Affinage

NR2F6

Nuclear receptor subfamily 2 group F member 6 · UniProt P10588

Length
404 aa
Mass
43.0 kDa
Annotated
2026-06-10
66 papers in source corpus 37 papers cited in narrative 38 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NR2F6 (EAR-2) is an orphan nuclear receptor that functions principally as a sequence-specific transcriptional repressor, binding direct-repeat TGACC(T/C) hormone response elements and cytokine gene promoters to restrain target gene expression across immune, metabolic, and developmental programs (PMID:12690040, PMID:18701084, PMID:22921335). It recognizes such elements with nanomolar affinity (e.g., the ApoB and ApoCIII regulatory elements) and silences target promoters either by active repression or by competing with activators for overlapping DNA elements, as shown for the oxytocin, apolipoprotein, LH receptor, and renin genes (PMID:1639815, PMID:9343308, PMID:12690040). NR2F6 can act through several distinct molecular routes: direct physical inhibition of transcription factors such as the thyroid hormone receptor TRβ1, which it binds via its ligand-binding domain to block DNA binding in an SRC-1-reversible manner (PMID:10713182); recruitment of histone deacetylases including HDAC2 to target promoters such as PDGFRB (PMID:32203934); and, in T cells, direct interference with DNA binding of the NFAT:AP-1 complex and RORγt across the IL-2, IL-17A, IFN-γ, and IL-21 cytokine loci (PMID:18701084, PMID:22921335, PMID:26387951, PMID:31509749). In the immune system NR2F6 operates as a cell-intrinsic checkpoint: it is a PKC substrate whose phosphorylation relieves repression, and its loss produces hyperreactive effector CD4+, CD8+, Tfh, and NK cells, enhanced antitumor immunity, and susceptibility to Th17-driven autoimmunity (PMID:18701084, PMID:26387951, PMID:29670099, PMID:31509749). Beyond immunity, NR2F6 governs developmental and metabolic gene programs—it is required for locus coeruleus development by acting between Mash1 and Phox2a/b (PMID:15741322), maintains intestinal barrier integrity by transactivating Muc2 (PMID:28779026), promotes brown adipogenesis by activating PPARγ (PMID:38307386), and drives hepatic triglyceride accumulation by binding the CD36 promoter and recruiting SRC-1 (PMID:33173745). A 2025 crystal structure resolved the apo NR2F6 ligand-binding domain in an autorepressed homodimeric conformation in which helix 12 occludes the canonical coregulator groove, generating an alternative surface for the non-canonical coregulator NSD1 (PMID:40931005).

Mechanistic history

Synthesis pass · year-by-year structured walk · 20 steps
  1. 1992 Medium

    Established that NR2F6/EAR-2 is a high-affinity DNA-binding repressor, defining its core biochemical activity at apolipoprotein regulatory elements.

    Evidence EMSA with Kd determination and cotransfection reporter assays in HepG2 cells

    PMID:1639815

    Open questions at the time
    • No corepressor or coactivator identified
    • Mechanism of repression (competition vs active) not yet distinguished
  2. 1997 Medium

    Showed NR2F6 mediates active repression rather than mere activator competition, refining the mechanism at the oxytocin promoter.

    Evidence DNase I footprinting, EMSA, mutagenesis and reporter assays

    PMID:9343308 PMID:9605516

    Open questions at the time
    • Did not identify the recruited corepressor machinery
    • Restricted to a single promoter context
  3. 1998 Medium

    Extended NR2F6 function to myeloid differentiation by showing it directly binds and inhibits RUNX1, providing a protein-protein mechanism distinct from DNA element occupancy.

    Evidence Direct binding/Co-IP and G-CSF differentiation assays in 32Dc13 myeloid progenitors

    PMID:9461615 PMID:9465099

    Open questions at the time
    • Interaction domains not mapped
    • Link between RUNX1 inhibition and differentiation block correlative
  4. 1999 Medium

    Defined NR2F6's dimerization behavior, showing it heterodimerizes with ARP1/COUP-TFI with distinct DNA specificity, expanding the combinatorial repertoire of its target recognition.

    Evidence Yeast two-hybrid, pull-down, EMSA on DR elements and tissue expression mapping

    PMID:10318855

    Open questions at the time
    • Functional consequence of heterodimer vs homodimer on specific genes not resolved
  5. 2000 High

    Demonstrated NR2F6 represses nuclear receptor signaling by binding TRβ1 through its LBD and that coactivator SRC-1 can reverse this, revealing a tunable repression mechanism.

    Evidence Yeast two-hybrid, GST pull-down, Co-IP, EMSA and reporter assays

    PMID:10713182

    Open questions at the time
    • SRC-1 competition not tested at endogenous loci
    • Physiological ligand for the LBD unknown
  6. 2003 High

    Confirmed NR2F6 as a direct repressor of an endogenous gene (renin), binding the TGACCT enhancer element and repressing both basal and retinoid-induced activity.

    Evidence Yeast one-hybrid, EMSA, fractionation, reporter and endogenous gene repression assays in As4.1 cells

    PMID:12690040 PMID:22278040

    Open questions at the time
    • Corepressor recruited at the renin enhancer not identified in these studies
  7. 2005 High

    Placed NR2F6 in a developmental cascade, establishing it as essential for locus coeruleus neuron specification between Mash1 and Phox2a/b.

    Evidence Germline Ear2-/- knockout with in situ hybridization, noradrenaline measurement and circadian gene analysis

    PMID:15741322

    Open questions at the time
    • Direct target genes downstream of NR2F6 in LC progenitors not identified
    • Whether activity is repressive or activating in this context unclear
  8. 2008 High

    Identified NR2F6 as a PKC-regulated intracellular immune checkpoint that directly blocks NFAT:AP-1 DNA binding to suppress IL-2 and IL-17, with knockout mice prone to autoimmunity.

    Evidence PKC phosphorylation assay, EMSA/DNA-binding competition, Nr2f6-/- mice and EAE model

    PMID:18701084

    Open questions at the time
    • PKC phosphosites and their effect on DNA binding not fully mapped
    • Selectivity against NF-κB mechanism not detailed
  9. 2012 High

    Showed NR2F6 represses the Il17a locus by both antagonizing NFAT binding and occupying HREs that interfere with RORγt access, integrating two repressive modes at one locus.

    Evidence ChIP in primary Th17 cells, EMSA, and loss/gain-of-function genetic mouse models

    PMID:22921335

    Open questions at the time
    • How NR2F6 occupancy mechanically excludes RORγt not resolved at structural level
  10. 2011 Medium

    Identified Rasd1 as an LBD-interacting partner that relieves NR2F6-mediated renin repression, linking NR2F6 activity to hormonal (dexamethasone) signaling.

    Evidence Yeast two-hybrid, reciprocal endogenous Co-IP, reporter assays and shRNA knockdown

    PMID:21247419

    Open questions at the time
    • Mechanism by which Rasd1 binding inhibits repression unknown
    • Generalizability beyond renin not tested
  11. 2013 Medium

    Characterized NR2F6 gain-of-function effects in hematopoiesis, showing it blocks T cell development and leukemic differentiation, implicating it in myeloid/lymphoid malignancy.

    Evidence Retroviral overexpression, OP9-DL1 co-culture, BM transplantation and expression profiling

    PMID:21637284 PMID:21696885 PMID:24096122

    Open questions at the time
    • Direct transcriptional targets driving the differentiation block not defined
    • XIAP link is correlative (Low confidence)
  12. 2015 High

    Demonstrated T-cell-intrinsic NR2F6 directly represses IL-2 and IFN-γ promoters and that its deletion enables T cells to delay tumor outgrowth, establishing therapeutic relevance.

    Evidence ChIP on cytokine promoters, Nr2f6-/- mice, TRAMP and adoptive transfer tumor models

    PMID:26387951

    Open questions at the time
    • Whether repression requires the same NFAT-interference mechanism at IFN-γ as at IL-17 not directly shown
  13. 2017 High

    Revealed NR2F6 can act as a transcriptional activator, transactivating Muc2 in intestinal epithelium to maintain barrier integrity, separating an epithelial role from its immune-cell role.

    Evidence ChIP on Muc2 promoter and BM reconstitution separating epithelial vs immune compartments in colitis models

    PMID:28779026

    Open questions at the time
    • Coactivators mediating Muc2 transactivation not identified
    • Determinants of activator vs repressor switching unknown
  14. 2018 High

    Defined NR2F6 as a non-redundant, druggable T-cell checkpoint conserved between mouse and human, correlating with PD-1/CTLA-4 in human tumor-infiltrating T cells and synergizing with PD-L1 blockade.

    Evidence Germline and acute-silencing models in mouse and human T cells, IHC on human NSCLC, combination checkpoint blockade

    PMID:29670099 PMID:30555701

    Open questions at the time
    • Mechanistic basis of synergy with PD-L1 blockade not dissected
    • HDAC-recruitment mechanism (idx 19) shown in myeloid context, not T cells
  15. 2020 High

    Established that NR2F6 directs metabolic gene programs through both coactivator recruitment (SRC-1 at CD36 in liver) and HDAC2-mediated corepression (PDGFRB in cancer), unifying activator and repressor modes mechanistically.

    Evidence ChIP for coactivator/histone-mark enrichment and HDAC2 recruitment, AAV liver-specific manipulation and NAFLD models

    PMID:32203934 PMID:33173745

    Open questions at the time
    • What dictates SRC-1 vs HDAC2 recruitment at different promoters unknown
  16. 2022 Medium

    Positioned NR2F6 (Ear2) as a downstream effector of myeloid TLR4 negative feedback enforcing an anti-inflammatory macrophage state.

    Evidence scRNA-seq and siRNA knockdown in TLR4-deficient BMDMs with LPS stimulation

    PMID:35484716 PMID:36119482

    Open questions at the time
    • Direct NR2F6 targets in macrophages not mapped
    • HNRNPD interaction (idx 27) is a single Co-IP, Low confidence
  17. 2024 High

    Extended NR2F6's role to brown adipogenesis and skeletal muscle, showing it transactivates PPARγ for BAT thermogenesis while repressing UCP3/PGC-1α in muscle, demonstrating tissue-specific bidirectional transcriptional control.

    Evidence ChIP-qPCR, conditional and germline knockouts, promoter-reporter assays and metabolic/contractility phenotyping (human cells included)

    PMID:38307386 PMID:38682559

    Open questions at the time
    • Cofactors distinguishing activation (PPARγ) from repression (UCP3) in metabolic tissues not identified
  18. 2025 High

    Solved the first NR2F6 LBD structure, revealing an autorepressed apo homodimer with helix 12 occluding the canonical groove and creating a non-canonical NSD1-binding surface that is covalently druggable.

    Evidence Co-crystallization with NSD1 peptide, X-ray crystallography and covalent probe screening with recruitment assays

    PMID:40931005

    Open questions at the time
    • Whether an endogenous ligand displaces helix 12 in vivo not established here
    • Structural basis of DNA-bound complexes not solved
  19. 2025 Medium

    Expanded NR2F6's immune-checkpoint role to NK cells and red pulp macrophages, where it represses NKp46 and Sirpα respectively to license maturation and phagocytosis.

    Evidence Nr2f6-/- mice, transcriptomics, Sirpα/IL-15 rescue experiments and infection/metastasis models

    PMID:39920136 PMID:40605423

    Open questions at the time
    • Direct promoter binding at NKp46 and Sirpa loci not shown by ChIP in these studies
  20. 2026 Medium

    Identified palmitoylethanolamide as a candidate endogenous NR2F6 ligand and linked NR2F6 to breast cancer migration and proliferation networks, addressing the long-standing orphan status of the receptor.

    Evidence MS-based ligand identification with shRNA knockdown and transcriptomic/migration assays

    PMID:41803880

    Open questions at the time
    • Whether palmitoylethanolamide functionally modulates NR2F6 transcriptional activity not established
    • Single-lab ligand assignment requires orthogonal validation

Open questions

Synthesis pass · forward-looking unresolved questions
  • How NR2F6 switches between repressor (cytokines, renin, UCP3) and activator (Muc2, PPARγ, CD36) modes at different loci, and whether ligand binding to its now-structurally-defined LBD controls this switch in vivo, remains unresolved.
  • No unified rule linking promoter context to cofactor choice (SRC-1 vs HDAC2)
  • Functional consequences of endogenous ligand binding in physiological tissues untested
  • Structures of DNA-bound and ligand-bound NR2F6 complexes lacking

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 8 GO:0003677 DNA binding 6 GO:0098772 molecular function regulator activity 3
Localization
GO:0000228 nuclear chromosome 4 GO:0005634 nucleus 1
Pathway
R-HSA-168256 Immune System 8 R-HSA-74160 Gene expression (Transcription) 6 R-HSA-1266738 Developmental Biology 3 R-HSA-1430728 Metabolism 3
Partners
HDAC2HNRNPDNCOA1NR2F1NSD1RASD1RUNX1THRB

Evidence

Reading pass · 38 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1992 EAR-2 binds specifically to regulatory elements BA1 (-79 to -63) of ApoB and CIIIB (-87 to -63) of ApoCIII genes with dissociation constants of 1-3 nM, and represses transcription of reporter gene constructs driven by these elements in HepG2 cotransfection experiments. Gel mobility shift / EMSA, dissociation constant measurement, cotransfection reporter assay in HepG2 cells The Journal of biological chemistry Medium 1639815
1997 COUP-TFII and Ear-2 silence basal oxytocin gene promoter activity (by 54% and 75% respectively) by binding to a direct TGACC(T/C) repeat overlapping the ERE and to three proximal imperfect direct repeats (R1-R3); this represents active repression rather than simple competition with activators. Cotransfection reporter assay, 5' deletion analysis, DNase I footprinting, EMSA, site-directed mutagenesis Journal of molecular endocrinology Medium 9343308
1998 EAR-2 directly binds to PEBP2alphaB (AML1/Runx1) and inhibits its function; overexpression of Ear-2 in 32Dc13 myeloid progenitor cells prevents G-CSF-induced granulocytic differentiation, identifying Ear-2 as a key negative regulator of this process. Co-immunoprecipitation/direct binding, overexpression in 32Dc13 cells, G-CSF differentiation assay Proceedings of the National Academy of Sciences of the United States of America Medium 9465099
1998 EAR-2 binds to the CIIC hormone response element (-159 to -116) of the apoC-II promoter/HCR-1, but not to CIIB, and contributes to repression of hepatic apoC-II gene transcription in a manner requiring synergistic interaction with other elements. DNase I footprinting with nuclear extracts, EMSA, cotransfection reporter assay, site-directed mutagenesis The Journal of biological chemistry Medium 9461615
1998 COUP-TFII and Ear-2 are expressed in oxytocin-producing uterine epithelial cells (demonstrated by Northern blot and immunocytochemistry) and antagonize estrogen receptor-mediated induction of the oxytocin promoter by binding to a direct TGACC repeat that overlaps but is distinct from the palindromic ERE. Northern blot, immunocytochemistry, cotransfection reporter assay, site-directed mutagenesis, EMSA Molecular and cellular endocrinology Medium 9605516
1999 ARP1 and Ear2 form heterodimers in solution and on directly repeated response elements with high efficiency and a specificity differing from homodimeric complexes; this interaction was confirmed in mammalian cells and the tissue distribution of Ear2 transcripts overlaps precisely with ARP1. Yeast two-hybrid, biochemical pull-down, EMSA on DR elements, mammalian cell co-expression interaction assay, Northern blot tissue distribution The Journal of biological chemistry Medium 10318855
2000 Ear-2 physically interacts with thyroid hormone receptor beta1 (TRbeta1) via its ligand binding domain, inhibits TRbeta1 binding to T3 response elements, and represses both basal and T3-dependent TRbeta1-mediated transcription in a manner reversible by steroid receptor coactivator 1 (SRC-1). Yeast two-hybrid, GST pull-down, co-immunoprecipitation in cells, EMSA, reporter cotransfection assay Molecular and cellular biology High 10713182
2001 EAR2 and EAR3/COUP-TFI bind to a direct-repeat motif (DR) in the rat LH receptor promoter and repress rLHR gene transcription in rat granulosa cells; hCG treatment reduces EAR2 and EAR3 protein levels contributing to derepression of LHR promoter activity. EMSA, cotransfection reporter assay in granulosa cells, Western blot for protein levels Molecular endocrinology (Baltimore, Md.) Medium 11682620
2003 Ear2 (NR2F6) is a nuclear protein in As4.1 renin-expressing cells that binds specifically to the TGACCT direct-repeat motif in the mouse renin enhancer, dose-dependently represses basal and retinoid-induced renin promoter activity, and represses endogenous renin gene transcription; mutations abolishing Ear2 binding to TGACCT also abolish transcriptional repression. Yeast one-hybrid screen, recombinant protein purification, EMSA, subcellular fractionation/immunolocalization, cotransfection reporter assay, site-directed mutagenesis, endogenous gene repression assay Circulation research High 12690040
2005 NR2F6/Ear2 is required for normal locus coeruleus (LC) development: in Ear2-/- embryos Phox2a/b-expressing LC progenitors are reduced ~3-fold while Mash1 expression is unaffected, placing Ear2 between Mash1 and Phox2a/b in the LC developmental cascade. >70% of LC neurons are absent in adults, cortical noradrenaline is 4-fold reduced, and the circadian Period1 expression pattern is abolished in the forebrain. Genetic knockout (Ear2-/-), in situ hybridization, immunostaining (Phox2a/b, DBH, TH), noradrenaline measurement, circadian gene expression analysis, behavioral assays Genes & development High 15741322
2008 NR2F6 is a PKC substrate in T lymphocytes and acts as a transcriptional repressor that directly interferes with DNA binding of the NFAT:AP-1 complex (but not NF-κB) on the IL-17A promoter, suppressing IL-2 and IL-17 cytokine gene expression; Nr2f6-deficient mice develop hyperreactive lymphocytes and are hypersusceptible to Th17-dependent EAE. PKC phosphorylation assay, EMSA/DNA-binding competition, cotransfection reporter assay, Nr2f6-/- mouse model, EAE disease model Immunity High 18701084
2011 Rasd1 physically interacts with the ligand binding domain of Ear2 (NR2F6) in vitro and in transfected COS-7 cells as well as between endogenous proteins from HEK293T cells and mouse brain; Rasd1 inhibits Ear2-mediated transcriptional repression of the renin promoter, and shRNA knockdown of Rasd1 augments Ear2-dependent renin repression while dexamethasone-induced Rasd1 counteracts it. Yeast two-hybrid, in vitro binding, co-immunoprecipitation (transfected and endogenous), luciferase reporter assay, shRNA knockdown, RT-PCR BMC molecular biology Medium 21247419
2011 EAR-2 (NR2F6) expression is greater in AML clonogenic cells; exogenous EAR-2 expression increases growth of U937 cells and prevents proliferative arrest and terminal differentiation, while EAR-2 shRNA silencing initiates terminal differentiation, demonstrating a role for EAR-2 in controlling the clonogenicity/differentiation balance in leukemia cells. Microarray analysis, retroviral overexpression, shRNA knockdown, proliferation and differentiation assays in U937 and 32Dcl3 cells Leukemia Medium 21637284
2011 EAR2 knockdown reduces expression of X-linked inhibitor of apoptosis protein (XIAP) and induces apoptosis of colon cancer cells, while knockdown inhibits xenograft tumor growth in vivo. shRNA knockdown, apoptosis assays, Western blot for XIAP, xenograft tumor model Cancer letters Low 21696885
2012 NR2F6 directly antagonizes NFAT binding to critical regions of the Il17a gene promoter and also binds to hormone response elements (HREs) within the Il17a locus, thereby interfering with RORγt DNA access; NFAT and RORγt binding within the Il17a locus were enhanced in Nr2f6-deficient CD4+ Th17 cells and decreased in Nr2f6-overexpressing transgenic T cells. Chromatin immunoprecipitation (ChIP), EMSA, Nr2f6-/- and transgenic overexpression mouse models, Th17 differentiation assays Journal of autoimmunity High 22921335
2012 Nr2f6 negatively regulates the renin promoter through direct binding to the HRE within the renin enhancer (confirmed by ChIP); knockdown of Nr2f6 (but not Nr2f2) increased baseline endogenous renin expression 2-fold in As4.1 cells. Luciferase reporter assay, gel-shift/EMSA, chromatin immunoprecipitation (ChIP), siRNA knockdown with RT-PCR American journal of physiology. Renal physiology Medium 22278040
2013 Retrovirus-mediated overexpression of Ear-2 in bone marrow HSCs causes a block in T cell development at the DN4 to DP transition accompanied by increased apoptosis, cell cycle arrest associated with upregulation of p21/p27 and Hes1/Notch3/Egr1, and decreased BclXL; this is mediated by a cell-intrinsic defect. Retroviral overexpression in BM HSCs, OP9-DL1 co-culture, BM transplantation, gene expression profiling, flow cytometry, apoptosis assays Experimental hematology Medium 24096122
2015 CD4+ and CD8+ T cell-intrinsic NR2F6 acts as a direct repressor of the NFAT/AP-1 complex on both the IL-2 and IFN-γ cytokine promoters; adoptive transfer of Nr2f6-deficient T cells into tumor-bearing immunocompetent mice is sufficient to delay tumor outgrowth. ChIP on cytokine promoters, Nr2f6-/- mouse model, TRAMP prostate cancer model, tumor rechallenge, adoptive T cell transfer Cell reports High 26387951
2017 NR2F6 binds to a consensus sequence at -2 kb of the Muc2 promoter and transactivates Muc2 expression in intestinal epithelial cells; loss of NR2F6 in the intestinal epithelium (not the immune compartment) increases permeability, reduces Muc2 expression and causes spontaneous late-onset colitis. ChIP on Muc2 promoter, bone marrow reconstitution experiments (separating immune vs. epithelial contribution), Nr2f6-/- mouse model, intestinal permeability assay, DSS colitis model, T cell transfer colitis Gut High 28779026
2018 EAR-2 (NR2F6) inhibits maturation of normal bone marrow in vitro and in vivo; BM chimeras with EAR-2-transduced cells show features of MDS; EAR-2 functions through recruitment of histone deacetylases, and inhibition of differentiation in 32D cells is dependent on the DNA binding domain. Retroviral overexpression, BM transplantation/chimera experiments, shRNA knockdown, in vitro differentiation assays, HDAC co-recruitment assay Biomarker research Medium 30555701
2018 Genetic ablation of Nr2f6 in T cells delays tumor progression and improves survival in mouse tumor models; acute Nr2f6 silencing in both mouse and human T cells induces T cell hyper-responsiveness, establishing a non-redundant T-cell-inhibitory function; NR2F6 protein expression in tumor-infiltrating T cells in human NSCLC correlates with PD-1 and CTLA-4 expression. Germline Nr2f6-/- mouse tumor models, acute siRNA silencing in human T cells, ex vivo functional assays, IHC on human tumor samples, PD-L1 combination blockade experiments Nature communications High 29670099
2019 NR2F6 sustains activated Notch3 signaling in epithelial ovarian cancer cells conferring cisplatin resistance; shown by luciferase assay, ChIP, and co-immunoprecipitation establishing NR2F6 binding to the Notch3 regulatory regions. Bioinformatics, luciferase assay, ChIP, co-immunoprecipitation, in vitro sphere/MTT/apoptosis assays, orthotopic transplantation model International journal of cancer Medium 30895619
2019 NR2F6 directly binds to the IL-21 promoter and a conserved noncoding sequence near the Il21 gene in resting CD4+ T cells; this direct DNA interaction is abolished during Tfh cell differentiation, and loss of NR2F6 causes enhanced IL-21 expression and excessive Tfh cell accumulation reversible by IL-21R blockade. ChIP in resting CD4+ T cells, Nr2f6-/- mouse model, T cell-dependent immunization, adoptive transfer, IL-21R blocking experiments Cell reports High 31509749
2020 NR2F6 promotes hepatic triglyceride accumulation by binding directly to the CD36 promoter in hepatocytes, increasing enrichment of nuclear receptor coactivator 1 (SRC-1) and histone acetylation at the CD36 promoter; AAV-mediated liver NR2F6 overexpression promotes TG accumulation in lean mice while hepatic-specific NR2F6 suppression improves obesity-associated steatosis. ChIP for NR2F6 binding at CD36 promoter and SRC-1/histone acetylation, AAV-mediated liver-specific overexpression and knockdown, NAFLD mouse models Advanced science (Weinheim, Baden-Wurttemberg, Germany) High 33173745
2020 NR2F6 acts as a corepressor of PDGFRB transcription by recruiting HDAC2 onto the PDGFRB promoter; BCa cells with insufficient NR2F6 expression are less responsive to docetaxel, and stable PDGFRB inhibition ameliorates NR2F6 deficiency-impaired DTX response. ChIP for HDAC2 recruitment at PDGFRB promoter, genetically engineered cell models, patient-derived xenograft models Endocrine-related cancer Medium 32203934
2021 Loss of NR2F6 enhances antigen-specific CD8+ memory T cell formation following Listeria infection in a T cell-intrinsic manner; the augmented memory formation is IFN-γ mediated, as IFN-γ blocking normalizes MPEC formation in Nr2f6-deficient OT-I T cells. Germline Nr2f6-/- mouse model, adoptive transfer of OT-I Nr2f6-/- T cells, Listeria monocytogenes infection model, IFN-γ blocking antibody, flow cytometry Cell death & disease Medium 33589606
2022 Deletion of TLR4 from macrophages activates a Nr4a1/Ear2-expressing anti-inflammatory macrophage phenotype; silencing of Nr2f6 (Ear2) in TLR4-deficient BMDMs reverses their anti-inflammatory phenotype and restores LPS-stimulated M1 proinflammatory responses, placing NR2F6 as a key downstream effector of the myeloid-TLR4 negative feedback mechanism. Single-cell RNA sequencing, in vitro BMDM siRNA knockdown, LPS stimulation assays, flow cytometry Advanced science (Weinheim, Baden-Wurttemberg, Germany) Medium 35484716
2022 NR2F6 physically interacts with HNRNPD (heterogeneous nuclear ribonucleoprotein D) in lung cancer cells as demonstrated by co-immunoprecipitation; both proteins positively regulate lung cancer cell proliferation. Co-immunoprecipitation, siRNA knockdown, proliferation assays Frontiers in oncology Low 36119482
2024 NR2F6 transcriptionally activates PPARγ expression to promote brown adipogenesis; depletion of NR2F6 in preadipocytes inhibits brown adipogenesis, causes brown adipocyte hypertrophy and impairs BAT thermogenic function without affecting white adipose tissue development, shown by ChIP-qPCR demonstrating NR2F6 binding to the PPARγ promoter. ChIP-qPCR on PPARγ promoter, Pdgfra-Cre conditional Nr2f6 knockout mice, primary and immortalized brown adipocyte differentiation assays, high-fat diet metabolic phenotyping Molecular metabolism High 38307386
2024 NR2F6 represses uncoupling protein 3 (UCP3) and PGC-1α promoter activities in skeletal muscle cells; Nr2f6 overexpression in mouse tibialis anterior causes muscle atrophy (15% reduction in mass), reduced myofibre content, impaired force production, and an inflammation-like signature; Nr2f6 knockdown increases maximal lipid oxidative capacity by 75% and upregulates myosin heavy chain genes. Promoter-reporter assays for UCP3 and PGC-1α, in vivo Nr2f6 overexpression in mouse tibialis anterior, Nr2f6 knockdown in C2C12 and primary human muscle cells, RNA-seq, ex vivo contractility experiments, histology Journal of cachexia, sarcopenia and muscle High 38682559
2024 NR2F6 binds to the MAP3K5 promoter, activates the AP-1/c-Jun pathway to promote HSV-1 replication, and is itself transcriptionally repressed by c-Jun forming a negative feedback loop; NR2F6 promotes viral replication independently of the cGAS/STING pathway, and cGAS/STING represses NR2F6 through STAT3. H3K27ac ChIP-Seq, ChIP for NR2F6 at MAP3K5 promoter, reporter assay, in vitro and in vivo viral replication assays, cGAS/STING pathway analysis, STAT3 inhibitor experiments PLoS pathogens Medium 38829910
2024 TLR3-NR2F6 axis drives programmed destruction of UPK3A+ umbrella cells in Hunner-type interstitial cystitis urothelium; in vitro and in vivo experiments confirmed this axis as a therapeutic target for urothelial barrier damage. Single-cell RNA sequencing, pseudotime analysis, in vitro and in vivo experiments targeting TLR3-NR2F6 axis The Journal of pathology Low 38551071
2025 The NR2F6 ligand binding domain adopts an autorepressed, homodimeric conformation in the apo (unliganded) state in which helix 12 folds over the canonical coregulator binding site, generating an alternative contact surface for NSD1 binding; covalent probes targeting a cysteine near the NSD1 binding site inhibit NR2F6 coregulator recruitment. Co-crystallization of NR2F6 LBD with NSD1 coregulator peptide, X-ray crystallography (first structure of NR2F6 LBD), covalent compound screening on focused library, biochemical coregulator recruitment assay ACS chemical biology High 40931005
2025 NR2F6 loss in splenic red pulp macrophages upregulates signal-regulatory protein alpha (Sirpa), impairing phagocytosis of red blood cells and Salmonella Typhimurium; blocking Sirpα restores phagocytic activity of Nr2f6-deficient macrophages to wild-type levels, partially increasing Salmonella loads in vivo. Nr2f6-/- mouse model, Salmonella Typhimurium infection model, transcriptomic analysis of red pulp macrophages, in vitro phagocytosis assays, anti-Sirpα blocking antibody in vitro and in vivo Advanced science (Weinheim, Baden-Wurttemberg, Germany) Medium 40605423
2025 NR2F6 represses expression of the activating NK cell receptor NKp46; loss of NR2F6 causes impaired terminal maturation of peripheral NK cells (despite normal BM development), and IL-15-dependent NK cell priming is limited in Nr2f6-deficient mice due to reduced cDC1 and macrophage populations; exogenous IL-15 complex compensates these deficits. Nr2f6-/- mouse model, flow cytometry for NK maturation stages, transcriptome analysis, in vitro and in vivo IL-15 complex treatment, B16-F10 lung metastasis model Cell death & disease Medium 39920136
2025 NR2F6 forced expression in cortical neurons doubles neurite length in culture; after pyramidotomy or complete thoracic spinal crush, NR2F6 overexpression drives robust CST axon sprouting and regeneration; mechanistically NR2F6 binds predominantly to distal enhancers, imposes a broad translational down-shift via a conserved corepressor domain, and re-packages chromatin into new topologically associating domains clustering growth genes with activated regulatory hubs. Multi-omics (RNA-seq, ATAC-seq, ChIP-seq, Hi-C), viral overexpression in cortical neurons, in vitro neurite length assay, pyramidotomy and thoracic crush in vivo models, behavioral assessment bioRxivpreprint Medium
2026 Palmitoylethanolamide was identified as an endogenous molecule binding NR2F6 with high affinity by mass spectrometry-based ligand screening (immunoprecipitation coupled to flow-injection high-resolution MS); NR2F6 knockdown in breast cancer cells upregulates gene networks related to cell-cell/matrix interactions and downregulates cell-cycle/proliferation networks, and NR2F6 silencing reduces directional migration of MDA-MB-231 cells. Immunoprecipitation coupled with flow-injection high-resolution mass spectrometry for ligand identification, stable shRNA knockdown, whole-genome RNA-seq, proliferation, clonogenicity, and migration assays Cell communication and signaling : CCS Medium 41803880
2014 Snail inhibits adipogenesis by downregulating Nr2f6; NR2F6 is required for adipocyte differentiation (demonstrated by knockdown in 3T3-L1 cells), and ectopic Nr2f6 expression reverses Snail-mediated inhibition of adipogenesis; NR2F6 normally suppresses IL-17 expression, and Snail-induced IL-17 (via NR2F6 downregulation) acts as an anti-adipogenic cytokine. SILAC quantitative proteomics, Western blot, siRNA knockdown in 3T3-L1 and mMSC cells, ectopic NR2F6 expression, IL-17 blocking experiment, adipocyte differentiation assay Molecular & cellular proteomics : MCP Medium 25505127

Source papers

Stage 0 corpus · 66 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1992 Transcriptional regulation of human apolipoprotein genes ApoB, ApoCIII, and ApoAII by members of the steroid hormone receptor superfamily HNF-4, ARP-1, EAR-2, and EAR-3. The Journal of biological chemistry 285 1639815
2019 Circular RNA circRHOT1 promotes hepatocellular carcinoma progression by initiation of NR2F6 expression. Molecular cancer 278 31324186
2001 The fasciated ear2 gene encodes a leucine-rich repeat receptor-like protein that regulates shoot meristem proliferation in maize. Genes & development 238 11641280
2013 Quantitative variation in maize kernel row number is controlled by the FASCIATED EAR2 locus. Nature genetics 176 23377180
2018 The CLAVATA receptor FASCIATED EAR2 responds to distinct CLE peptides by signaling through two downstream effectors. eLife 83 29543153
2005 Abnormal development of the locus coeruleus in Ear2(Nr2f6)-deficient mice impairs the functionality of the forebrain clock and affects nociception. Genes & development 81 15741322
2008 The nuclear orphan receptor NR2F6 suppresses lymphocyte activation and T helper 17-dependent autoimmunity. Immunity 79 18701084
1998 Negative regulation of granulocytic differentiation in the myeloid precursor cell line 32Dcl3 by ear-2, a mammalian homolog of Drosophila seven-up, and a chimeric leukemogenic gene, AML1/ETO. Proceedings of the National Academy of Sciences of the United States of America 76 9465099
2018 Nuclear receptor NR2F6 inhibition potentiates responses to PD-L1/PD-1 cancer immune checkpoint blockade. Nature communications 62 29670099
2014 Ear2 deletion causes early memory and learning deficits in APP/PS1 mice. The Journal of neuroscience : the official journal of the Society for Neuroscience 62 24966384
2015 The Nuclear Orphan Receptor NR2F6 Is a Central Checkpoint for Cancer Immune Surveillance. Cell reports 54 26387951
2020 The Nuclear Orphan Receptor NR2F6 Promotes Hepatic Steatosis through Upregulation of Fatty Acid Transporter CD36. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 52 33173745
2003 Identification of a nuclear orphan receptor (Ear2) as a negative regulator of renin gene transcription. Circulation research 51 12690040
2012 Nuclear orphan receptor NR2F6 directly antagonizes NFAT and RORγt binding to the Il17a promoter. Journal of autoimmunity 46 22921335
2011 The orphan nuclear receptor EAR2 is overexpressed in colorectal cancer and it regulates survivability of colon cancer cells. Cancer letters 41 21696885
2019 MiR-142-3p suppresses the proliferation, migration and invasion through inhibition of NR2F6 in lung adenocarcinoma. Human cell 39 31168689
2017 Nuclear orphan receptor NR2F6 as a safeguard against experimental murine colitis. Gut 37 28779026
2019 Systems Biology Reveals NR2F6 and TGFB1 as Key Regulators of Feed Efficiency in Beef Cattle. Frontiers in genetics 36 30967894
2019 Nuclear orphan receptor NR2F6 confers cisplatin resistance in epithelial ovarian cancer cells by activating the Notch3 signaling pathway. International journal of cancer 35 30895619
2014 Orphan nuclear receptor NR2F6 acts as an essential gatekeeper of Th17 CD4+ T cell effector functions. Cell communication and signaling : CCS 34 24919548
2014 A proteomic analysis reveals that Snail regulates the expression of the nuclear orphan receptor Nuclear Receptor Subfamily 2 Group F Member 6 (Nr2f6) and interleukin 17 (IL-17) to inhibit adipocyte differentiation. Molecular & cellular proteomics : MCP 33 25505127
2000 The orphan nuclear receptor Ear-2 is a negative coregulator for thyroid hormone nuclear receptor function. Molecular and cellular biology 32 10713182
1997 The nuclear orphan receptors COUP-TFII and Ear-2 act as silencers of the human oxytocin gene promoter. Journal of molecular endocrinology 32 9343308
1999 Heterodimeric interactions between chicken ovalbumin upstream promoter-transcription factor family members ARP1 and ear2. The Journal of biological chemistry 29 10318855
2019 Orphan Nuclear Receptor NR2F6 Suppresses T Follicular Helper Cell Accumulation through Regulation of IL-21. Cell reports 28 31509749
2011 Identification of a role for the nuclear receptor EAR-2 in the maintenance of clonogenic status within the leukemia cell hierarchy. Leukemia 27 21637284
2001 EAR2 and EAR3/COUP-TFI regulate transcription of the rat LH receptor. Molecular endocrinology (Baltimore, Md.) 27 11682620
1998 A short proximal promoter and the distal hepatic control region-1 (HCR-1) contribute to the liver specificity of the human apolipoprotein C-II gene. Hepatic enhancement by HCR-1 requires two proximal hormone response elements which have different binding specificities for orphan receptors HNF-4, ARP-1, and EAR-2. The Journal of biological chemistry 24 9461615
1998 Nuclear orphan receptors COUP-TFII and Ear-2: presence in oxytocin-producing uterine cells and functional interaction with the oxytocin gene promoter. Molecular and cellular endocrinology 23 9605516
2022 Single-cell RNA Sequencing Identified Novel Nr4a1+ Ear2+ Anti-Inflammatory Macrophage Phenotype under Myeloid-TLR4 Dependent Regulation in Anti-Glomerular Basement Membrane (GBM) Crescentic Glomerulonephritis (cGN). Advanced science (Weinheim, Baden-Wurttemberg, Germany) 22 35484716
2020 Targeting the orphan nuclear receptor NR2F6 in T cells primes tumors for immune checkpoint therapy. Cell communication and signaling : CCS 22 31937317
2016 Beyond CTLA-4 and PD-1: Orphan nuclear receptor NR2F6 as T cell signaling switch and emerging target in cancer immunotherapy. Immunology letters 21 26992368
2021 Loss of the orphan nuclear receptor NR2F6 enhances CD8+ T-cell memory via IFN-γ. Cell death & disease 19 33589606
2021 Emerging Next-Generation Target for Cancer Immunotherapy Research: The Orphan Nuclear Receptor NR2F6. Cancers 18 34073258
2020 Regulation of docetaxel chemosensitivity by NR2F6 in breast cancer. Endocrine-related cancer 17 32203934
2022 Ultra-thin layered double hydroxide-mediated photothermal therapy combine with asynchronous blockade of PD-L1 and NR2F6 inhibit hepatocellular carcinoma. Journal of nanobiotechnology 16 35907841
2013 The orphan nuclear receptor Ear-2 (Nr2f6) is a novel negative regulator of T cell development. Experimental hematology 16 24096122
2011 Rasd1 interacts with Ear2 (Nr2f6) to regulate renin transcription. BMC molecular biology 15 21247419
2012 Regulation of renin expression by the orphan nuclear receptors Nr2f2 and Nr2f6. American journal of physiology. Renal physiology 13 22278040
2023 Melanoma-intrinsic NR2F6 activity regulates antitumor immunity. Science advances 12 37406115
2024 UPK3A+ umbrella cell damage mediated by TLR3-NR2F6 triggers programmed destruction of urothelium in Hunner-type interstitial cystitis/painful bladder syndrome. The Journal of pathology 11 38551071
2018 The orphan nuclear receptor EAR-2 (NR2F6) inhibits hematopoietic cell differentiation and induces myeloid dysplasia in vivo. Biomarker research 10 30555701
2022 High throughput screening for compounds to the orphan nuclear receptor NR2F6. SLAS discovery : advancing life sciences R & D 9 35331960
2023 NR2F6, a new immune checkpoint that acts as a potential biomarker of immunosuppression and contributes to poor clinical outcome in human glioma. Frontiers in immunology 8 37575237
2025 Regulation of NK cell development, maturation, and antitumor responses by the nuclear receptor NR2F6. Cell death & disease 7 39920136
2024 NR2F6 is essential for brown adipocyte differentiation and systemic metabolic homeostasis. Molecular metabolism 7 38307386
2022 The expression and biological effect of NR2F6 in non-small cell lung cancer. Frontiers in oncology 7 36119482
2021 Incomplete thermal ablation-induced up-regulation of transcription factor nuclear receptor subfamily 2, group F, member 6 (NR2F6) contributes to the rapid progression of residual liver tumor in hepatoblastoma. Bioengineered 7 34304715
1994 The sequence of a murine cDNA encoding Ear-2, a nuclear orphan receptor. Gene 7 8194772
2024 The rice microRNA159-SPOROCYTELESS EAR2 module regulates starch biosynthesis during pollen development and maintains male fertility. The Plant cell 6 39665752
2006 Cloning, expression and regulation of chicken ovalbumin upstream promoter transcription factors (COUP-TFII and EAR-2) in the rat anterior pituitary gland. Neuroendocrinology 6 16721029
2025 Insights into the emerging immune checkpoint NR2F6 in cancer immunity. Journal of leukocyte biology 5 39722227
2025 Loss of NR2F6 Protects from Salmonella Typhimurium Infection. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 4 40605423
2024 Concerted regulation of skeletal muscle metabolism and contractile properties by the orphan nuclear receptor Nr2f6. Journal of cachexia, sarcopenia and muscle 4 38682559
2022 A role for the nuclear receptor NR2F6 in peritoneal B cell homeostasis. Frontiers in immunology 4 36052079
2024 The roles of nuclear orphan receptor NR2F6 in anti-viral innate immunity. PLoS pathogens 3 38829910
2023 Overexpression of the orphan nuclear receptor NR2F6 is associated with improved survival across molecular subgroups in endometrial cancer patients. Journal of cancer research and clinical oncology 3 36884115
2023 In Silico Analysis Predicts Nuclear Factors NR2F6 and YAP1 as Mesenchymal Subtype-Specific Therapeutic Targets for Ovarian Cancer Patients. Cancers 2 37370765
2021 [The role of nuclear receptor transcription factor NR2F6 in tumor]. Sheng wu gong cheng xue bao = Chinese journal of biotechnology 2 34472280
2026 NR2F6 deletion revives CAR-T cell function and induces antigen-agnostic immune memory in solid tumors. Nature communications 1 41760655
2025 NR2F6 regulates stem cell hematopoiesis and myelopoiesis in mice. Frontiers in immunology 1 39840064
2025 NR2F6 as a Disease Driver and Candidate Therapeutic Target in Experimental Cerebral Malaria. Cells 1 40801595
2025 NR2F6 regulates Temozolomide resistance in glioma via the E2F2-PARP1 pathway. Cancer cell international 1 41121148
2026 Orphan Nuclear Receptors expression and function in breast cancer cells: oncogenic action of the NR2F6 receptor. Cell communication and signaling : CCS 0 41803880
2026 Reduced NR2F6 expression reshapes the VPA-induced transcriptome in human hepatocytes and increases lipid accumulation. Toxicology 0 41936854
2025 Structural Elucidation and Covalent Modulation of the Autorepressed Orphan Nuclear Receptor NR2F6. ACS chemical biology 0 40931005

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