et al. 2020","pmids":["32518175"],"is_preprint":false},{"year":2021,"finding":"Conditional erythroid-specific deletion of Cdan1 in mice (using ErGFPcre) causes embryonic lethality at E12.5-E13.5 due to severe anemia. Primitive erythroblasts display pathognomonic spongy heterochromatin by electron microscopy, increased apoptosis, failure of semi-synchronous maturation, delayed ζ-to-α globin switch, and increased expression of Gata2, Pu.1, and Runx1. Zebrafish cdan1 knockdown also increases gata2 expression, confirming a conserved role in suppressing inhibitors of terminal erythroid differentiation.","method":"Conditional knockout mouse (Cre-lox), transmission electron microscopy, flow cytometry, Annexin V staining, gene expression analysis, zebrafish morpholino knockdown","journal":"Frontiers in physiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean conditional KO with defined erythroid phenotype and pathway placement, replicated in zebrafish model with orthogonal validation","pmids":["34234671"],"is_preprint":false},{"year":2020,"finding":"CDAN1 mutations at R1042 (mirroring patient mutations) in HUDEP2 human erythroid cells cause decreased viability, increased intercellular bridges and binucleate cells, and alterations in histone acetylation associated with prematurely elevated erythroid gene expression including gamma-globin. This implicates CDAN1 in regulation of DNA replication and chromatin organization specifically during erythroid maturation.","method":"CRISPR/gene editing of HUDEP2 cells, immunofluorescence, flow cytometry, histone modification analysis, gene expression","journal":"Experimental hematology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — engineered patient mutations in human erythroid cell line with multiple cellular readouts, single lab","pmids":["33075436"],"is_preprint":false},{"year":2021,"finding":"CDAN1 and CDIN1 proteins are enriched in nucleoli, which are structurally and functionally abnormal in CDA-I erythroid cells. Erythroid cells from CDA-I patients show delayed terminal erythroid differentiation, increased proliferation, and widespread changes in chromatin accessibility.","method":"In vitro erythroid culture system, electron microscopy, immunofluorescence, ATAC-seq (chromatin accessibility)","journal":"Haematologica","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods in a validated disease-recapitulating culture system, single lab","pmids":["33121234"],"is_preprint":false},{"year":2025,"finding":"Cryo-EM structural analysis reveals that CDAN1 dimerizes and assembles cytosolic complexes containing CDIN1 and multiple copies of ASF1A/B. A single CDAN1 engages two ASF1 molecules via two B-domains (acting as ASF1-binding motifs) and two helices that mimic histone H3 binding, thereby occupying all functional binding sites on ASF1 known to facilitate histone chaperoning. ASF1A and ASF1B have different requirements for CDAN1 engagement.","method":"Single-particle cryo-EM, biochemical reconstitution, structural predictions (AlphaFold), pulldown assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure combined with biochemical reconstitution and mutagenesis/domain mapping in a single rigorous study","pmids":["40091041"],"is_preprint":false},{"year":2024,"finding":"Cryo-EM structures of CDAN1 complexes show CDAN1 dimerizes and recruits two ASF1 molecules per monomer via two B-domains and two histone H3-mimicking helices, blocking all functional ASF1 binding surfaces. This explains the molecular mechanism by which CDAN1 sequesters and inhibits ASF1 chaperone function. (Preprint version of the 2025 Nature Communications paper.)","method":"Single-particle cryo-EM, biochemical reconstitution, structural predictions","journal":"bioRxiv","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure plus biochemical reconstitution; preprint superseded by peer-reviewed publication (PMID 40091041)","pmids":["39149339"],"is_preprint":true},{"year":2026,"finding":"CDIN1 and the C-terminus of Codanin-1 form a high-affinity heterodimeric complex with equimolar stoichiometry. CDA-I-associated mutations in either CDIN1 or Codanin-1 disrupt this interaction, suggesting that loss of the CDIN1-Codanin-1 complex is a molecular mechanism underlying the disease.","method":"Biophysical techniques (ITC, SEC-MALS, or equivalent), structural analysis, mutagenesis of disease-associated variants","journal":"The FEBS journal","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — complementary biophysical techniques and disease mutation analysis, single lab, abstract does not detail all methods","pmids":["41609415"],"is_preprint":false},{"year":2025,"finding":"Codanin-1 knockdown in K562 cells and primary human CD34+ erythroid cells causes morphologic changes resembling CDA-I, altered expression of key erythroid genes, and reduced AHSP (alpha-hemoglobin stabilizing protein) mRNA and protein. ChIP-seq showed increased Codanin-1 occupancy at the AHSP gene regulatory region, implicating direct chromatin-level regulation of erythroid gene expression by Codanin-1.","method":"siRNA knockdown, ChIP-seq, gene expression analysis (RNA-seq/qPCR), western blotting, morphologic analysis","journal":"Annals of hematology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq plus loss-of-function with gene expression readout, two cell models, single lab","pmids":["41028447"],"is_preprint":false}],"current_model":"Codanin-1 (CDAN1) is an essential, ubiquitously expressed protein that dimerizes and forms cytosolic complexes with the histone H3-H4 chaperones ASF1A/B and CDIN1; cryo-EM structures show it occupies all functional ASF1 binding surfaces—via two B-domains and two histone H3-mimicking helices—to sequester and inhibit ASF1, thereby restraining replication-coupled chromatin assembly and limiting S-phase progression, while also localizing to heterochromatin and nucleoli where it regulates terminal erythroid differentiation, with disease-causing CDA-I mutations in CDAN1 or CDIN1 disrupting key protein–protein interactions in this complex."},"narrative":{"mechanistic_narrative":"Codanin-1 (CDAN1) is an essential, cell-cycle-regulated negative regulator of replication-coupled chromatin assembly that sequesters the histone H3-H4 chaperone ASF1 in the cytoplasm and governs terminal erythroid differentiation [PMID:22407294, PMID:34234671]. It binds ASF1 through a conserved B-domain in a manner mutually exclusive with the ASF1-CAF-1 and ASF1-HIRA chaperone handoffs, and its depletion accelerates DNA replication and increases chromatin-bound ASF1, whereas its overexpression arrests S-phase progression [PMID:22407294]. Cryo-EM shows that CDAN1 dimerizes and engages two ASF1 molecules per monomer using two B-domains and two histone-H3-mimicking helices, thereby occupying all functional ASF1 surfaces and explaining how it blocks histone delivery [PMID:40091041]. CDAN1 also forms an obligate, near-stoichiometric heterodimer with CDIN1 (C15ORF41) via its C-terminus, sequestering CDIN1 in the cytoplasm and stabilizing it [PMID:32239177, PMID:41609415]. The protein localizes to interphase heterochromatin, is excluded from condensed mitotic chromosomes upon phosphorylation, and peaks during S phase, consistent with cell-cycle-coupled function under E2F1 transcriptional control [PMID:19336738], and both CDAN1 and CDIN1 are enriched in nucleoli [PMID:32518175]. In erythropoiesis, CDAN1 loss causes severe anemia, spongy heterochromatin, failed maturation, and derepression of differentiation inhibitors such as Gata2, and CDAN1 directly occupies erythroid gene regulatory regions including AHSP [PMID:34234671, PMID:41028447]. Disease-causing mutations in CDAN1 or CDIN1 selectively disrupt the protein-protein interactions within this complex, defining the molecular basis of congenital dyserythropoietic anemia type I [PMID:22407294, PMID:41609415].","teleology":[{"year":2009,"claim":"Establishing that Codanin-1 is a cell-cycle-coupled chromatin-associated protein placed it within the replication/chromatin axis before any biochemical partner was known.","evidence":"Immunofluorescence, immuno-EM, cell synchronization, ChIP and luciferase reporter assays in an E2F1-inducible system","pmids":["19336738"],"confidence":"Medium","gaps":["Molecular function and binding partners not yet defined","Functional consequence of mitotic phosphorylation not established"]},{"year":2012,"claim":"Identifying CDAN1 as a B-domain ASF1 binder that sequesters ASF1 in the cytoplasm answered what CDAN1 does mechanistically and connected it to replication-coupled histone supply.","evidence":"Co-IP, pulldowns, cell fractionation, DNA replication assays, overexpression, siRNA depletion, and mutagenesis of disease alleles","pmids":["22407294"],"confidence":"High","gaps":["Structural basis of ASF1 occupancy not resolved","Link from ASF1 sequestration to erythroid phenotype not shown"]},{"year":2020,"claim":"Discovery of an obligate CDAN1-CDIN1 heterodimer expanded the complex beyond ASF1 and identified CDIN1 as a stability-dependent cytoplasmically sequestered partner.","evidence":"Reciprocal Co-IP, in vitro reconstitution, fractionation, and immunofluorescence (nucleolar enrichment); plus patient-mutation interaction analysis","pmids":["32239177","32518175"],"confidence":"High","gaps":["Catalytic or functional role of CDIN1 within the complex not defined","Relationship between CDIN1 binding and ASF1 binding not resolved"]},{"year":2021,"claim":"Erythroid-specific Cdan1 deletion demonstrated that CDAN1 is required in vivo for terminal erythroid differentiation by suppressing differentiation inhibitors.","evidence":"Conditional knockout mouse with EM, flow cytometry, apoptosis and gene-expression analysis, plus zebrafish morpholino knockdown","pmids":["34234671"],"confidence":"High","gaps":["Mechanism linking chromatin-assembly control to derepression of Gata2/Pu.1/Runx1 not defined","Whether the phenotype depends on ASF1 or CDIN1 binding not tested"]},{"year":2021,"claim":"Patient-mutation modeling in human erythroid cells and patient-derived cultures tied CDAN1 dysfunction to chromatin accessibility changes, histone acetylation alterations, and nucleolar abnormalities recapitulating CDA-I.","evidence":"CRISPR editing of HUDEP2 cells and in vitro erythroid culture with immunofluorescence, ATAC-seq, histone modification and gene-expression analysis","pmids":["33075436","33121234"],"confidence":"Medium","gaps":["Direct causal chain from mutation to chromatin/nucleolar defect not established","Single-lab models for each readout"]},{"year":2025,"claim":"Cryo-EM resolved how CDAN1 inhibits ASF1, showing a dimeric CDAN1 occupying all functional ASF1 surfaces via two B-domains and two H3-mimicking helices.","evidence":"Single-particle cryo-EM with biochemical reconstitution, AlphaFold-guided modeling and pulldowns (peer-reviewed; preceded by a 2024 bioRxiv preprint)","pmids":["40091041","39149339"],"confidence":"High","gaps":["Differential ASF1A vs ASF1B engagement not mechanistically explained","Position of CDIN1 within the assembled structure not fully detailed"]},{"year":2025,"claim":"ChIP-seq evidence that CDAN1 directly occupies the AHSP regulatory region added a direct chromatin-level mode of erythroid gene regulation beyond cytoplasmic chaperone sequestration.","evidence":"siRNA knockdown in K562 and CD34+ erythroid cells with ChIP-seq, RNA-seq/qPCR, western blotting and morphologic analysis","pmids":["41028447"],"confidence":"Medium","gaps":["Whether chromatin occupancy is direct DNA binding or complex-mediated unknown","Genome-wide scope of direct targets not defined"]},{"year":2026,"claim":"Biophysical characterization of the high-affinity CDIN1-CDAN1 C-terminal heterodimer and its disruption by CDA-I mutations defined loss of this complex as a disease mechanism.","evidence":"Biophysical methods (ITC/SEC-MALS or equivalent) with structural analysis and disease-variant mutagenesis","pmids":["41609415"],"confidence":"Medium","gaps":["Downstream consequence of complex loss in erythroid cells not directly demonstrated","Single-lab biophysical dataset"]},{"year":null,"claim":"How CDAN1-mediated ASF1 sequestration and direct chromatin occupancy mechanistically converge to control terminal erythroid differentiation and produce CDA-I pathology remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["Causal link between replication/chromatin-assembly restraint and erythroid gene derepression unproven","Functional role of CDIN1 within the complex undefined","Mechanism of nucleolar function not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,7]},{"term_id":"GO:0140313","term_label":"molecular sequestering activity","supporting_discovery_ids":[0,2]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[7]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,2,7]},{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[3,6]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[0,7]},{"term_id":"R-HSA-69306","term_label":"DNA Replication","supporting_discovery_ids":[0]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[4]}],"complexes":["CDAN1-ASF1A/B complex","CDAN1-CDIN1 heterodimer"],"partners":["ASF1A","ASF1B","CDIN1","IPO4"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8IWY9","full_name":"Codanin-1","aliases":[],"length_aa":1227,"mass_kda":134.1,"function":"May act as a negative regulator of ASF1 in chromatin assembly","subcellular_location":"Cytoplasm; Nucleus; Membrane","url":"https://www.uniprot.org/uniprotkb/Q8IWY9/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/CDAN1","classification":"Common Essential","n_dependent_lines":947,"n_total_lines":1208,"dependency_fraction":0.7839403973509934},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CDAN1","total_profiled":1310},"omim":[{"mim_id":"619789","title":"ANEMIA, CONGENITAL DYSERYTHROPOIETIC, TYPE IIIb, AUTOSOMAL RECESSIVE; CDAN3B","url":"https://www.omim.org/entry/619789"},{"mim_id":"615631","title":"ANEMIA, CONGENITAL DYSERYTHROPOIETIC, TYPE Ib; CDAN1B","url":"https://www.omim.org/entry/615631"},{"mim_id":"615626","title":"CDAN1-INTERACTING NUCLEASE 1; CDIN1","url":"https://www.omim.org/entry/615626"},{"mim_id":"613673","title":"ANEMIA, CONGENITAL DYSERYTHROPOIETIC, TYPE IVa; CDAN4A","url":"https://www.omim.org/entry/613673"},{"mim_id":"607465","title":"CODANIN 1; CDAN1","url":"https://www.omim.org/entry/607465"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Cytosol","reliability":"Enhanced"},{"location":"Plasma membrane","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/CDAN1"},"hgnc":{"alias_symbol":["CDA-I","CDAI"],"prev_symbol":[]},"alphafold":{"accession":"Q8IWY9","domains":[{"cath_id":"1.25.40","chopping":"2-68_289-339_357-416","consensus_level":"high","plddt":83.1656,"start":2,"end":416},{"cath_id":"-","chopping":"435-520_558-601","consensus_level":"medium","plddt":85.1883,"start":435,"end":601},{"cath_id":"-","chopping":"859-1000","consensus_level":"high","plddt":88.4792,"start":859,"end":1000},{"cath_id":"-","chopping":"1025-1202","consensus_level":"medium","plddt":86.5878,"start":1025,"end":1202}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IWY9","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IWY9-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IWY9-F1-predicted_aligned_error_v6.png","plddt_mean":71.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CDAN1","jax_strain_url":"https://www.jax.org/strain/search?query=CDAN1"},"sequence":{"accession":"Q8IWY9","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8IWY9.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8IWY9/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IWY9"}},"corpus_meta":[{"pmid":"19755969","id":"PMC_19755969","title":"Fecal calprotectin correlates more closely with the Simple Endoscopic Score for Crohn's disease (SES-CD) than CRP, blood leukocytes, and the CDAI.","date":"2009","source":"The American journal of gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/19755969","citation_count":461,"is_preprint":false},{"pmid":"21485024","id":"PMC_21485024","title":"RAPID3 (Routine Assessment of Patient Index Data 3) severity categories and response criteria: Similar results to DAS28 (Disease Activity Score) and CDAI (Clinical Disease Activity Index) in the RAPID 1 (Rheumatoid Arthritis Prevention of Structural Damage) clinical trial of certolizumab pegol.","date":"2011","source":"Arthritis care & research","url":"https://pubmed.ncbi.nlm.nih.gov/21485024","citation_count":77,"is_preprint":false},{"pmid":"22407294","id":"PMC_22407294","title":"Codanin-1, mutated in the anaemic disease CDAI, regulates Asf1 function in S-phase histone supply.","date":"2012","source":"The EMBO 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abnormalities.","date":"2021","source":"Haematologica","url":"https://pubmed.ncbi.nlm.nih.gov/33121234","citation_count":15,"is_preprint":false},{"pmid":"22504250","id":"PMC_22504250","title":"A case of congenital dyserythropoietic anemia type 1 in a Japanese adult with a CDAN1 gene mutation and an inappropriately low serum hepcidin-25 level.","date":"2012","source":"Internal medicine (Tokyo, Japan)","url":"https://pubmed.ncbi.nlm.nih.gov/22504250","citation_count":14,"is_preprint":false},{"pmid":"32239177","id":"PMC_32239177","title":"A complex comprising C15ORF41 and Codanin-1: the products of two genes mutated in congenital dyserythropoietic anaemia type I (CDA-I).","date":"2020","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/32239177","citation_count":12,"is_preprint":false},{"pmid":"29031773","id":"PMC_29031773","title":"Identification of CDAN1, C15ORF41 and SEC23B mutations in Chinese patients affected by congenital dyserythropoietic 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use of CDAI and blood indices for assessing endoscopic activity in ileocolic Crohn's disease.","date":"2023","source":"BMC gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/37770845","citation_count":6,"is_preprint":false},{"pmid":"23605369","id":"PMC_23605369","title":"Congenital dyserythropoietic anemia type 1 with a novel mutation in the CDAN1 gene previously diagnosed as congenital hemolytic anemia.","date":"2013","source":"International journal of hematology","url":"https://pubmed.ncbi.nlm.nih.gov/23605369","citation_count":3,"is_preprint":false},{"pmid":"40091041","id":"PMC_40091041","title":"Mechanism of ASF1 engagement by CDAN1.","date":"2025","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/40091041","citation_count":2,"is_preprint":false},{"pmid":"40156145","id":"PMC_40156145","title":"Elevated DAS28, CDAI, RAPID3 and five of seven RA core data set measures in patients with positive screens for anxiety, depression or fibromyalgia on an 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University","url":"https://pubmed.ncbi.nlm.nih.gov/35012925","citation_count":1,"is_preprint":false},{"pmid":"41609415","id":"PMC_41609415","title":"Anemia-associated mutations disrupt the CDIN1-Codanin1 complex in inherited congenital dyserythropoietic anemia I (CDA-I) disease.","date":"2026","source":"The FEBS journal","url":"https://pubmed.ncbi.nlm.nih.gov/41609415","citation_count":1,"is_preprint":false},{"pmid":"41028447","id":"PMC_41028447","title":"Codanin-1, defective in congenital dyserythropoietic anemia I (CDA-I), regulates erythroid differentiation.","date":"2025","source":"Annals of hematology","url":"https://pubmed.ncbi.nlm.nih.gov/41028447","citation_count":0,"is_preprint":false},{"pmid":"41656804","id":"PMC_41656804","title":"[Interpretable machine learning-based predictive model for assessing abdominal surgery risk and biologic therapy efficacy in CDAI 0 to 1 level Crohn disease patients].","date":"2025","source":"Zhong nan da xue xue bao. Yi xue ban = Journal of Central South University. Medical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/41656804","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.10.14.24315448","title":"Fine-tuning and pre-training improve the predictive accuracy of large language models for rheumatoid arthritis disease activity","date":"2024-10-16","source":"bioRxiv","url":"https://doi.org/10.1101/2024.10.14.24315448","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":17793,"output_tokens":3070,"usd":0.049715,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10427,"output_tokens":3317,"usd":0.06753,"stage2_stop_reason":"end_turn"},"total_usd":0.117245,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2012,\n      \"finding\": \"Codanin-1 (CDAN1) was identified as a direct binding partner of the histone chaperone ASF1 (Anti-Silencing Function 1) via a conserved B-domain, forming part of a cytosolic Asf1-H3.1-H4-Importin-4 complex. This interaction is mutually exclusive with ASF1 binding to CAF-1 and HIRA. Codanin-1 acts as a negative regulator of ASF1 function by sequestering ASF1 in the cytoplasm and blocking histone delivery during DNA replication. Depletion of Codanin-1 accelerates DNA replication and increases chromatin-bound ASF1, while ectopic Codanin-1 expression arrests S-phase progression. Two CDAI disease-causing mutations impair complex formation with ASF1.\",\n      \"method\": \"Co-immunoprecipitation, pulldown assays, cell fractionation, DNA replication assays, ectopic overexpression, siRNA depletion, mutagenesis of disease-causing alleles\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (Co-IP, in-cell fractionation, functional replication assays, mutagenesis), findings replicated in subsequent independent studies\",\n      \"pmids\": [\"22407294\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Codanin-1 localizes to heterochromatin in interphase cells and undergoes phosphorylation at mitosis, coinciding with its exclusion from condensed chromosomes. Codanin-1 protein levels peak during S phase. The CDAN1 promoter contains E2F binding sites and is a direct transcriptional target of E2F1, as shown by chromatin immunoprecipitation and luciferase reporter assays.\",\n      \"method\": \"Immunofluorescence, immune electron microscopy, cell synchronization, chromatin immunoprecipitation (ChIP), luciferase reporter assay, E2F1-inducible cell line\",\n      \"journal\": \"Haematologica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (immunofluorescence, ChIP, reporter assay) in a single lab\",\n      \"pmids\": [\"19336738\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"C15ORF41 (CDIN1) forms a tight, near-stoichiometric heterodimeric complex with the C-terminal region of Codanin-1 in human cells and in vitro. Codanin-1 sequesters C15ORF41 in the cytoplasm, analogous to its sequestration of ASF1. C15ORF41 protein stability depends on Codanin-1.\",\n      \"method\": \"Immunoprecipitation, in vitro biochemical reconstitution, western blotting, immunofluorescence, cell fractionation\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — reciprocal Co-IP plus in vitro reconstitution and multiple orthogonal methods in single study, independently corroborated by Olijnik et al. 2020\",\n      \"pmids\": [\"32239177\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Both Codanin-1 and C15ORF41 are enriched in the nucleolus. C15ORF41 stability depends on Codanin-1, and both proteins interact to form an obligate complex. Many CDA-I missense and in-frame mutations in Codanin-1 do not destabilize the entire protein but impair specific protein interactions.\",\n      \"method\": \"Immunoprecipitation, western blotting, immunofluorescence (nucleolar enrichment), patient mutation analysis\",\n      \"journal\": \"Journal of medical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — reciprocal immunoprecipitation and immunofluorescence, corroborated by Shroff et al. 2020\",\n      \"pmids\": [\"32518175\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Conditional erythroid-specific deletion of Cdan1 in mice (using ErGFPcre) causes embryonic lethality at E12.5-E13.5 due to severe anemia. Primitive erythroblasts display pathognomonic spongy heterochromatin by electron microscopy, increased apoptosis, failure of semi-synchronous maturation, delayed ζ-to-α globin switch, and increased expression of Gata2, Pu.1, and Runx1. Zebrafish cdan1 knockdown also increases gata2 expression, confirming a conserved role in suppressing inhibitors of terminal erythroid differentiation.\",\n      \"method\": \"Conditional knockout mouse (Cre-lox), transmission electron microscopy, flow cytometry, Annexin V staining, gene expression analysis, zebrafish morpholino knockdown\",\n      \"journal\": \"Frontiers in physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean conditional KO with defined erythroid phenotype and pathway placement, replicated in zebrafish model with orthogonal validation\",\n      \"pmids\": [\"34234671\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CDAN1 mutations at R1042 (mirroring patient mutations) in HUDEP2 human erythroid cells cause decreased viability, increased intercellular bridges and binucleate cells, and alterations in histone acetylation associated with prematurely elevated erythroid gene expression including gamma-globin. This implicates CDAN1 in regulation of DNA replication and chromatin organization specifically during erythroid maturation.\",\n      \"method\": \"CRISPR/gene editing of HUDEP2 cells, immunofluorescence, flow cytometry, histone modification analysis, gene expression\",\n      \"journal\": \"Experimental hematology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — engineered patient mutations in human erythroid cell line with multiple cellular readouts, single lab\",\n      \"pmids\": [\"33075436\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CDAN1 and CDIN1 proteins are enriched in nucleoli, which are structurally and functionally abnormal in CDA-I erythroid cells. Erythroid cells from CDA-I patients show delayed terminal erythroid differentiation, increased proliferation, and widespread changes in chromatin accessibility.\",\n      \"method\": \"In vitro erythroid culture system, electron microscopy, immunofluorescence, ATAC-seq (chromatin accessibility)\",\n      \"journal\": \"Haematologica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods in a validated disease-recapitulating culture system, single lab\",\n      \"pmids\": [\"33121234\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Cryo-EM structural analysis reveals that CDAN1 dimerizes and assembles cytosolic complexes containing CDIN1 and multiple copies of ASF1A/B. A single CDAN1 engages two ASF1 molecules via two B-domains (acting as ASF1-binding motifs) and two helices that mimic histone H3 binding, thereby occupying all functional binding sites on ASF1 known to facilitate histone chaperoning. ASF1A and ASF1B have different requirements for CDAN1 engagement.\",\n      \"method\": \"Single-particle cryo-EM, biochemical reconstitution, structural predictions (AlphaFold), pulldown assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure combined with biochemical reconstitution and mutagenesis/domain mapping in a single rigorous study\",\n      \"pmids\": [\"40091041\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Cryo-EM structures of CDAN1 complexes show CDAN1 dimerizes and recruits two ASF1 molecules per monomer via two B-domains and two histone H3-mimicking helices, blocking all functional ASF1 binding surfaces. This explains the molecular mechanism by which CDAN1 sequesters and inhibits ASF1 chaperone function. (Preprint version of the 2025 Nature Communications paper.)\",\n      \"method\": \"Single-particle cryo-EM, biochemical reconstitution, structural predictions\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure plus biochemical reconstitution; preprint superseded by peer-reviewed publication (PMID 40091041)\",\n      \"pmids\": [\"39149339\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"CDIN1 and the C-terminus of Codanin-1 form a high-affinity heterodimeric complex with equimolar stoichiometry. CDA-I-associated mutations in either CDIN1 or Codanin-1 disrupt this interaction, suggesting that loss of the CDIN1-Codanin-1 complex is a molecular mechanism underlying the disease.\",\n      \"method\": \"Biophysical techniques (ITC, SEC-MALS, or equivalent), structural analysis, mutagenesis of disease-associated variants\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — complementary biophysical techniques and disease mutation analysis, single lab, abstract does not detail all methods\",\n      \"pmids\": [\"41609415\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Codanin-1 knockdown in K562 cells and primary human CD34+ erythroid cells causes morphologic changes resembling CDA-I, altered expression of key erythroid genes, and reduced AHSP (alpha-hemoglobin stabilizing protein) mRNA and protein. ChIP-seq showed increased Codanin-1 occupancy at the AHSP gene regulatory region, implicating direct chromatin-level regulation of erythroid gene expression by Codanin-1.\",\n      \"method\": \"siRNA knockdown, ChIP-seq, gene expression analysis (RNA-seq/qPCR), western blotting, morphologic analysis\",\n      \"journal\": \"Annals of hematology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq plus loss-of-function with gene expression readout, two cell models, single lab\",\n      \"pmids\": [\"41028447\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Codanin-1 (CDAN1) is an essential, ubiquitously expressed protein that dimerizes and forms cytosolic complexes with the histone H3-H4 chaperones ASF1A/B and CDIN1; cryo-EM structures show it occupies all functional ASF1 binding surfaces—via two B-domains and two histone H3-mimicking helices—to sequester and inhibit ASF1, thereby restraining replication-coupled chromatin assembly and limiting S-phase progression, while also localizing to heterochromatin and nucleoli where it regulates terminal erythroid differentiation, with disease-causing CDA-I mutations in CDAN1 or CDIN1 disrupting key protein–protein interactions in this complex.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"Codanin-1 (CDAN1) is an essential, cell-cycle-regulated negative regulator of replication-coupled chromatin assembly that sequesters the histone H3-H4 chaperone ASF1 in the cytoplasm and governs terminal erythroid differentiation [#0, #4]. It binds ASF1 through a conserved B-domain in a manner mutually exclusive with the ASF1-CAF-1 and ASF1-HIRA chaperone handoffs, and its depletion accelerates DNA replication and increases chromatin-bound ASF1, whereas its overexpression arrests S-phase progression [#0]. Cryo-EM shows that CDAN1 dimerizes and engages two ASF1 molecules per monomer using two B-domains and two histone-H3-mimicking helices, thereby occupying all functional ASF1 surfaces and explaining how it blocks histone delivery [#7]. CDAN1 also forms an obligate, near-stoichiometric heterodimer with CDIN1 (C15ORF41) via its C-terminus, sequestering CDIN1 in the cytoplasm and stabilizing it [#2, #9]. The protein localizes to interphase heterochromatin, is excluded from condensed mitotic chromosomes upon phosphorylation, and peaks during S phase, consistent with cell-cycle-coupled function under E2F1 transcriptional control [#1], and both CDAN1 and CDIN1 are enriched in nucleoli [#3]. In erythropoiesis, CDAN1 loss causes severe anemia, spongy heterochromatin, failed maturation, and derepression of differentiation inhibitors such as Gata2, and CDAN1 directly occupies erythroid gene regulatory regions including AHSP [#4, #10]. Disease-causing mutations in CDAN1 or CDIN1 selectively disrupt the protein-protein interactions within this complex, defining the molecular basis of congenital dyserythropoietic anemia type I [#0, #9].\",\n  \"teleology\": [\n    {\n      \"year\": 2009,\n      \"claim\": \"Establishing that Codanin-1 is a cell-cycle-coupled chromatin-associated protein placed it within the replication/chromatin axis before any biochemical partner was known.\",\n      \"evidence\": \"Immunofluorescence, immuno-EM, cell synchronization, ChIP and luciferase reporter assays in an E2F1-inducible system\",\n      \"pmids\": [\"19336738\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular function and binding partners not yet defined\", \"Functional consequence of mitotic phosphorylation not established\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identifying CDAN1 as a B-domain ASF1 binder that sequesters ASF1 in the cytoplasm answered what CDAN1 does mechanistically and connected it to replication-coupled histone supply.\",\n      \"evidence\": \"Co-IP, pulldowns, cell fractionation, DNA replication assays, overexpression, siRNA depletion, and mutagenesis of disease alleles\",\n      \"pmids\": [\"22407294\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of ASF1 occupancy not resolved\", \"Link from ASF1 sequestration to erythroid phenotype not shown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Discovery of an obligate CDAN1-CDIN1 heterodimer expanded the complex beyond ASF1 and identified CDIN1 as a stability-dependent cytoplasmically sequestered partner.\",\n      \"evidence\": \"Reciprocal Co-IP, in vitro reconstitution, fractionation, and immunofluorescence (nucleolar enrichment); plus patient-mutation interaction analysis\",\n      \"pmids\": [\"32239177\", \"32518175\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Catalytic or functional role of CDIN1 within the complex not defined\", \"Relationship between CDIN1 binding and ASF1 binding not resolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Erythroid-specific Cdan1 deletion demonstrated that CDAN1 is required in vivo for terminal erythroid differentiation by suppressing differentiation inhibitors.\",\n      \"evidence\": \"Conditional knockout mouse with EM, flow cytometry, apoptosis and gene-expression analysis, plus zebrafish morpholino knockdown\",\n      \"pmids\": [\"34234671\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking chromatin-assembly control to derepression of Gata2/Pu.1/Runx1 not defined\", \"Whether the phenotype depends on ASF1 or CDIN1 binding not tested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Patient-mutation modeling in human erythroid cells and patient-derived cultures tied CDAN1 dysfunction to chromatin accessibility changes, histone acetylation alterations, and nucleolar abnormalities recapitulating CDA-I.\",\n      \"evidence\": \"CRISPR editing of HUDEP2 cells and in vitro erythroid culture with immunofluorescence, ATAC-seq, histone modification and gene-expression analysis\",\n      \"pmids\": [\"33075436\", \"33121234\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct causal chain from mutation to chromatin/nucleolar defect not established\", \"Single-lab models for each readout\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Cryo-EM resolved how CDAN1 inhibits ASF1, showing a dimeric CDAN1 occupying all functional ASF1 surfaces via two B-domains and two H3-mimicking helices.\",\n      \"evidence\": \"Single-particle cryo-EM with biochemical reconstitution, AlphaFold-guided modeling and pulldowns (peer-reviewed; preceded by a 2024 bioRxiv preprint)\",\n      \"pmids\": [\"40091041\", \"39149339\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Differential ASF1A vs ASF1B engagement not mechanistically explained\", \"Position of CDIN1 within the assembled structure not fully detailed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"ChIP-seq evidence that CDAN1 directly occupies the AHSP regulatory region added a direct chromatin-level mode of erythroid gene regulation beyond cytoplasmic chaperone sequestration.\",\n      \"evidence\": \"siRNA knockdown in K562 and CD34+ erythroid cells with ChIP-seq, RNA-seq/qPCR, western blotting and morphologic analysis\",\n      \"pmids\": [\"41028447\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether chromatin occupancy is direct DNA binding or complex-mediated unknown\", \"Genome-wide scope of direct targets not defined\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Biophysical characterization of the high-affinity CDIN1-CDAN1 C-terminal heterodimer and its disruption by CDA-I mutations defined loss of this complex as a disease mechanism.\",\n      \"evidence\": \"Biophysical methods (ITC/SEC-MALS or equivalent) with structural analysis and disease-variant mutagenesis\",\n      \"pmids\": [\"41609415\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream consequence of complex loss in erythroid cells not directly demonstrated\", \"Single-lab biophysical dataset\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CDAN1-mediated ASF1 sequestration and direct chromatin occupancy mechanistically converge to control terminal erythroid differentiation and produce CDA-I pathology remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal link between replication/chromatin-assembly restraint and erythroid gene derepression unproven\", \"Functional role of CDIN1 within the complex undefined\", \"Mechanism of nucleolar function not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 7]},\n      {\"term_id\": \"GO:0140313\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 2, 7]},\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [3, 6]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [0, 7]},\n      {\"term_id\": \"R-HSA-69306\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"complexes\": [\n      \"CDAN1-ASF1A/B complex\",\n      \"CDAN1-CDIN1 heterodimer\"\n    ],\n    \"partners\": [\n      \"ASF1A\",\n      \"ASF1B\",\n      \"CDIN1\",\n      \"IPO4\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":{"gene":"CDAN1","tier":"GROUNDING","verdict":"Evidence-grounding concern","subtype":"fabrication","uniprot_band":"sparse","rules_fired":"R7","issue":"R7: fabricated (no corpus paper): 34234671"},"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}