{"gene":"RERE","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":2010,"finding":"RERE (Atrophin2) forms a protein complex with Nr2f2, p300 (Ep300), and a retinoic acid receptor that is recruited to the retinoic acid regulatory element (RARE) of retinoic acid target gene promoters (e.g., Rarb), thereby positively regulating retinoic acid-dependent transcription. Knockdown of Nr2f2 and/or Rere decreases retinoic acid signaling, and loss of Rere in mice leads to asymmetrical somite formation analogous to retinoic acid deficiency.","method":"Co-immunoprecipitation of complex components, promoter-reporter assays, knockdown experiments in mouse embryos, genetic loss-of-function (Rere mutant mice)","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal complex assembly demonstrated, functional promoter recruitment shown, genetic phenocopy of RA deficiency, replicated across multiple orthogonal methods in one rigorous study","pmids":["20164929"],"is_preprint":false},{"year":2001,"finding":"RERE protein localizes predominantly to the nucleus, where it co-localizes with promyelocytic leukemia (PML) protein at PML oncogenic domains (PODs). Overexpression of RERE recruits a fraction of the pro-apoptotic protein BAX to PODs and induces caspase-dependent apoptosis.","method":"Immunofluorescence co-localization, overexpression in cell lines, caspase activity assays, flow cytometry for apoptosis","journal":"Cell growth & differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization by immunofluorescence with functional consequence (apoptosis induction), single lab with two orthogonal readouts","pmids":["11331249"],"is_preprint":false},{"year":2017,"finding":"RERE co-immunoprecipitates with CBF1 (RBPjκ) and the Notch intracellular domain (NICD), and is recruited to nuclear foci formed by overexpressed NICD1. RERE is required for NICD-mediated activation of Notch target genes (Hes genes) and promotes NICD stability, thereby facilitating assembly of the NICD/CBF1 transcriptional activating complex in vertebrate neural progenitors.","method":"Co-immunoprecipitation in mammalian cells, overexpression/knockdown in chick spinal cord, reporter gene assays for Notch targets, immunofluorescence of nuclear foci","journal":"Journal of neurochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP showing complex formation, functional target gene assays, knockdown phenotype, single lab with multiple orthogonal methods","pmids":["28144959"],"is_preprint":false},{"year":2018,"finding":"RERE co-localizes with GATA4 in the endocardium of the atrioventricular (AV) canal and positively regulates transcription from the Gata4 promoter. RERE deficiency leads to reduced GATA4 levels in the AV canal, decreased epithelial-to-mesenchymal transition (EMT) and mesenchymal cell proliferation in AV endocardial cushions, and ventricular septal defects (VSDs). Genetic interaction between Rere and Gata4 in CHD development was demonstrated by in vivo epistasis. Tissue-specific ablation of Rere in the endocardium (Wnt1-Cre) recapitulates EMT defects and VSDs but does not reduce GATA4 expression, indicating a cell-autonomous RERE function in EMT independent of GATA4.","method":"Immunofluorescence co-localization, promoter-luciferase reporter assays, conditional knockout (endocardium-specific Cre), genetic epistasis (Rere/Gata4 compound mutants), cell counting of cushion mesenchymal cells","journal":"Disease models & mechanisms","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods including genetic epistasis, tissue-specific KO, promoter assays, and in vivo cellular phenotyping in a single study","pmids":["30061196"],"is_preprint":false},{"year":2014,"finding":"RERE deficiency in mice leads to delayed maturation and migration of Purkinje cells during prenatal cerebellar development, reduced sonic hedgehog (SHH) secretion from Purkinje cells, and consequently reduced granule cell precursor (GCP) proliferation. Postnatally, RERE loss causes incomplete cerebellar lobule formation and decreased Purkinje cell dendritic branching.","method":"Analysis of RERE-deficient hypomorphic mouse embryos (Rere^om/eyes3), immunohistochemistry for Purkinje cell markers and NeuN, BrdU proliferation assays, SHH expression analysis","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined cellular phenotype with pathway placement (SHH pathway) using loss-of-function mouse model with multiple histological readouts, single lab","pmids":["24466353"],"is_preprint":false},{"year":2013,"finding":"An allelic series of RERE-deficient mice (null om allele and hypomorphic eyes3 allele) demonstrates that RERE is required for development of the eye, brain, inner ear, heart, and kidney. RERE functions as a positive regulator of retinoic acid signaling in vivo across multiple organ systems.","method":"ENU mutagenesis screen, generation of compound heterozygous mice (om/eyes3), histological phenotyping, NeuN immunostaining, audiological testing","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function with defined multi-organ phenotypic readouts, allelic series provides dose-response validation, single lab","pmids":["23451234"],"is_preprint":false},{"year":2021,"finding":"RERE is expressed in retinal ganglion cells (RGCs), lens epithelium, and ciliary body embryonically, and expands to the outer and inner nuclear layers postnatally. RERE deficiency causes progressive apoptosis of retinal cells in the ganglion cell layer starting at E17.5, loss of RGCs, and optic nerve atrophy.","method":"Immunohistochemistry for RERE expression, TUNEL assay for apoptosis, RGC counting in RERE-deficient mice, histological analysis of retina and optic nerve","journal":"Developmental dynamics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization tied to functional apoptotic phenotype in loss-of-function mouse model, single lab, multiple time points","pmids":["33742727"],"is_preprint":false},{"year":2021,"finding":"RERE deficiency in cranial neural crest (CNC) cells, mediated by Wnt1-Cre conditional ablation, leads to delayed elevation of palatal shelves, reduced proliferation of palatal mesenchymal cells, and cleft palate. RERE is broadly expressed in the palate during mouse embryonic development.","method":"Conditional knockout (Rereflox/flox; Wnt1-Cre), immunohistochemistry for RERE expression, BrdU/EdU proliferation assays in palatal shelves, histological staging of palate elevation","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — tissue-specific conditional KO with defined cellular mechanism (proliferation defect), single lab","pmids":["33772547"],"is_preprint":false},{"year":2023,"finding":"RERE negatively regulates Sonic hedgehog (SHH) signaling, and loss of RERE function in zebrafish rerea (babyface) mutants causes expansion of the optic stalk domain and optic fissure closure defects (coloboma). NEDBEH-associated human RERE variants function as hypomorphs in their ability to repress SHH signaling and some exhibit abnormal nuclear localization. Pharmacological inhibition of SHH signaling with HPI-1 rescues coloboma in rerea mutants.","method":"Zebrafish rerea mutant analysis, cell-based SHH signaling reporter assays with human RERE variants, immunofluorescence for nuclear localization of variants, pharmacological rescue with HPI-1 inhibitor","journal":"Developmental dynamics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function with pharmacological rescue confirming pathway, cell-based assays for human variants, single lab with multiple orthogonal methods","pmids":["36576487"],"is_preprint":false},{"year":2023,"finding":"A CRISPR/Cas9-introduced RERE frameshift variant in human cells leads to downregulation of the SHH signaling pathway and upregulation of the Hippo pathway, as well as decreased expression of ASD-associated genes (CNTNAP2, STX1A, FARP2, GPC1) and alterations in HDAC1 and HDAC2 (members of the WHHERE complex). The mutant RERE protein shows altered subcellular localization by immunofluorescence.","method":"CRISPR/Cas9 point mutation cell line, RNA-sequencing for transcriptome, mass spectrometry for proteome, immunofluorescence for localization of mutant RERE","journal":"Clinical genetics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single cell line with broad transcriptomic/proteomic readouts but limited mechanistic resolution; no direct biochemical assay of pathway components","pmids":["38018232"],"is_preprint":false},{"year":2026,"finding":"RERE interacts with RARB and RXRA at the Grin2a promoter to regulate expression of the schizophrenia risk gene Grin2a (encoding an NMDAR subunit). Risk alleles at intronic variants rs159961 and rs301792 increase enhancer activity by altering REST and POLR2A binding, leading to RERE upregulation. RERE overexpression impairs neurogenesis, alters dendritic spine density and dendritic complexity, and impairs excitatory synaptic transmission.","method":"Allele-specific enhancer luciferase assays, ChIP for REST and POLR2A binding, promoter-reporter assays for Grin2a, overexpression in neurons with dendritic spine and electrophysiology readouts","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter interaction (RARB/RXRA) demonstrated with reporter assays, allele-specific ChIP, neuronal functional readouts; single lab","pmids":["41580391"],"is_preprint":false},{"year":2025,"finding":"RERE is identified as a component of a sixth unique HDAC1/2-containing multiprotein complex (named RERE complex, alongside SIN3, NuRD, CoREST, MIDAC, and MIER) by co-immunoprecipitation of HDAC1-Flag followed by mass spectrometry in mouse embryonic stem cells.","method":"Co-immunoprecipitation of HDAC1-Flag followed by mass spectrometry, structural comparison of HDAC1 complex interfaces","journal":"bioRxiv (preprint)","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP/MS experiment identifying RERE as an HDAC1 complex component; preprint, no independent replication reported","pmids":[],"is_preprint":true}],"current_model":"RERE is a nuclear receptor co-regulator that positively regulates retinoic acid signaling by forming a complex with Nr2f2, p300, and retinoic acid receptors recruited to target gene promoters; it also co-operates with CBF1/NICD to activate Notch target genes, positively regulates GATA4 transcription and EMT in cardiac development, represses SHH signaling to control optic fissure closure, interacts with RARB/RXRA at the Grin2a promoter to regulate NMDA receptor expression, localizes to PML nuclear bodies where it recruits BAX and promotes caspase-dependent apoptosis, and participates in an HDAC1/2-containing chromatin-modifying complex."},"narrative":{"mechanistic_narrative":"RERE (Atrophin2) is a nuclear transcriptional co-regulator that integrates multiple developmental signaling pathways during organogenesis [PMID:20164929, PMID:23451234]. It positively regulates retinoic acid signaling by assembling a complex with Nr2f2, p300, and a retinoic acid receptor that is recruited to retinoic acid response elements of target gene promoters; loss of Rere phenocopies retinoic acid deficiency in vivo and disrupts development of the eye, brain, inner ear, heart, and kidney [PMID:20164929, PMID:23451234]. Beyond retinoic acid signaling, RERE co-operates with the NICD/CBF1 complex to stabilize NICD and activate Notch target genes in neural progenitors [PMID:28144959], positively regulates the Gata4 promoter and drives endothelial-to-mesenchymal transition in cardiac AV cushion development [PMID:30061196], and acts as a negative regulator of SHH signaling, where hypomorphic human variants fail to repress SHH and cause optic fissure closure defects rescuable by SHH pathway inhibition [PMID:36576487]. In specific tissues RERE supports cell survival and proliferation: it is required for Purkinje cell maturation and SHH-driven granule cell precursor proliferation in the cerebellum [PMID:24466353], for survival of retinal ganglion cells [PMID:33742727], and for proliferation of palatal mesenchyme, with its loss causing cleft palate [PMID:33772547]. RERE localizes to PML nuclear bodies where its overexpression recruits BAX and induces caspase-dependent apoptosis [PMID:11331249], and it also acts at the Grin2a promoter together with RARB and RXRA, with RERE overexpression impairing neurogenesis and excitatory synaptic transmission [PMID:41580391].","teleology":[{"year":2001,"claim":"Established RERE's subcellular address and a first functional consequence — defining it as a nuclear, PML-body-associated protein capable of promoting apoptosis.","evidence":"Immunofluorescence co-localization with PML and BAX, plus caspase activity and apoptosis assays in overexpressing cell lines","pmids":["11331249"],"confidence":"Medium","gaps":["Apoptotic role rests on overexpression rather than loss-of-function","Mechanism by which RERE recruits BAX to PODs not defined","No endogenous-level validation"]},{"year":2010,"claim":"Resolved the core biochemical mechanism by showing RERE is a positive co-regulator of retinoic acid signaling assembled into a defined promoter-bound complex.","evidence":"Co-immunoprecipitation of Nr2f2/p300/RAR complex, RARE promoter-reporter assays, and Rere mutant mice phenocopying RA deficiency","pmids":["20164929"],"confidence":"High","gaps":["Stoichiometry and order of complex assembly not resolved","Whether RERE binds DNA directly or only via partners unknown"]},{"year":2013,"claim":"Demonstrated that RERE is required across multiple organ systems, generalizing its role as an in vivo positive regulator of retinoic acid signaling.","evidence":"Allelic series (null om and hypomorphic eyes3) with multi-organ histological and audiological phenotyping","pmids":["23451234"],"confidence":"Medium","gaps":["Organ-level phenotypes not connected to specific molecular targets","Does not distinguish RA-dependent from RA-independent functions"]},{"year":2014,"claim":"Placed RERE within the SHH axis of cerebellar development by linking its loss to reduced Purkinje cell SHH secretion and granule cell precursor proliferation.","evidence":"Hypomorphic Rere mouse embryos with Purkinje cell marker IHC, BrdU proliferation, and SHH expression analysis","pmids":["24466353"],"confidence":"Medium","gaps":["Whether RERE regulates SHH transcriptionally or indirectly not established","Cell-autonomy of the defect not dissected"]},{"year":2017,"claim":"Extended RERE's co-activator role to the Notch pathway, showing it stabilizes NICD and is required for Notch target activation.","evidence":"Co-IP with CBF1/NICD, nuclear foci co-localization, and knockdown/overexpression with Notch reporter assays in chick spinal cord","pmids":["28144959"],"confidence":"Medium","gaps":["Direct vs bridged interaction with CBF1 not resolved","Mechanism of NICD stabilization unknown","Single lab, no reciprocal validation"]},{"year":2018,"claim":"Dissected RERE's cardiac function, separating a GATA4-promoter co-activation role from a cell-autonomous EMT-driving role.","evidence":"Gata4 promoter-luciferase assays, endocardium-specific conditional KO, and Rere/Gata4 genetic epistasis in compound mutants","pmids":["30061196"],"confidence":"High","gaps":["GATA4-independent EMT effector targets not identified","Whether GATA4 regulation is direct at the promoter not biochemically resolved"]},{"year":2021,"claim":"Defined tissue-specific developmental requirements for RERE in retinal cell survival and in palatal mesenchyme proliferation.","evidence":"RERE expression IHC with TUNEL and RGC counting in the retina, and Wnt1-Cre conditional KO with EdU proliferation assays in palate","pmids":["33742727","33772547"],"confidence":"Medium","gaps":["Molecular pathway linking RERE loss to apoptosis vs proliferation defects not specified","Downstream effectors in each tissue undefined"]},{"year":2023,"claim":"Clarified RERE as a repressor of SHH signaling and connected disease-associated human variants to this activity via hypomorphism and mislocalization.","evidence":"Zebrafish rerea coloboma mutants, SHH reporter assays of human variants, localization IF, and HPI-1 pharmacological rescue","pmids":["36576487"],"confidence":"Medium","gaps":["Direct molecular mechanism of SHH repression by RERE not identified","How variant mislocalization translates to reduced repression unclear"]},{"year":2023,"claim":"Provided a transcriptome/proteome-level view of RERE loss, linking it to SHH, Hippo, ASD genes, and the HDAC1/2 WHHERE complex.","evidence":"CRISPR/Cas9 frameshift human cell line with RNA-seq, mass spectrometry, and mutant RERE localization IF","pmids":["38018232"],"confidence":"Low","gaps":["Single cell line with broad readouts and no direct biochemical pathway assay","Causal direction of pathway changes not established","HDAC complex membership not validated here"]},{"year":2026,"claim":"Linked RERE to NMDAR-subunit gene regulation, showing it acts with RARB/RXRA at the Grin2a promoter and that its dysregulation alters neuronal connectivity.","evidence":"Allele-specific enhancer luciferase, ChIP for REST/POLR2A, Grin2a promoter reporters, and neuronal dendritic spine and electrophysiology readouts","pmids":["41580391"],"confidence":"Medium","gaps":["Whether RERE binds the Grin2a promoter directly or via RARB/RXRA not resolved","Single lab; in vivo relevance to schizophrenia phenotypes not established"]},{"year":2025,"claim":"Proposed RERE as the defining subunit of a distinct HDAC1/2-containing chromatin-modifying complex.","evidence":"HDAC1-Flag Co-IP/mass spectrometry in mouse ES cells with structural interface comparison (preprint)","pmids":[],"confidence":"Low","gaps":["Single Co-IP/MS experiment in a preprint without independent replication","Complex composition and genomic targets not defined","Functional role of the complex not tested"]},{"year":null,"claim":"How RERE mechanistically toggles between positive co-activation (retinoic acid, Notch, GATA4) and repression (SHH), and whether HDAC1/2 recruitment underlies its repressive activity, remains unresolved.","evidence":"No single study reconciles the activating and repressing activities at a biochemical level","pmids":[],"confidence":"Low","gaps":["No structure of RERE in any of its complexes","No defined direct DNA-binding activity","Context determinants of activation vs repression unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,2,3,10]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,2]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1,8,9]}],"pathway":[{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[0,3,5,7]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,2,8]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,3,10]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[1,6]}],"complexes":["Nr2f2/p300/RAR retinoic acid co-activator complex","NICD/CBF1 Notch activating complex","RERE HDAC1/2 complex (WHHERE)"],"partners":["NR2F2","EP300","RBPJ","GATA4","RARB","RXRA","HDAC1","BAX"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9P2R6","full_name":"Arginine-glutamic acid dipeptide repeats protein","aliases":["Atrophin-1-like protein","Atrophin-1-related protein"],"length_aa":1566,"mass_kda":172.4,"function":"Plays a role as a transcriptional repressor during development. May play a role in the control of cell survival. Overexpression of RERE recruits BAX to the nucleus particularly to POD and triggers caspase-3 activation, leading to cell death","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9P2R6/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/RERE","classification":"Not Classified","n_dependent_lines":13,"n_total_lines":1208,"dependency_fraction":0.01076158940397351},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/RERE","total_profiled":1310},"omim":[{"mim_id":"618494","title":"CONGENITAL HYPOTONIA, EPILEPSY, DEVELOPMENTAL DELAY, AND DIGITAL ANOMALIES; CHEDDA","url":"https://www.omim.org/entry/618494"},{"mim_id":"616975","title":"NEURODEVELOPMENTAL DISORDER WITH OR WITHOUT ANOMALIES OF THE BRAIN, EYE, OR HEART; NEDBEH","url":"https://www.omim.org/entry/616975"},{"mim_id":"607872","title":"CHROMOSOME 1p36 DELETION SYNDROME, DISTAL","url":"https://www.omim.org/entry/607872"},{"mim_id":"607462","title":"ATROPHIN 1; ATN1","url":"https://www.omim.org/entry/607462"},{"mim_id":"607270","title":"ACTIVATOR OF TRANSCRIPTION AND DEVELOPMENTAL REGULATOR AUTS2; AUTS2","url":"https://www.omim.org/entry/607270"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nuclear bodies","reliability":"Supported"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/RERE"},"hgnc":{"alias_symbol":["KIAA0458","ARP","ARG","DNB1","ATN2"],"prev_symbol":["ATN1L"]},"alphafold":{"accession":"Q9P2R6","domains":[{"cath_id":"2.30.30.490","chopping":"84-135_177-286","consensus_level":"medium","plddt":85.7405,"start":84,"end":286},{"cath_id":"-","chopping":"325-450","consensus_level":"medium","plddt":87.2573,"start":325,"end":450},{"cath_id":"3.30.50.10","chopping":"505-552","consensus_level":"medium","plddt":81.2304,"start":505,"end":552},{"cath_id":"-","chopping":"1119-1164","consensus_level":"medium","plddt":74.1602,"start":1119,"end":1164}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9P2R6","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9P2R6-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9P2R6-F1-predicted_aligned_error_v6.png","plddt_mean":53.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RERE","jax_strain_url":"https://www.jax.org/strain/search?query=RERE"},"sequence":{"accession":"Q9P2R6","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9P2R6.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9P2R6/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9P2R6"}},"corpus_meta":[{"pmid":"20164929","id":"PMC_20164929","title":"Rere controls retinoic acid signalling and somite bilateral symmetry.","date":"2010","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/20164929","citation_count":94,"is_preprint":false},{"pmid":"27087320","id":"PMC_27087320","title":"De Novo Mutations of RERE Cause a Genetic Syndrome with Features that Overlap Those Associated with Proximal 1p36 Deletions.","date":"2016","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/27087320","citation_count":73,"is_preprint":false},{"pmid":"35733354","id":"PMC_35733354","title":"N6 -methyladenosine-modified circRNA RERE modulates osteoarthritis by regulating β-catenin ubiquitination and degradation.","date":"2022","source":"Cell proliferation","url":"https://pubmed.ncbi.nlm.nih.gov/35733354","citation_count":47,"is_preprint":false},{"pmid":"11331249","id":"PMC_11331249","title":"Human RERE is localized to nuclear promyelocytic leukemia oncogenic domains and enhances apoptosis.","date":"2001","source":"Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/11331249","citation_count":46,"is_preprint":false},{"pmid":"29330883","id":"PMC_29330883","title":"Genotype-phenotype correlations in individuals with pathogenic RERE variants.","date":"2018","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/29330883","citation_count":43,"is_preprint":false},{"pmid":"23451234","id":"PMC_23451234","title":"An allelic series of mice reveals a role for RERE in the development of multiple organs affected in chromosome 1p36 deletions.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23451234","citation_count":40,"is_preprint":false},{"pmid":"24466353","id":"PMC_24466353","title":"Mouse model reveals the role of RERE in cerebellar foliation and the migration and maturation of Purkinje cells.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24466353","citation_count":31,"is_preprint":false},{"pmid":"34956563","id":"PMC_34956563","title":"CircRNA RERE Promotes the Oxidative Stress-Induced Apoptosis and Autophagy of Nucleus Pulposus Cells through the miR-299-5p/Galectin-3 Axis.","date":"2021","source":"Journal of healthcare engineering","url":"https://pubmed.ncbi.nlm.nih.gov/34956563","citation_count":11,"is_preprint":false},{"pmid":"30061196","id":"PMC_30061196","title":"RERE deficiency leads to decreased expression of GATA4 and the development of ventricular septal defects.","date":"2018","source":"Disease models & mechanisms","url":"https://pubmed.ncbi.nlm.nih.gov/30061196","citation_count":9,"is_preprint":false},{"pmid":"28144959","id":"PMC_28144959","title":"Atrophin protein RERE positively regulates Notch targets in the developing vertebrate spinal cord.","date":"2017","source":"Journal of neurochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/28144959","citation_count":9,"is_preprint":false},{"pmid":"36053530","id":"PMC_36053530","title":"Phenotypic variability in RERE-related disorders and the first report of an inherited variant.","date":"2022","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/36053530","citation_count":7,"is_preprint":false},{"pmid":"33772547","id":"PMC_33772547","title":"RERE deficiency contributes to the development of orofacial clefts in humans and mice.","date":"2021","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/33772547","citation_count":6,"is_preprint":false},{"pmid":"30558068","id":"PMC_30558068","title":"Familial intracranial arachnoid cysts with a missense mutation (c.2576C > T) in RERE: A case report.","date":"2018","source":"Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/30558068","citation_count":6,"is_preprint":false},{"pmid":"33742727","id":"PMC_33742727","title":"RERE deficiency causes retinal and optic nerve atrophy through degeneration of retinal cells.","date":"2021","source":"Developmental dynamics : an official publication of the American Association of Anatomists","url":"https://pubmed.ncbi.nlm.nih.gov/33742727","citation_count":3,"is_preprint":false},{"pmid":"39574120","id":"PMC_39574120","title":"RERE-AS1 enhances the effect of CDK4/6 inhibitor Ribociclib and suppresses malignant phenotype in breast cancer via MEK/ERK pathway.","date":"2024","source":"Journal of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/39574120","citation_count":3,"is_preprint":false},{"pmid":"36576487","id":"PMC_36576487","title":"Zebrafish model of RERE syndrome recapitulates key ophthalmic defects that are rescued by small molecule inhibitor of shh signaling.","date":"2023","source":"Developmental dynamics : an official publication of the American Association of Anatomists","url":"https://pubmed.ncbi.nlm.nih.gov/36576487","citation_count":3,"is_preprint":false},{"pmid":"38018232","id":"PMC_38018232","title":"A de novo variant in RERE causes autistic behavior by disrupting related genes and signaling pathway.","date":"2023","source":"Clinical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/38018232","citation_count":2,"is_preprint":false},{"pmid":"40890291","id":"PMC_40890291","title":"A de novo variant of RERE was identified in a patient with neurodevelopmental disorder, enuresis and scoliosis.","date":"2025","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/40890291","citation_count":2,"is_preprint":false},{"pmid":"30245899","id":"PMC_30245899","title":"Type IV Laryngotracheoesophageal Cleft Associated with Type III Esophageal Atresia in 1p36 Deletions Containing the RERE Gene: Is There a Causal Role for the Genetic Alteration?","date":"2018","source":"Case reports in pediatrics","url":"https://pubmed.ncbi.nlm.nih.gov/30245899","citation_count":1,"is_preprint":false},{"pmid":"25484675","id":"PMC_25484675","title":"Crystal structure of tetra-kis-(μ-n-butyrato-κ(2) O:O')bis-[chlorido-rhenium(III)](Re-Re).","date":"2014","source":"Acta crystallographica. Section E, Structure reports online","url":"https://pubmed.ncbi.nlm.nih.gov/25484675","citation_count":1,"is_preprint":false},{"pmid":"41298505","id":"PMC_41298505","title":"Spatiotemporal dynamics of RERE in schizophrenia pathogenesis: insights from multi-omics and single-cell sequencing.","date":"2025","source":"Schizophrenia (Heidelberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/41298505","citation_count":0,"is_preprint":false},{"pmid":"41417117","id":"PMC_41417117","title":"RERE-AS1 as a regulator of immune modulation and therapeutic response in breast cancer.","date":"2025","source":"Cancer immunology, immunotherapy : CII","url":"https://pubmed.ncbi.nlm.nih.gov/41417117","citation_count":0,"is_preprint":false},{"pmid":"41580391","id":"PMC_41580391","title":"Functional variants at 1p36.23 confer risk of schizophrenia through modulating RERE.","date":"2026","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/41580391","citation_count":0,"is_preprint":false},{"pmid":"41863965","id":"PMC_41863965","title":"Circ-RERE promotes autophagy and immune escape in acute myeloid leukemia involving the miR-128-3p/ZEB1/PD-L1 axis.","date":"2026","source":"Clinics (Sao Paulo, Brazil)","url":"https://pubmed.ncbi.nlm.nih.gov/41863965","citation_count":0,"is_preprint":false},{"pmid":"41988794","id":"PMC_41988794","title":"New genotype-phenotype correlations and management recommendations for individuals with RERE variants.","date":"2026","source":"Genetics in medicine : official journal of the American College of Medical Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/41988794","citation_count":0,"is_preprint":false},{"pmid":"41669386","id":"PMC_41669386","title":"Expanding the Clinical Spectrum of RERE-Related Disorders: A Case Report of Neurodevelopmental Disorder with Brain Malformations Including Chiari Type I.","date":"2025","source":"Molecular syndromology","url":"https://pubmed.ncbi.nlm.nih.gov/41669386","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.09.16.670041","title":"Structural analysis of HERC2/UBE3A and HERC2/DOCK10 complexes provides new insights into the molecular basis of Angelman, Angelman-like and Dup15q Syndromes","date":"2025-09-16","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.16.670041","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.02.24.639909","title":"Mutations on the surface of HDAC1 reveal molecular determinants of specific complex assembly and their requirement for gene regulation","date":"2025-02-27","source":"bioRxiv","url":"https://doi.org/10.1101/2025.02.24.639909","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.08.26.25334245","title":"Refining the genetic landscape of anophthalmia and microphthalmia: a comprehensive framework with deep learning and updated gene panels","date":"2025-08-28","source":"bioRxiv","url":"https://doi.org/10.1101/2025.08.26.25334245","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.12.27.24319460","title":"Deleterious coding variation associated with autism is consistent across populations, as exemplified by admixed Latin American populations","date":"2025-01-06","source":"bioRxiv","url":"https://doi.org/10.1101/2024.12.27.24319460","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":18043,"output_tokens":3452,"usd":0.052955,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10966,"output_tokens":3817,"usd":0.075127,"stage2_stop_reason":"end_turn"},"total_usd":0.128082,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2010,\n      \"finding\": \"RERE (Atrophin2) forms a protein complex with Nr2f2, p300 (Ep300), and a retinoic acid receptor that is recruited to the retinoic acid regulatory element (RARE) of retinoic acid target gene promoters (e.g., Rarb), thereby positively regulating retinoic acid-dependent transcription. Knockdown of Nr2f2 and/or Rere decreases retinoic acid signaling, and loss of Rere in mice leads to asymmetrical somite formation analogous to retinoic acid deficiency.\",\n      \"method\": \"Co-immunoprecipitation of complex components, promoter-reporter assays, knockdown experiments in mouse embryos, genetic loss-of-function (Rere mutant mice)\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal complex assembly demonstrated, functional promoter recruitment shown, genetic phenocopy of RA deficiency, replicated across multiple orthogonal methods in one rigorous study\",\n      \"pmids\": [\"20164929\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"RERE protein localizes predominantly to the nucleus, where it co-localizes with promyelocytic leukemia (PML) protein at PML oncogenic domains (PODs). Overexpression of RERE recruits a fraction of the pro-apoptotic protein BAX to PODs and induces caspase-dependent apoptosis.\",\n      \"method\": \"Immunofluorescence co-localization, overexpression in cell lines, caspase activity assays, flow cytometry for apoptosis\",\n      \"journal\": \"Cell growth & differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization by immunofluorescence with functional consequence (apoptosis induction), single lab with two orthogonal readouts\",\n      \"pmids\": [\"11331249\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"RERE co-immunoprecipitates with CBF1 (RBPjκ) and the Notch intracellular domain (NICD), and is recruited to nuclear foci formed by overexpressed NICD1. RERE is required for NICD-mediated activation of Notch target genes (Hes genes) and promotes NICD stability, thereby facilitating assembly of the NICD/CBF1 transcriptional activating complex in vertebrate neural progenitors.\",\n      \"method\": \"Co-immunoprecipitation in mammalian cells, overexpression/knockdown in chick spinal cord, reporter gene assays for Notch targets, immunofluorescence of nuclear foci\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP showing complex formation, functional target gene assays, knockdown phenotype, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"28144959\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"RERE co-localizes with GATA4 in the endocardium of the atrioventricular (AV) canal and positively regulates transcription from the Gata4 promoter. RERE deficiency leads to reduced GATA4 levels in the AV canal, decreased epithelial-to-mesenchymal transition (EMT) and mesenchymal cell proliferation in AV endocardial cushions, and ventricular septal defects (VSDs). Genetic interaction between Rere and Gata4 in CHD development was demonstrated by in vivo epistasis. Tissue-specific ablation of Rere in the endocardium (Wnt1-Cre) recapitulates EMT defects and VSDs but does not reduce GATA4 expression, indicating a cell-autonomous RERE function in EMT independent of GATA4.\",\n      \"method\": \"Immunofluorescence co-localization, promoter-luciferase reporter assays, conditional knockout (endocardium-specific Cre), genetic epistasis (Rere/Gata4 compound mutants), cell counting of cushion mesenchymal cells\",\n      \"journal\": \"Disease models & mechanisms\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods including genetic epistasis, tissue-specific KO, promoter assays, and in vivo cellular phenotyping in a single study\",\n      \"pmids\": [\"30061196\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"RERE deficiency in mice leads to delayed maturation and migration of Purkinje cells during prenatal cerebellar development, reduced sonic hedgehog (SHH) secretion from Purkinje cells, and consequently reduced granule cell precursor (GCP) proliferation. Postnatally, RERE loss causes incomplete cerebellar lobule formation and decreased Purkinje cell dendritic branching.\",\n      \"method\": \"Analysis of RERE-deficient hypomorphic mouse embryos (Rere^om/eyes3), immunohistochemistry for Purkinje cell markers and NeuN, BrdU proliferation assays, SHH expression analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined cellular phenotype with pathway placement (SHH pathway) using loss-of-function mouse model with multiple histological readouts, single lab\",\n      \"pmids\": [\"24466353\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"An allelic series of RERE-deficient mice (null om allele and hypomorphic eyes3 allele) demonstrates that RERE is required for development of the eye, brain, inner ear, heart, and kidney. RERE functions as a positive regulator of retinoic acid signaling in vivo across multiple organ systems.\",\n      \"method\": \"ENU mutagenesis screen, generation of compound heterozygous mice (om/eyes3), histological phenotyping, NeuN immunostaining, audiological testing\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function with defined multi-organ phenotypic readouts, allelic series provides dose-response validation, single lab\",\n      \"pmids\": [\"23451234\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"RERE is expressed in retinal ganglion cells (RGCs), lens epithelium, and ciliary body embryonically, and expands to the outer and inner nuclear layers postnatally. RERE deficiency causes progressive apoptosis of retinal cells in the ganglion cell layer starting at E17.5, loss of RGCs, and optic nerve atrophy.\",\n      \"method\": \"Immunohistochemistry for RERE expression, TUNEL assay for apoptosis, RGC counting in RERE-deficient mice, histological analysis of retina and optic nerve\",\n      \"journal\": \"Developmental dynamics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization tied to functional apoptotic phenotype in loss-of-function mouse model, single lab, multiple time points\",\n      \"pmids\": [\"33742727\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"RERE deficiency in cranial neural crest (CNC) cells, mediated by Wnt1-Cre conditional ablation, leads to delayed elevation of palatal shelves, reduced proliferation of palatal mesenchymal cells, and cleft palate. RERE is broadly expressed in the palate during mouse embryonic development.\",\n      \"method\": \"Conditional knockout (Rereflox/flox; Wnt1-Cre), immunohistochemistry for RERE expression, BrdU/EdU proliferation assays in palatal shelves, histological staging of palate elevation\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — tissue-specific conditional KO with defined cellular mechanism (proliferation defect), single lab\",\n      \"pmids\": [\"33772547\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"RERE negatively regulates Sonic hedgehog (SHH) signaling, and loss of RERE function in zebrafish rerea (babyface) mutants causes expansion of the optic stalk domain and optic fissure closure defects (coloboma). NEDBEH-associated human RERE variants function as hypomorphs in their ability to repress SHH signaling and some exhibit abnormal nuclear localization. Pharmacological inhibition of SHH signaling with HPI-1 rescues coloboma in rerea mutants.\",\n      \"method\": \"Zebrafish rerea mutant analysis, cell-based SHH signaling reporter assays with human RERE variants, immunofluorescence for nuclear localization of variants, pharmacological rescue with HPI-1 inhibitor\",\n      \"journal\": \"Developmental dynamics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function with pharmacological rescue confirming pathway, cell-based assays for human variants, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"36576487\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"A CRISPR/Cas9-introduced RERE frameshift variant in human cells leads to downregulation of the SHH signaling pathway and upregulation of the Hippo pathway, as well as decreased expression of ASD-associated genes (CNTNAP2, STX1A, FARP2, GPC1) and alterations in HDAC1 and HDAC2 (members of the WHHERE complex). The mutant RERE protein shows altered subcellular localization by immunofluorescence.\",\n      \"method\": \"CRISPR/Cas9 point mutation cell line, RNA-sequencing for transcriptome, mass spectrometry for proteome, immunofluorescence for localization of mutant RERE\",\n      \"journal\": \"Clinical genetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single cell line with broad transcriptomic/proteomic readouts but limited mechanistic resolution; no direct biochemical assay of pathway components\",\n      \"pmids\": [\"38018232\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"RERE interacts with RARB and RXRA at the Grin2a promoter to regulate expression of the schizophrenia risk gene Grin2a (encoding an NMDAR subunit). Risk alleles at intronic variants rs159961 and rs301792 increase enhancer activity by altering REST and POLR2A binding, leading to RERE upregulation. RERE overexpression impairs neurogenesis, alters dendritic spine density and dendritic complexity, and impairs excitatory synaptic transmission.\",\n      \"method\": \"Allele-specific enhancer luciferase assays, ChIP for REST and POLR2A binding, promoter-reporter assays for Grin2a, overexpression in neurons with dendritic spine and electrophysiology readouts\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter interaction (RARB/RXRA) demonstrated with reporter assays, allele-specific ChIP, neuronal functional readouts; single lab\",\n      \"pmids\": [\"41580391\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RERE is identified as a component of a sixth unique HDAC1/2-containing multiprotein complex (named RERE complex, alongside SIN3, NuRD, CoREST, MIDAC, and MIER) by co-immunoprecipitation of HDAC1-Flag followed by mass spectrometry in mouse embryonic stem cells.\",\n      \"method\": \"Co-immunoprecipitation of HDAC1-Flag followed by mass spectrometry, structural comparison of HDAC1 complex interfaces\",\n      \"journal\": \"bioRxiv (preprint)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP/MS experiment identifying RERE as an HDAC1 complex component; preprint, no independent replication reported\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"RERE is a nuclear receptor co-regulator that positively regulates retinoic acid signaling by forming a complex with Nr2f2, p300, and retinoic acid receptors recruited to target gene promoters; it also co-operates with CBF1/NICD to activate Notch target genes, positively regulates GATA4 transcription and EMT in cardiac development, represses SHH signaling to control optic fissure closure, interacts with RARB/RXRA at the Grin2a promoter to regulate NMDA receptor expression, localizes to PML nuclear bodies where it recruits BAX and promotes caspase-dependent apoptosis, and participates in an HDAC1/2-containing chromatin-modifying complex.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"RERE (Atrophin2) is a nuclear transcriptional co-regulator that integrates multiple developmental signaling pathways during organogenesis [#0, #5]. It positively regulates retinoic acid signaling by assembling a complex with Nr2f2, p300, and a retinoic acid receptor that is recruited to retinoic acid response elements of target gene promoters; loss of Rere phenocopies retinoic acid deficiency in vivo and disrupts development of the eye, brain, inner ear, heart, and kidney [#0, #5]. Beyond retinoic acid signaling, RERE co-operates with the NICD/CBF1 complex to stabilize NICD and activate Notch target genes in neural progenitors [#2], positively regulates the Gata4 promoter and drives endothelial-to-mesenchymal transition in cardiac AV cushion development [#3], and acts as a negative regulator of SHH signaling, where hypomorphic human variants fail to repress SHH and cause optic fissure closure defects rescuable by SHH pathway inhibition [#8]. In specific tissues RERE supports cell survival and proliferation: it is required for Purkinje cell maturation and SHH-driven granule cell precursor proliferation in the cerebellum [#4], for survival of retinal ganglion cells [#6], and for proliferation of palatal mesenchyme, with its loss causing cleft palate [#7]. RERE localizes to PML nuclear bodies where its overexpression recruits BAX and induces caspase-dependent apoptosis [#1], and it also acts at the Grin2a promoter together with RARB and RXRA, with RERE overexpression impairing neurogenesis and excitatory synaptic transmission [#10].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established RERE's subcellular address and a first functional consequence — defining it as a nuclear, PML-body-associated protein capable of promoting apoptosis.\",\n      \"evidence\": \"Immunofluorescence co-localization with PML and BAX, plus caspase activity and apoptosis assays in overexpressing cell lines\",\n      \"pmids\": [\"11331249\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Apoptotic role rests on overexpression rather than loss-of-function\",\n        \"Mechanism by which RERE recruits BAX to PODs not defined\",\n        \"No endogenous-level validation\"\n      ]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Resolved the core biochemical mechanism by showing RERE is a positive co-regulator of retinoic acid signaling assembled into a defined promoter-bound complex.\",\n      \"evidence\": \"Co-immunoprecipitation of Nr2f2/p300/RAR complex, RARE promoter-reporter assays, and Rere mutant mice phenocopying RA deficiency\",\n      \"pmids\": [\"20164929\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Stoichiometry and order of complex assembly not resolved\",\n        \"Whether RERE binds DNA directly or only via partners unknown\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Demonstrated that RERE is required across multiple organ systems, generalizing its role as an in vivo positive regulator of retinoic acid signaling.\",\n      \"evidence\": \"Allelic series (null om and hypomorphic eyes3) with multi-organ histological and audiological phenotyping\",\n      \"pmids\": [\"23451234\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Organ-level phenotypes not connected to specific molecular targets\",\n        \"Does not distinguish RA-dependent from RA-independent functions\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Placed RERE within the SHH axis of cerebellar development by linking its loss to reduced Purkinje cell SHH secretion and granule cell precursor proliferation.\",\n      \"evidence\": \"Hypomorphic Rere mouse embryos with Purkinje cell marker IHC, BrdU proliferation, and SHH expression analysis\",\n      \"pmids\": [\"24466353\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether RERE regulates SHH transcriptionally or indirectly not established\",\n        \"Cell-autonomy of the defect not dissected\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Extended RERE's co-activator role to the Notch pathway, showing it stabilizes NICD and is required for Notch target activation.\",\n      \"evidence\": \"Co-IP with CBF1/NICD, nuclear foci co-localization, and knockdown/overexpression with Notch reporter assays in chick spinal cord\",\n      \"pmids\": [\"28144959\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct vs bridged interaction with CBF1 not resolved\",\n        \"Mechanism of NICD stabilization unknown\",\n        \"Single lab, no reciprocal validation\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Dissected RERE's cardiac function, separating a GATA4-promoter co-activation role from a cell-autonomous EMT-driving role.\",\n      \"evidence\": \"Gata4 promoter-luciferase assays, endocardium-specific conditional KO, and Rere/Gata4 genetic epistasis in compound mutants\",\n      \"pmids\": [\"30061196\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"GATA4-independent EMT effector targets not identified\",\n        \"Whether GATA4 regulation is direct at the promoter not biochemically resolved\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined tissue-specific developmental requirements for RERE in retinal cell survival and in palatal mesenchyme proliferation.\",\n      \"evidence\": \"RERE expression IHC with TUNEL and RGC counting in the retina, and Wnt1-Cre conditional KO with EdU proliferation assays in palate\",\n      \"pmids\": [\"33742727\", \"33772547\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Molecular pathway linking RERE loss to apoptosis vs proliferation defects not specified\",\n        \"Downstream effectors in each tissue undefined\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Clarified RERE as a repressor of SHH signaling and connected disease-associated human variants to this activity via hypomorphism and mislocalization.\",\n      \"evidence\": \"Zebrafish rerea coloboma mutants, SHH reporter assays of human variants, localization IF, and HPI-1 pharmacological rescue\",\n      \"pmids\": [\"36576487\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct molecular mechanism of SHH repression by RERE not identified\",\n        \"How variant mislocalization translates to reduced repression unclear\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Provided a transcriptome/proteome-level view of RERE loss, linking it to SHH, Hippo, ASD genes, and the HDAC1/2 WHHERE complex.\",\n      \"evidence\": \"CRISPR/Cas9 frameshift human cell line with RNA-seq, mass spectrometry, and mutant RERE localization IF\",\n      \"pmids\": [\"38018232\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Single cell line with broad readouts and no direct biochemical pathway assay\",\n        \"Causal direction of pathway changes not established\",\n        \"HDAC complex membership not validated here\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Linked RERE to NMDAR-subunit gene regulation, showing it acts with RARB/RXRA at the Grin2a promoter and that its dysregulation alters neuronal connectivity.\",\n      \"evidence\": \"Allele-specific enhancer luciferase, ChIP for REST/POLR2A, Grin2a promoter reporters, and neuronal dendritic spine and electrophysiology readouts\",\n      \"pmids\": [\"41580391\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether RERE binds the Grin2a promoter directly or via RARB/RXRA not resolved\",\n        \"Single lab; in vivo relevance to schizophrenia phenotypes not established\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Proposed RERE as the defining subunit of a distinct HDAC1/2-containing chromatin-modifying complex.\",\n      \"evidence\": \"HDAC1-Flag Co-IP/mass spectrometry in mouse ES cells with structural interface comparison (preprint)\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Single Co-IP/MS experiment in a preprint without independent replication\",\n        \"Complex composition and genomic targets not defined\",\n        \"Functional role of the complex not tested\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How RERE mechanistically toggles between positive co-activation (retinoic acid, Notch, GATA4) and repression (SHH), and whether HDAC1/2 recruitment underlies its repressive activity, remains unresolved.\",\n      \"evidence\": \"No single study reconciles the activating and repressing activities at a biochemical level\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No structure of RERE in any of its complexes\",\n        \"No defined direct DNA-binding activity\",\n        \"Context determinants of activation vs repression unknown\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 2, 3, 10]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 8, 9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0, 3, 5, 7]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 2, 8]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 3, 10]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [1, 6]}\n    ],\n    \"complexes\": [\n      \"Nr2f2/p300/RAR retinoic acid co-activator complex\",\n      \"NICD/CBF1 Notch activating complex\",\n      \"RERE HDAC1/2 complex (WHHERE)\"\n    ],\n    \"partners\": [\n      \"NR2F2\",\n      \"EP300\",\n      \"RBPJ\",\n      \"GATA4\",\n      \"RARB\",\n      \"RXRA\",\n      \"HDAC1\",\n      \"BAX\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}