Affinage

RERE

Arginine-glutamic acid dipeptide repeats protein · UniProt Q9P2R6

Length
1566 aa
Mass
172.4 kDa
Annotated
2026-06-10
26 papers in source corpus 11 papers cited in narrative 12 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2001 Medium

    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

    PMID:11331249

    Open questions at the time
    • Apoptotic role rests on overexpression rather than loss-of-function
    • Mechanism by which RERE recruits BAX to PODs not defined
    • No endogenous-level validation
  2. 2010 High

    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

    PMID:20164929

    Open questions at the time
    • Stoichiometry and order of complex assembly not resolved
    • Whether RERE binds DNA directly or only via partners unknown
  3. 2013 Medium

    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

    PMID:23451234

    Open questions at the time
    • Organ-level phenotypes not connected to specific molecular targets
    • Does not distinguish RA-dependent from RA-independent functions
  4. 2014 Medium

    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

    PMID:24466353

    Open questions at the time
    • Whether RERE regulates SHH transcriptionally or indirectly not established
    • Cell-autonomy of the defect not dissected
  5. 2017 Medium

    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

    PMID:28144959

    Open questions at the time
    • Direct vs bridged interaction with CBF1 not resolved
    • Mechanism of NICD stabilization unknown
    • Single lab, no reciprocal validation
  6. 2018 High

    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

    PMID:30061196

    Open questions at the time
    • GATA4-independent EMT effector targets not identified
    • Whether GATA4 regulation is direct at the promoter not biochemically resolved
  7. 2021 Medium

    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

    PMID:33742727 PMID:33772547

    Open questions at the time
    • Molecular pathway linking RERE loss to apoptosis vs proliferation defects not specified
    • Downstream effectors in each tissue undefined
  8. 2023 Medium

    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

    PMID:36576487

    Open questions at the time
    • Direct molecular mechanism of SHH repression by RERE not identified
    • How variant mislocalization translates to reduced repression unclear
  9. 2023 Low

    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

    PMID:38018232

    Open questions at the time
    • 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
  10. 2026 Medium

    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

    PMID:41580391

    Open questions at the time
    • Whether RERE binds the Grin2a promoter directly or via RARB/RXRA not resolved
    • Single lab; in vivo relevance to schizophrenia phenotypes not established
  11. 2025 Low

    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)

    Open questions at the time
    • 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

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • No structure of RERE in any of its complexes
  • No defined direct DNA-binding activity
  • Context determinants of activation vs repression unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 4 GO:0098772 molecular function regulator activity 2
Localization
GO:0005634 nucleus 3
Pathway
R-HSA-1266738 Developmental Biology 4 R-HSA-162582 Signal Transduction 3 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-5357801 Programmed Cell Death 2
Partners
BAXEP300GATA4HDAC1NR2F2RARBRBPJRXRA
Complex memberships
NICD/CBF1 Notch activating complexNr2f2/p300/RAR retinoic acid co-activator complexRERE HDAC1/2 complex (WHHERE)

Evidence

Reading pass · 12 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2010 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. Co-immunoprecipitation of complex components, promoter-reporter assays, knockdown experiments in mouse embryos, genetic loss-of-function (Rere mutant mice) Nature High 20164929
2001 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. Immunofluorescence co-localization, overexpression in cell lines, caspase activity assays, flow cytometry for apoptosis Cell growth & differentiation Medium 11331249
2017 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. Co-immunoprecipitation in mammalian cells, overexpression/knockdown in chick spinal cord, reporter gene assays for Notch targets, immunofluorescence of nuclear foci Journal of neurochemistry Medium 28144959
2018 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. Immunofluorescence co-localization, promoter-luciferase reporter assays, conditional knockout (endocardium-specific Cre), genetic epistasis (Rere/Gata4 compound mutants), cell counting of cushion mesenchymal cells Disease models & mechanisms High 30061196
2014 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. Analysis of RERE-deficient hypomorphic mouse embryos (Rere^om/eyes3), immunohistochemistry for Purkinje cell markers and NeuN, BrdU proliferation assays, SHH expression analysis PloS one Medium 24466353
2013 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. ENU mutagenesis screen, generation of compound heterozygous mice (om/eyes3), histological phenotyping, NeuN immunostaining, audiological testing PloS one Medium 23451234
2021 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. Immunohistochemistry for RERE expression, TUNEL assay for apoptosis, RGC counting in RERE-deficient mice, histological analysis of retina and optic nerve Developmental dynamics Medium 33742727
2021 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. Conditional knockout (Rereflox/flox; Wnt1-Cre), immunohistochemistry for RERE expression, BrdU/EdU proliferation assays in palatal shelves, histological staging of palate elevation Human molecular genetics Medium 33772547
2023 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. 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 Developmental dynamics Medium 36576487
2023 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. CRISPR/Cas9 point mutation cell line, RNA-sequencing for transcriptome, mass spectrometry for proteome, immunofluorescence for localization of mutant RERE Clinical genetics Low 38018232
2026 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. 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 Nature communications Medium 41580391
2025 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. Co-immunoprecipitation of HDAC1-Flag followed by mass spectrometry, structural comparison of HDAC1 complex interfaces bioRxiv (preprint)preprint Low

Source papers

Stage 0 corpus · 26 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2010 Rere controls retinoic acid signalling and somite bilateral symmetry. Nature 94 20164929
2016 De Novo Mutations of RERE Cause a Genetic Syndrome with Features that Overlap Those Associated with Proximal 1p36 Deletions. American journal of human genetics 73 27087320
2022 N6 -methyladenosine-modified circRNA RERE modulates osteoarthritis by regulating β-catenin ubiquitination and degradation. Cell proliferation 47 35733354
2001 Human RERE is localized to nuclear promyelocytic leukemia oncogenic domains and enhances apoptosis. Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research 46 11331249
2018 Genotype-phenotype correlations in individuals with pathogenic RERE variants. Human mutation 43 29330883
2013 An allelic series of mice reveals a role for RERE in the development of multiple organs affected in chromosome 1p36 deletions. PloS one 40 23451234
2014 Mouse model reveals the role of RERE in cerebellar foliation and the migration and maturation of Purkinje cells. PloS one 31 24466353
2021 CircRNA RERE Promotes the Oxidative Stress-Induced Apoptosis and Autophagy of Nucleus Pulposus Cells through the miR-299-5p/Galectin-3 Axis. Journal of healthcare engineering 11 34956563
2018 RERE deficiency leads to decreased expression of GATA4 and the development of ventricular septal defects. Disease models & mechanisms 9 30061196
2017 Atrophin protein RERE positively regulates Notch targets in the developing vertebrate spinal cord. Journal of neurochemistry 9 28144959
2022 Phenotypic variability in RERE-related disorders and the first report of an inherited variant. American journal of medical genetics. Part A 7 36053530
2021 RERE deficiency contributes to the development of orofacial clefts in humans and mice. Human molecular genetics 6 33772547
2018 Familial intracranial arachnoid cysts with a missense mutation (c.2576C > T) in RERE: A case report. Medicine 6 30558068
2024 RERE-AS1 enhances the effect of CDK4/6 inhibitor Ribociclib and suppresses malignant phenotype in breast cancer via MEK/ERK pathway. Journal of translational medicine 3 39574120
2023 Zebrafish model of RERE syndrome recapitulates key ophthalmic defects that are rescued by small molecule inhibitor of shh signaling. Developmental dynamics : an official publication of the American Association of Anatomists 3 36576487
2021 RERE deficiency causes retinal and optic nerve atrophy through degeneration of retinal cells. Developmental dynamics : an official publication of the American Association of Anatomists 3 33742727
2025 A de novo variant of RERE was identified in a patient with neurodevelopmental disorder, enuresis and scoliosis. Scientific reports 2 40890291
2023 A de novo variant in RERE causes autistic behavior by disrupting related genes and signaling pathway. Clinical genetics 2 38018232
2018 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? Case reports in pediatrics 1 30245899
2014 Crystal structure of tetra-kis-(μ-n-butyrato-κ(2) O:O')bis-[chlorido-rhenium(III)](Re-Re). Acta crystallographica. Section E, Structure reports online 1 25484675
2026 Functional variants at 1p36.23 confer risk of schizophrenia through modulating RERE. Nature communications 0 41580391
2026 Circ-RERE promotes autophagy and immune escape in acute myeloid leukemia involving the miR-128-3p/ZEB1/PD-L1 axis. Clinics (Sao Paulo, Brazil) 0 41863965
2026 New genotype-phenotype correlations and management recommendations for individuals with RERE variants. Genetics in medicine : official journal of the American College of Medical Genetics 0 41988794
2025 Spatiotemporal dynamics of RERE in schizophrenia pathogenesis: insights from multi-omics and single-cell sequencing. Schizophrenia (Heidelberg, Germany) 0 41298505
2025 RERE-AS1 as a regulator of immune modulation and therapeutic response in breast cancer. Cancer immunology, immunotherapy : CII 0 41417117
2025 Expanding the Clinical Spectrum of RERE-Related Disorders: A Case Report of Neurodevelopmental Disorder with Brain Malformations Including Chiari Type I. Molecular syndromology 0 41669386

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