Affinage

ESRRB

Steroid hormone receptor ERR2 · UniProt O95718

Length
433 aa
Mass
48.1 kDa
Annotated
2026-04-28
74 papers in source corpus 32 papers cited in narrative 32 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ESRRB is an orphan nuclear receptor that serves as a central transcriptional regulator of naive pluripotency, trophoblast development, and specialized post-mitotic cell identities in the inner ear, retina, and motor neurons. In embryonic stem cells, ESRRB operates downstream of Gsk3/Tcf3 and Nanog/LIF-Stat3 signaling to directly activate Oct4, Dax1, Gata6, Elf5, Eomes, and formative-state genes, cooperating with Nr5a2 and Sox2 at shared regulatory elements and recruiting co-activators Ncoa3 and p300; it also functions as a pioneer factor that binds methylated, nucleosome-occupied chromatin to recruit Oct4-Sox2-Nanog during reprogramming, and as a mitotic bookmarking factor that maintains regulatory element accessibility through cell division (PMID:23040478, PMID:23040477, PMID:29910149, PMID:27723719, PMID:34397088). ESRRB activity is tuned by post-translational modifications—O-GlcNAcylation at S25 stabilizes the protein and enhances pluripotency factor interactions, lactylation at K228/K232 augments target-gene binding, and ERK phosphorylation at S42/S43 redirects binding from pluripotency to extraembryonic endoderm genes—establishing a phosphorylation-dependent switch between self-renewal and lineage commitment (PMID:31492838, PMID:38473939, PMID:39919750). Loss-of-function mutations in ESRRB cause autosomal-recessive nonsyndromic hearing impairment DFNB35 (PMID:18179891).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 1997 High

    The first loss-of-function study established that ESRRB is cell-autonomously required for chorion/trophoblast development, revealing its essential role in extraembryonic tissue formation.

    Evidence Targeted knockout mouse with tetraploid rescue demonstrating placental-restricted phenotype

    PMID:9285590

    Open questions at the time
    • Downstream transcriptional targets in trophoblast were unknown
    • Whether ESRRB has embryonic (non-extraembryonic) roles was unresolved
  2. 2007 High

    Beyond placenta, ESRRB was shown to control cell fate in the inner ear (strial marginal cells) and to physically interact with Nrf2 to repress antioxidant response element-mediated transcription, broadening its known tissue repertoire and revealing a protein-interaction-based repressive mechanism.

    Evidence Inner ear knockout with transcriptomic and mosaic analysis; Co-IP and reporter assays for Nrf2 interaction

    PMID:17765677 PMID:17920186

    Open questions at the time
    • Whether Nrf2 repression is physiologically relevant in vivo was not tested
    • Mechanism of ESRRB-driven cell identity specification in inner ear was not resolved at the chromatin level
  3. 2008 High

    ESRRB was placed at the heart of the pluripotency network by showing it directly activates Oct4 transcription via ERRE sites and physically interacts with NANOG through DNA-binding domains; simultaneously, human genetic studies linked ESRRB loss-of-function mutations to DFNB35 hearing impairment.

    Evidence ChIP, reporter assays, Co-IP with domain mapping in ESCs; homozygosity mapping and mutation analysis in multiple families

    PMID:18179891 PMID:18957414

    Open questions at the time
    • Upstream signals regulating ESRRB expression in ESCs were unknown
    • How mutations in distinct domains (DBD vs LBD) differentially affect function was not mechanistically resolved
  4. 2009 High

    ESRRB was demonstrated to be sufficient to replace Klf4 in somatic cell reprogramming to iPSCs, establishing it as a functional reprogramming factor and not merely a marker of pluripotency.

    Evidence Retroviral transduction of Esrrb with Oct4/Sox2 generating iPSCs with chimaera contribution

    PMID:19136965

    Open questions at the time
    • Mechanism by which ESRRB accesses closed chromatin during reprogramming was unknown
    • Whether ESRRB functions as a pioneer factor was not yet addressed
  5. 2010 High

    ESRRB was shown to coordinate metabolic gene programs (ATP generation/consumption) essential for rod photoreceptor survival, with inverse agonists causing rapid degeneration rescued by constitutively active mutants, revealing a ligand-responsive metabolic function in post-mitotic neurons.

    Evidence Knockout, overexpression, pharmacological inverse agonists, and epistasis with Crx in mouse retina

    PMID:20534447

    Open questions at the time
    • Identity of an endogenous ligand for ESRRB remained unresolved
    • Whether the metabolic role in photoreceptors generalizes to other ESRRB-expressing tissues was unknown
  6. 2012 High

    A burst of studies positioned ESRRB as the necessary and sufficient effector downstream of both the Gsk3/Tcf3 axis and Nanog, identified Ncoa3 as the co-activator bridging ESRRB to RNA Pol II, and defined Dax1 as a direct target and feedback repressor—mapping the core signaling and co-factor architecture of ESRRB in ESC self-renewal.

    Evidence Genetic epistasis, ChIP-seq, reciprocal Co-IP with domain mapping, microarray, knockout and overexpression in ESCs and EpiSCs

    PMID:23019124 PMID:23040477 PMID:23040478

    Open questions at the time
    • Whether other co-activators or chromatin remodelers are involved was unknown
    • Structural basis of Ncoa3-ESRRB interaction was not determined
  7. 2013 Medium

    Co-motif discovery and functional studies showed that ESRRB and Sox2 co-bind a composite DNA element to regulate naive-specific genes, and detailed LXXLL-mediated Dax1-ESRRB interaction was mapped, refining the combinatorial logic at ESRRB-occupied regulatory elements.

    Evidence ChIP-seq co-motif analysis, domain mapping of LXXLL motifs, reporter assays, knockdown

    PMID:23169531 PMID:23508100

    Open questions at the time
    • Whether Esrrb-Sox2 composite binding is required vs. redundant with individual binding was not resolved
    • Structural basis of LXXLL-mediated repression not determined
  8. 2015 High

    Mass spectrometry of the ESRRB interactome in trophoblast stem cells revealed cell-type-specific partners including the Integrator complex and histone demethylase Lsd1, and showed that ESRRB directly regulates TS-specific transcription factors Elf5 and Eomes downstream of Fgf signaling.

    Evidence IP-MS interactome, ChIP-seq, Fgf pathway manipulation in trophoblast stem cells

    PMID:26206133

    Open questions at the time
    • Functional requirement for Lsd1 or Integrator in ESRRB-driven TS cell maintenance was not tested
    • Whether ESRRB recruits Lsd1 to specific loci was not shown
  9. 2016 High

    ESRRB was established as a mitotic bookmarking factor that remains dynamically bound to its DNA motif through cell division, ensuring rapid transcriptional re-activation of target genes in daughter cells—providing a mechanism for epigenetic memory of pluripotency through mitosis.

    Evidence Mitotic ChIP-seq, live-cell imaging, FRAP in ESCs

    PMID:27723719

    Open questions at the time
    • Whether mitotic bookmarking is essential for self-renewal or dispensable was not genetically tested
    • Mechanism by which ESRRB resists mitotic chromatin compaction was unresolved
  10. 2017 High

    ESRRB was shown to activate oxidative phosphorylation during reprogramming to naive pluripotency, establishing that it directly programs metabolic state (not just transcription factor networks) as part of cell identity conversion.

    Evidence Seahorse metabolic flux analysis, overexpression during reprogramming

    PMID:28467928

    Open questions at the time
    • Direct ESRRB target genes mediating OXPHOS activation were not fully characterized
    • Whether metabolic reprogramming is a cause or consequence of pluripotency acquisition was not disambiguated
  11. 2018 High

    Two studies resolved ESRRB's chromatin-level mechanisms: it acts as a pioneer factor that binds stable nucleosomes and hypermethylated DNA at silenced enhancers to recruit Oct4-Sox2-Nanog during reprogramming, and its downregulation during naive exit causes selective loss of NANOG and OCT4 occupancy at naive-specific regulatory elements.

    Evidence ATAC-seq, bisulfite sequencing, ChIP-seq time-course during EpiSC reprogramming; ChIP-seq in FACS-sorted Esrrb-positive vs -negative ESCs

    PMID:29910149 PMID:30275266

    Open questions at the time
    • Whether ESRRB's pioneer activity requires specific co-factors or is intrinsic to its DBD was not determined
    • The relationship between pioneer binding and mitotic bookmarking was not explored
  12. 2019 High

    O-GlcNAcylation at S25 by OGT was identified as the first post-translational modification tuning ESRRB, stabilizing the protein and enhancing its interactions with OCT4 and NANOG; separately, ESRRB was shown to directly activate a Bmp4 enhancer in trophoblast stem cells to regulate primordial germ cell specification.

    Evidence Metabolic labeling, mass spectrometry, S25 mutagenesis, Co-IP in ESCs; ChIP-seq and CRISPR enhancer deletion at Bmp4 locus

    PMID:31315026 PMID:31492838

    Open questions at the time
    • Whether O-GlcNAcylation affects pioneer or bookmarking activity was not tested
    • Whether other glycosylation sites exist on ESRRB was not exhaustively mapped
  13. 2021 High

    ESRRB and Nr5a2 were shown to jointly occupy regulatory elements and together control Oct4/Sox2/Nanog binding genome-wide; double knockout collapsed the pluripotency network, revealing functional redundancy that had masked ESRRB's full essentiality in earlier single-knockout studies.

    Evidence Double knockout ESCs, ChIP-seq, transcriptome analysis

    PMID:34397088

    Open questions at the time
    • Whether Nr5a2 compensates for ESRRB at the pioneer/bookmarking level was not tested
    • Structural basis for Nr5a2 and ESRRB co-occupancy at the same elements was not resolved
  14. 2022 High

    Cell-cycle-resolved studies showed that ESRRB is upregulated during G2/M and drives extraembryonic endoderm differentiation in a cell-cycle-dependent manner; separately, ESRRB was found essential for gamma motor neuron functional properties, extending its post-mitotic roles beyond sensory cells to the motor system.

    Evidence Cell-cycle reporter with scRNA-seq, CRISPR KO and overexpression in ESCs; selective motor neuron knockout with electrophysiology

    PMID:35594859 PMID:36542664

    Open questions at the time
    • How cell-cycle phase mechanistically alters ESRRB target selection was not determined
    • Direct transcriptional targets in gamma motor neurons were not fully defined
  15. 2023 High

    ESRRB was shown to be required for formative-state gene activation during the naive-to-formative epiblast transition, and in cervical cancer it activates SMAD7 to inhibit TGFβ signaling and forms a positive feedback loop with MYC, revealing context-dependent transcriptional programs beyond pluripotency maintenance.

    Evidence Genetic inactivation and gain-of-function in 3D organoid and PGCLC assays; CRISPR KO and rescue with xenograft in cancer cells

    PMID:37106060 PMID:37350664

    Open questions at the time
    • Whether the ESRRB-SMAD7-MYC loop operates in normal development was not tested
    • How ESRRB transitions from naive to formative gene programs mechanistically was not resolved
  16. 2024 High

    Lactylation at K228/K232 was identified as a metabolite-responsive modification that enhances ESRRB binding to target genes and promotes both self-renewal and XEN differentiation, linking glycolytic metabolism to ESRRB chromatin function; ERK-mediated phosphorylation at S42/S43 was then shown to act as a binary switch redirecting ESRRB from pluripotency to XEN gene targets.

    Evidence Mass spectrometry, site-directed mutagenesis, ChIP-seq for lactylation; quantitative phosphoproteomics and phosphomutant ChIP-seq for ERK sites

    PMID:38473939 PMID:39919750

    Open questions at the time
    • Whether lactylation and phosphorylation act combinatorially on the same ESRRB molecule was not tested
    • Structural mechanism by which phosphorylation alters DNA-binding specificity is unknown
  17. 2025 Medium

    ESRRB was found to co-opt ancient MIR SINE-derived enhancers for naive-specific gene expression, co-occupying these elements with YY1 and promoting enhancer-to-super-enhancer loop formation, revealing a transposable element exaptation mechanism for ESRRB-dependent regulatory architecture.

    Evidence Hi-C, H3K27ac HiChIP, CRISPR MIR enhancer deletion, ChIP-seq in naive ESCs

    PMID:40296153

    Open questions at the time
    • Whether MIR enhancer co-option is species-specific or conserved across mammals was not tested
    • Functional significance of YY1 co-occupancy at MIR elements is not established beyond co-binding

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include whether ESRRB has an endogenous ligand, how its pioneer/bookmarking activities are coordinated or distinguished, the structural basis for phosphorylation-dependent target switching, and whether its diverse tissue-specific roles (ear, retina, motor neuron, trophoblast, ESC) share a common metabolic or chromatin-level mechanism.
  • No endogenous ligand identified despite pharmacological evidence of ligand responsiveness
  • No structural model of ESRRB bound to chromatin or co-factors
  • Integration of multiple PTM inputs on a single ESRRB molecule not assessed

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 12 GO:0003677 DNA binding 4 GO:0098772 molecular function regulator activity 2
Localization
GO:0005634 nucleus 4 GO:0005694 chromosome 1
Pathway
R-HSA-74160 Gene expression (Transcription) 9 R-HSA-1266738 Developmental Biology 5 R-HSA-162582 Signal Transduction 3 R-HSA-4839726 Chromatin organization 3
Partners
DAX1EP300NANOGNCOA3NR5A2OGTSOX2YY1

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 Targeted disruption of Esrrb in mice causes severely impaired placental formation with overabundance of trophoblast giant cells and deficiency of diploid trophoblast, and this phenotype is rescued by aggregation with tetraploid wild-type cells contributing exclusively to extra-embryonic tissues, establishing Esrrb's cell-autonomous role in chorion/trophoblast development. Targeted gene disruption (knockout mouse), tetraploid rescue experiment Nature High 9285590
2007 ERRβ (Esrrb) controls the cell fate and gene expression of endolymph-producing epithelial cells (strial marginal cells and vestibular dark cells) in the inner ear; loss of Nr3b2 causes failure to express ion channel/transporter genes and partial transformation toward adjacent Pendrin-expressing epithelial fate, with secondary loss of underlying intermediate cells and strial capillaries. Nr3b2 knockout mouse, transcriptome comparison, genetically mosaic mice Developmental cell High 17765677
2007 Short-form human ERRβ (SFhERRbeta) physically interacts with Nrf2 (not by competing for ARE DNA-binding sites) and potently represses Nrf2 transcriptional activity on antioxidant response element-mediated gene expression; SFhERRbeta also alters the subcellular localization of Nrf2, and deletion mapping showed interaction through multiple sites of SFhERRbeta. Co-immunoprecipitation, confocal immunofluorescence, deletion mutant analysis, reporter assays Molecular and cellular endocrinology Medium 17920186
2008 ESRRB binds two ERRE sites in the proximal 5'-UTR of the mouse Oct4 gene to activate its transcription; ESRRB physically interacts with NANOG through their DNA-binding domains, and this interaction reciprocally modulates their transcriptional activities to maintain ESC pluripotency. Reporter assay, ChIP, co-immunoprecipitation, domain mapping, stable transfection The Journal of biological chemistry High 18957414
2008 Loss-of-function mutations in ESRRB (frameshift, missense in DNA-binding domain at p.A110V, and ligand-binding domain at p.L320P, p.V342L, p.L347P) cause autosomal-recessive nonsyndromic hearing impairment DFNB35; molecular modeling indicates mutations affect structure/stability of DNA-binding and ligand-binding domains. Homozygosity mapping, mutation analysis, molecular modeling, RNA in situ hybridization, immunohistochemistry American journal of human genetics High 18179891
2009 Esrrb functions in conjunction with Oct4 and Sox2 to mediate reprogramming of mouse embryonic fibroblasts to induced pluripotent stem cells, and Esrrb targets many genes involved in self-renewal and pluripotency in ES cells, enabling reprogramming without exogenous Klf transcription factors. Retroviral transduction, iPSC generation, expression and epigenetic profiling, in vivo differentiation, chimaera formation Nature cell biology High 19136965
2010 ERRβ overexpression in retina induces rod-specific gene expression; ERRβ mutation causes rod photoreceptor dysfunction and degeneration; inverse agonists of ERRβ trigger rapid rod degeneration rescued by constitutively active ERRβ mutants; ERRβ coordinates expression of genes rate-limiting for ATP generation and consumption in photoreceptors; ERRβ activity rescues Crx loss-of-function photoreceptor defects. Overexpression in wild-type and Nrl-/- retinas, knockout mouse, pharmacological inverse agonists, constitutively active mutants, epistasis with Crx Proceedings of the National Academy of Sciences of the United States of America High 20534447
2012 Esrrb is a direct target of Tcf3 repression downstream of Gsk3 inhibition in ESCs; Esrrb knockdown/knockout eliminates response to Gsk3 inhibition and causes loss of pluripotency, while forced Esrrb expression phenocopies Gsk3 inhibition or Tcf3 deletion by sustaining self-renewal, placing Esrrb as necessary and sufficient downstream of the Gsk3/Tcf3 axis. Genome localization (ChIP-seq), transcriptome analysis, knockdown, knockout, forced expression, functional colony-forming assays Cell stem cell High 23040478
2012 Nanog directly binds the Esrrb locus, enhances RNA Pol II binding, and stimulates Esrrb transcription; Esrrb overexpression maintains LIF-independent self-renewal in Nanog-/- ESCs and can reprogram Nanog-/- EpiSCs; Esrrb deletion abolishes Nanog's ability to confer LIF-independent self-renewal, placing Esrrb functionally downstream of Nanog. ChIP-seq, inducible Nanog protein systems, Nanog-/- ESCs, overexpression, rescue assays Cell stem cell High 23040477
2012 Ncoa3 interacts with Esrrb via Esrrb's ligand-binding domain and bridges Esrrb to RNA polymerase II complexes; Ncoa3 is required for Esrrb function in ESC self-renewal and reprogramming; Ncoa3 shares overlapping gene regulatory functions with Esrrb and cooperates genome-wide with Oct4-Sox2-Nanog circuitry at active enhancers. Co-immunoprecipitation, domain mapping, ChIP-seq, microarray, knockdown, overexpression Genes & development High 23019124
2013 Dax1 physically interacts with Esrrb through its LXXLL motifs (binding the activation- and ligand-binding domains of Esrrb) and represses Esrrb transcriptional activity; Esrrb directly binds the Dax1 promoter via ERRE1 to activate Dax1 expression independently of Oct3/4; Oct3/4, Dax1, and Esrrb show competitive inhibition among complexes, forming a regulatory loop for pluripotency. Co-immunoprecipitation, domain mapping (LXXLL motif), reporter assay, ChIP, gain-of-function/loss-of-function Molecular and cellular biology High 23508100
2013 Esrrb and Sox2 co-bind a constrained composite DNA motif (Esrrb-Sox motif, 2–8 bp gap) in ESCs as identified by genome-wide ChIP-seq co-motif discovery; the Esrrb-Sox2 complex regulates genes (e.g., Klf4, Klf5, Nr0b1) that distinguish ESCs from epiblast stem cells. ChIP-seq, co-motif discovery algorithm (fexcom), knockdown experiments Stem cells Medium 23169531
2014 ERRβ overexpression in breast cancer cells activates FST (Follistatin) and BCAS2 transcription via direct binding (identified by ChIP cloning and gel supershift); ERRβ physically interacts with ERα (Co-IP); ERRβ-mediated BCAS2 upregulation inhibits FST transcription through downregulation of β-catenin/TCF4 recruitment to the FST promoter, and FST promotes apoptosis/E-cadherin expression while BCAS2 downregulates cyclin D1 to block G1/S transition. ChIP cloning, gel supershift assay, Co-immunoprecipitation, western blot, confocal microscopy, qRT-PCR British journal of cancer Medium 24667650
2015 In trophoblast stem (TS) cells, Esrrb is a downstream target of Fgf signalling; Esrrb directly binds and regulates TS cell-specific transcription factors Elf5 and Eomes; Esrrb interactome in TS cells (by mass spectrometry) includes the histone demethylase Lsd1 and the RNA Polymerase II-associated Integrator complex, distinct from its ES cell interactome. ChIP-seq, mass spectrometry interactome, loss-of-function, gain-of-function, Fgf signaling manipulation Nature communications High 26206133
2016 Esrrb remains dynamically bound to key regulatory regions during mitosis in pluripotent ESCs (mitotic bookmarking); mitotic Esrrb binding is driven by specific recognition of its DNA-binding motif and is associated with early transcriptional re-activation of target genes after mitosis completion. Live-cell imaging, ChIP-seq during mitosis, FRAP, motif analysis Nature cell biology High 27723719
2016 Esrrb directly binds the Gata6 promoter at ERRE2 to activate Gata6 expression; this activity is repressed by Dax1 (which associates with Esrrb bound to ERRE2 but does not itself bind ERRE2) and enhanced by Ncoa3; Dax1 also associates with Ncoa3 to repress Ncoa3 transcriptional activity, maintaining ES cell undifferentiated state. Biotin DNA pulldown, ChIP, reporter assay, overexpression, co-immunoprecipitation Biochemical and biophysical research communications Medium 27601327
2018 Esrrb acts as a pioneer factor in reprogramming of epiblast stem cells to naive pluripotency by binding to silenced enhancers containing stable nucleosomes and hypermethylated DNA that are inaccessible to Oct4, Sox2, Nanog; Esrrb binding is accompanied by local loss of DNA methylation, LIF-dependent p300 engagement, and nucleosome displacement, leading to recruitment of core pluripotency factors within ~2 days. ATAC-seq, bisulfite sequencing, ChIP-seq, time-course reprogramming assays Cell stem cell High 29910149
2017 Esrrb activates oxidative phosphorylation (OXPHOS) during reprogramming while Zic3 represses it; the combined action of Esrrb (OXPHOS activation) and Zic3 (glycolysis activation) achieves a hybrid energy metabolism (glycolysis + OXPHOS) required for efficient naive pluripotency induction; Esrrb-mediated OXPHOS activation is also critical for conversion of primed PSCs to the naive state. Overexpression, metabolic flux analysis, seahorse assay, reprogramming efficiency assays Cell metabolism High 28467928
2018 Esrrb downregulation in Nanog-low ESCs triggers loss of NANOG and OCT4 binding at Class I regulatory elements associated with naive-specific genes, while Class II elements retain OCT4 but lose NANOG binding, demonstrating that Esrrb level determines the chromatin occupancy of core pluripotency TFs and restricts potency during naive pluripotency exit. Fluorescent reporter lines, FACS sorting, ChIP-seq in Esrrb-positive vs Esrrb-negative cells The EMBO journal High 30275266
2019 ESRRB is O-GlcNAcylated by O-GlcNAc transferase (OGT) at serine 25; this modification stabilizes ESRRB protein, promotes its transcriptional activity, and facilitates its interactions with OCT4 and NANOG, thereby supporting mESC self-renewal and pluripotency. Metabolic labeling with azido-sugar reporters, mass spectrometry, site-directed mutagenesis (S25 mutation), Co-immunoprecipitation, transcriptional activity assays Nature communications High 31492838
2019 In trophoblast stem cells, Esrrb directly binds an enhancer at the Bmp4 locus (identified by ChIP-seq and luciferase reporter assay) and activates Bmp4 expression in the extraembryonic ectoderm; loss of this enhancer (CRISPR deletion) or Esrrb itself reduces Bmp4 expression and primordial germ cell numbers. ChIP-seq, luciferase reporter assay, CRISPR/Cas9 enhancer deletion, microarray, PGC counting Developmental biology High 31315026
2020 ERRβ protein is targeted for proteasomal degradation by the SCF E3 ubiquitin ligase complex activated by NEDDylation; inhibition of NEDDylation with MLN4924 restores ERRβ expression in breast cancer cells, reduces proliferation and migration, and ERRβ recruits the co-activator p300 to target gene promoters (p21Cip1/Waf1, E-cadherin) to upregulate their expression. In vitro and in vivo degradation assays, MLN4924 inhibitor, ChIP (p300 recruitment), western blot, cell proliferation/migration assays Cell death & disease Medium 32839427
2020 The canonical Wnt/β-catenin pathway signals through Esrrb as its central downstream factor to regulate tissue-scale organization (morphogenesis and maintenance) of the murine pluripotent epiblast during diapause; autocrine Wnt activity controls epiblast architecture when development is paused. 3D in vitro model of epiblast development, Wnt pathway manipulation, Esrrb conditional knockout, live imaging Nature communications Medium 33127892
2021 Oocyte-specific linker histone H1foo physically interacts with Esrrb; Esrrb is necessary for H1foo-dependent chromatin decondensation at specific target loci (oocyte-specific genes), as shown by ChIP-seq of H1foo-overexpressing ESCs and endogenous H1foo in oocytes. ChIP-seq, Co-immunoprecipitation, overexpression, chromatin accessibility analysis Biochemical and biophysical research communications Medium 34023782
2021 Esrrb and Nr5a2 conjointly occupy a large common set of regulatory elements in naive mouse ESCs and together control binding of Oct4, Sox2, and Nanog to DNA; double knockout of Esrrb and Nr5a2 collapses the pluripotency network and causes ESC differentiation, paralleling the requirement for Oct4 and Sox2. Single and double knockout, ChIP-seq, transcriptome analysis Development High 34397088
2022 ERR2 (Esrrb/ERRβ) and ERR3 (ERRγ) are required in motor neurons for gamma motor neuron functional properties (low firing thresholds, high firing rates) necessary for muscle proprioception and movement control; gain-of-function in chick suggests ERR2/3 operate via transcriptional activation of neural activity modulators. Selective motor neuron knockout, electrophysiology, gain-of-function in chick, transcriptomics PLoS biology High 36542664
2022 Esrrb is upregulated during G2/M phase of the cell cycle and drives extraembryonic endoderm (XEN) differentiation in a cell-cycle-dependent manner; ESRRB knockout ESCs lose the potential to differentiate into XEN, and G1 cells forced to overexpress Esrrb acquire XEN differentiation capacity; ESRRB associates with XEN-poised enhancers. Cell-cycle reporter system, scRNA-seq, CRISPR knockout, overexpression, ATAC-seq/ChIP-seq on WT vs KO ESCs Stem cell reports Medium 35594859
2023 ESRRB activates transcription of SMAD7 (a TGFβ pathway inhibitor) in cervical cancer cells, blocking phosphorylation and nuclear translocation of SMAD2/3, thereby downregulating CDKN1A and upregulating CCNA2 and MYC; MYC in turn transactivates ESRRB and upregulates SMAD7, forming a positive feedback loop that promotes cell-cycle progression. CRISPR/Cas9 knockout, ectopic expression, reporter assays, western blot for pSMAD2/3, cell-cycle analysis, xenograft tumor model Cancer research High 37350664
2023 ESRRB is required and sufficient to activate formative gene expression programs in naive-to-formative epiblast transition; Esrrb genetic inactivation leads to illegitimate mesendoderm/extra-embryonic marker expression, impaired formative transcription, failure to self-organize in 3D, and impaired primordial germ cell generation; ESRRB occupies key formative gene loci in naive cells and throughout the formative state. Genetic inactivation, gain-of-function, 3D organoid self-organization assay, ChIP-seq, transcriptome analysis, PGCLC differentiation assay Nature cell biology High 37106060
2024 ESRRB is lactylated on K228 and K232 in response to intracellular lactate (linked to glycolysis); lactylation enhances ESRRB activity in promoting ESC self-renewal (in absence of LIF) and XEN differentiation by increasing its binding at target genes. Mass spectrometry, site-directed mutagenesis (K228/K232), ChIP-seq, functional self-renewal and differentiation assays International journal of molecular sciences Medium 38473939
2025 ERK phosphorylates ESRRB at Serine 42 and Serine 43; dephosphorylated ESRRB (mimicking MEK inhibition) shows enhanced binding to pluripotency genes and promotes self-renewal, while phosphorylated ESRRB shows increased binding to extraembryonic endoderm (XEN) genes and promotes XEN differentiation. Quantitative phosphoproteomics, site-directed mutagenesis (S42A/S43A phosphomutants), ChIP-seq, functional differentiation assays Stem cell reports High 39919750
2025 In naïve ESCs, ESRRB co-opts MIR (mammalian-wide interspersed repeat) SINE-derived enhancers for naïve-specific gene expression; ESRRB binding to MIR enhancers promotes formation of enhancer-to-super-enhancer loops regulating pluripotency genes; ESRRB co-occupies MIR elements with the structural protein YY1; loss of an ESRRB-bound MIR enhancer impairs self-renewal. Hi-C, H3K27ac HiChIP, CRISPR-guided TE proteomics, CRISPR MIR enhancer deletion, ChIP-seq Genome biology Medium 40296153

Source papers

Stage 0 corpus · 74 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 Reprogramming of fibroblasts into induced pluripotent stem cells with orphan nuclear receptor Esrrb. Nature cell biology 359 19136965
1997 Placental abnormalities in mouse embryos lacking the orphan nuclear receptor ERR-beta. Nature 340 9285590
2012 Esrrb is a pivotal target of the Gsk3/Tcf3 axis regulating embryonic stem cell self-renewal. Cell stem cell 320 23040478
2012 Esrrb is a direct Nanog target gene that can substitute for Nanog function in pluripotent cells. Cell stem cell 267 23040477
2008 Esrrb activates Oct4 transcription and sustains self-renewal and pluripotency in embryonic stem cells. The Journal of biological chemistry 130 18957414
2016 Mitotic binding of Esrrb marks key regulatory regions of the pluripotency network. Nature cell biology 120 27723719
2014 The expressions of stem cell markers: Oct4, Nanog, Sox2, nucleostemin, Bmi, Zfx, Tcl1, Tbx3, Dppa4, and Esrrb in bladder, colon, and prostate cancer, and certain cancer cell lines. Anatomy & cell biology 120 24693477
2019 Next-generation unnatural monosaccharides reveal that ESRRB O-GlcNAcylation regulates pluripotency of mouse embryonic stem cells. Nature communications 100 31492838
2007 Estrogen-related receptor beta/NR3B2 controls epithelial cell fate and endolymph production by the stria vascularis. Developmental cell 98 17765677
2005 Identification and structure-activity relationship of phenolic acyl hydrazones as selective agonists for the estrogen-related orphan nuclear receptors ERRbeta and ERRgamma. Journal of medicinal chemistry 92 15857113
2015 Fgf and Esrrb integrate epigenetic and transcriptional networks that regulate self-renewal of trophoblast stem cells. Nature communications 91 26206133
2008 Mutations of ESRRB encoding estrogen-related receptor beta cause autosomal-recessive nonsyndromic hearing impairment DFNB35. American journal of human genetics 84 18179891
2012 Ncoa3 functions as an essential Esrrb coactivator to sustain embryonic stem cell self-renewal and reprogramming. Genes & development 78 23019124
2004 Loss of PGC-specific expression of the orphan nuclear receptor ERR-beta results in reduction of germ cell number in mouse embryos. Mechanisms of development 71 15003627
2010 The orphan nuclear hormone receptor ERRbeta controls rod photoreceptor survival. Proceedings of the National Academy of Sciences of the United States of America 70 20534447
2017 Esrrb, an estrogen-related receptor involved in early development, pluripotency, and reprogramming. FEBS letters 66 28834535
2018 Esrrb Unlocks Silenced Enhancers for Reprogramming to Naive Pluripotency. Cell stem cell 63 29910149
2017 Hybrid Cellular Metabolism Coordinated by Zic3 and Esrrb Synergistically Enhances Induction of Naive Pluripotency. Cell metabolism 62 28467928
2020 Wnt/Beta-catenin/Esrrb signalling controls the tissue-scale reorganization and maintenance of the pluripotent lineage during murine embryonic diapause. Nature communications 48 33127892
2014 Significant association of full-thickness rotator cuff tears and estrogen-related receptor-β (ESRRB). Journal of shoulder and elbow surgery 48 25219474
2007 ERRbeta: a potent inhibitor of Nrf2 transcriptional activity. Molecular and cellular endocrinology 46 17920186
2014 ERRβ signalling through FST and BCAS2 inhibits cellular proliferation in breast cancer cells. British journal of cancer 41 24667650
2018 Esrrb Complementation Rescues Development of Nanog-Null Germ Cells. Cell reports 40 29320730
2009 Differential expression of estrogen-related receptors beta and gamma (ERRbeta and ERRgamma) and their clinical significance in human prostate cancer. Cancer science 33 20128821
2021 The combined action of Esrrb and Nr5a2 is essential for murine naïve pluripotency. Development (Cambridge, England) 31 34397088
2016 Estrogen-related receptor β (ERRβ) - renaissance receptor or receptor renaissance? Nuclear receptor signaling 31 27507929
2013 Co-motif discovery identifies an Esrrb-Sox2-DNA ternary complex as a mediator of transcriptional differences between mouse embryonic and epiblast stem cells. Stem cells (Dayton, Ohio) 30 23169531
2013 Dax1 associates with Esrrb and regulates its function in embryonic stem cells. Molecular and cellular biology 30 23508100
2020 NEDDylation negatively regulates ERRβ expression to promote breast cancer tumorigenesis and progression. Cell death & disease 28 32839427
1997 Chromosomal mapping of the human and murine orphan receptors ERRalpha (ESRRA) and ERRbeta (ESRRB) and identification of a novel human ERRalpha-related pseudogene. Genomics 28 9344655
2014 Role of estrogen related receptor beta (ESRRB) in DFN35B hearing impairment and dental decay. BMC medical genetics 25 25023176
2023 Esrrb guides naive pluripotent cells through the formative transcriptional programme. Nature cell biology 24 37106060
2023 ESRRB Inhibits the TGFβ Signaling Pathway to Drive Cell Proliferation in Cervical Cancer. Cancer research 24 37350664
2018 Esrrb extinction triggers dismantling of naïve pluripotency and marks commitment to differentiation. The EMBO journal 22 30275266
2015 ESRRB polymorphisms are associated with comorbidity of temporomandibular disorders and rotator cuff disease. International journal of oral and maxillofacial surgery 21 26584852
2015 Combined Overexpression of JARID2, PRDM14, ESRRB, and SALL4A Dramatically Improves Efficiency and Kinetics of Reprogramming to Induced Pluripotent Stem Cells. Stem cells (Dayton, Ohio) 20 26523946
2011 A novel missense mutation in the ESRRB gene causes DFNB35 hearing loss in a Tunisian family. European journal of medical genetics 20 21802533
2019 Esrrb plays important roles in maintaining self-renewal of trophoblast stem cells (TSCs) and reprogramming somatic cells to induced TSCs. Journal of molecular cell biology 19 30299501
2012 Pluripotency re-centered around Esrrb. The EMBO journal 19 23064149
2022 Esrrb is a cell-cycle-dependent associated factor balancing pluripotency and XEN differentiation. Stem cell reports 17 35594859
2015 ERRβ splice variants differentially regulate cell cycle progression. Cell cycle (Georgetown, Tex.) 17 25496115
2017 Identification of novel inverse agonists of estrogen-related receptors ERRγ and ERRβ. Bioorganic & medicinal chemistry 16 28189393
2020 Modulation of estrogen-related receptors subtype selectivity: Conversion of an ERRβ/γ selective agonist to ERRα/β/γ pan agonists. Bioorganic chemistry 15 32683181
2019 Esrrb function is required for proper primordial germ cell development in presomite stage mouse embryos. Developmental biology 14 31315026
2017 Naive-like ESRRB+ iPSCs with the Capacity for Rapid Neural Differentiation. Stem cell reports 14 29129686
2015 Messenger RNA profile analysis deciphers new Esrrb responsive genes in prostate cancer cells. BMC molecular biology 14 26627478
2010 Expression of estrogen-related receptor beta (ERRβ) in human skin. European journal of dermatology : EJD 13 20923753
2024 Glycolysis-Stimulated Esrrb Lactylation Promotes the Self-Renewal and Extraembryonic Endoderm Stem Cell Differentiation of Embryonic Stem Cells. International journal of molecular sciences 12 38473939
2022 ERR2 and ERR3 promote the development of gamma motor neuron functional properties required for proprioceptive movement control. PLoS biology 10 36542664
2019 The orphan nuclear receptor estrogen-related receptor beta (ERRβ) in triple-negative breast cancer. Breast cancer research and treatment 10 31741180
2011 A Novel ESRRB Deletion Is a Rare Cause of Autosomal Recessive Nonsyndromic Hearing Impairment among Pakistani Families. Genetics research international 10 22567352
2021 ESRRB Facilitates the Conversion of Trophoblast-Like Stem Cells From Induced Pluripotent Stem Cells by Directly Regulating CDX2. Frontiers in cell and developmental biology 9 34616727
2023 A bipartite function of ESRRB can integrate signaling over time to balance self-renewal and differentiation. Cell systems 8 37633265
2021 Differential repression of Otx2 underlies the capacity of NANOG and ESRRB to induce germline entry. Stem cell reports 8 34971561
2018 LIF-activated Jak signaling determines Esrrb expression during late-stage reprogramming. Biology open 8 29212799
2017 ESRRB plays a crucial role in the promotion of porcine cell reprograming. Journal of cellular physiology 8 28636277
2016 Esrrb directly binds to Gata6 promoter and regulates its expression with Dax1 and Ncoa3. Biochemical and biophysical research communications 8 27601327
2012 DFNB35 due to a novel mutation in the ESRRB gene in a Czech consanguineous family. International journal of pediatric otorhinolaryngology 8 22951369
2021 An Esrrb and Nanog Cell Fate Regulatory Module Controlled by Feed Forward Loop Interactions. Frontiers in cell and developmental biology 6 33816475
2023 Nilaparvata lugens ERR2 regulates moulting and ovary development is related to hormone signalling. Insect molecular biology 5 36861367
2016 Characterization and genetic manipulation of primed stem cells into a functional naïve state with ESRRB. World journal of stem cells 5 27822342
2015 Forced expression of Nanog or Esrrb preserves the ESC status in the absence of nucleostemin expression. Stem cells (Dayton, Ohio) 5 25522312
2025 Rewiring of SINE-MIR enhancer topology and Esrrb modulation in expanded and naive pluripotency. Genome biology 4 40296153
2023 Long Noncoding RNA ACTA2-AS1 Inhibits Cell Growth and Facilitates Apoptosis in Gastric Cancer by Binding with miR-6720-5p to Regulate ESRRB. Biochemical genetics 4 37222961
2025 Tetramethyl bisphenol F exposure induces human ovarian granulosa cell senescence and mouse ovarian damage by regulating ESRRB signalling. Ecotoxicology and environmental safety 3 40014986
2024 Functional pathogenicity of ESRRB variant of uncertain significance contributes to hearing loss (DFNB35). Scientific reports 3 39261511
2022 A novel missense variant in ESRRB gene causing autosomal recessive non-syndromic hearing loss: in silico analysis of a case. BMC medical genomics 3 35101039
2022 Esrrb Regulates Specific Feed-Forward Loops to Transit From Pluripotency Into Early Stages of Differentiation. Frontiers in cell and developmental biology 2 35652095
2021 Oocyte-specific linker histone H1foo interacts with Esrrb to induce chromatin decondensation at specific gene loci. Biochemical and biophysical research communications 2 34023782
2025 ERK phosphorylates ESRRB to regulate the self-renewal and differentiation of mouse embryonic stem cells. Stem cell reports 1 39919750
2015 [Cloning and regulation of pig estrogen related receptor β gene (ESRRB) promoter]. Sheng wu gong cheng xue bao = Chinese journal of biotechnology 1 26380406
2015 Esrrb-Cre excises loxP-flanked alleles in early four-cell embryos. Genesis (New York, N.Y. : 2000) 1 26663459
2025 Multi-omics analysis of early reperfused ischemic heart reveals ERRβ/γ activation protects against acute myocardial infarction injury. Journal of advanced research 0 41429340
2025 Calcium and Cadmium Activate ESRRB to Mediate Cell Stemness and Pluripotency. International journal of molecular sciences 0 41516107