Steroid hormone receptor ERR2 · UniProt O95718
ESRRB is an orphan nuclear receptor that acts as a sequence-specific transcription factor binding ERRE motifs to control cell-fate decisions in pluripotency, extraembryonic development, and specialized sensory and neuronal cell types (PMID:18957414, PMID:23040478). In naive embryonic stem cells it sits at the core of the self-renewal network: it is necessary and sufficient to mediate self-renewal downstream of Gsk3 inhibition (via relief of Tcf3 repression), it is a direct transcriptional target of Nanog, and together with the orphan receptor Nr5a2 it co-occupies regulatory elements and governs the genomic binding of OCT4, SOX2, and NANOG (PMID:23040477, PMID:23040478, PMID:34397088). It physically interacts with NANOG, SOX2, and DAX1 through its DNA-binding and ligand-binding domains and recruits the coactivator Ncoa3 to bridge target enhancers to RNA Polymerase II (PMID:18957414, PMID:23019124, PMID:23508100, PMID:23169531). ESRRB can replace KLF factors to reprogram fibroblasts to iPSCs and functions as a pioneer factor, binding silenced, nucleosome-occupied, methylated enhancers inaccessible to OCT4/SOX2/NANOG and triggering demethylation, p300 engagement, and nucleosome displacement that recruit core pluripotency factors (PMID:19136965, PMID:29910149). It also acts as a mitotic bookmarking factor, remaining bound to regulatory regions during mitosis to enable rapid post-mitotic transcriptional reactivation (PMID:27723719). ESRRB activity is tuned by post-translational modifications: O-GlcNAcylation at S25 stabilizes the protein and enhances OCT4/NANOG interactions, ERK phosphorylation at S42/S43 switches genome occupancy between pluripotency and extraembryonic endoderm loci, and lactylation at K228/K232 enhances target binding (PMID:31492838, PMID:39919750, PMID:38473939). Beyond pluripotency, ESRRB drives self-renewal of trophoblast stem cells by directly activating Elf5, Eomes, Cdx2, and Bmp4 (where in this context it engages Lsd1 and the Integrator complex) and directs PGC and formative epiblast development (PMID:26206133, PMID:30299501, PMID:37106060). ESRRB is required cell-autonomously for chorion/placenta formation, for the fate of endolymph-producing cells of the inner ear, and for functional properties of gamma motor neurons (PMID:9285590, PMID:17765677, PMID:36542664). Loss-of-function ESRRB mutations cause autosomal recessive nonsyndromic hearing loss DFNB35 through failure of inner ear endolymph-producing cell development (PMID:18179891).
Established that ERR-beta has an essential, cell-autonomous developmental role, defining its first in vivo function.
Evidence Targeted knockout in mice with tetraploid rescue aggregation
Identified the first synthetic agonists of ERRbeta, providing pharmacological handles for an otherwise orphan receptor.
Evidence Ligand binding and cell-based reporter assays with GSK4716/GSK9089
Showed ERRbeta governs specialized cell-fate and gene programs outside development, including endolymph-producing inner ear cells and transcriptional repression of Nrf2.
Evidence Knockout transcriptome/IHC of stria vascularis; CoIP, reporter, and imaging for Nrf2 repression
Linked ESRRB directly to the pluripotency network and to human disease, establishing both its molecular role with NANOG/Oct4 and a causative role in hearing loss.
Evidence ChIP/CoIP/reporter at the Oct4 locus plus LIF-withdrawal rescue; linkage and mutation analysis in DFNB35 families
Demonstrated ESRRB can substitute for KLF factors in reprogramming, defining it as a functional core pluripotency factor.
Evidence Retroviral reprogramming of MEFs with Oct4/Sox2/Esrrb, chimera and germline transmission assays
Extended ERRbeta function to a metabolic-transcriptional role in rod photoreceptor maintenance, showing ligand-tunable control of cell survival.
Evidence Knockout, overexpression, inverse agonist and constitutively active mutant rescue in retina
Positioned ESRRB within signalling-controlled self-renewal circuitry as a Nanog target and as the necessary/sufficient effector downstream of Gsk3/Tcf3, while requiring Ncoa3 as coactivator.
Evidence ChIP, genetic epistasis in Nanog-/- cells, ChIP-seq, KO/OE, and reciprocal CoIP domain mapping
PMID:23019124 PMID:23040477 PMID:23040478
Resolved the combinatorial DNA-binding logic of ESRRB, identifying a constrained Esrrb-Sox2 composite motif and DAX1 as a competitive regulator.
Evidence ChIP-seq co-motif analysis with knockdown; CoIP domain mapping, ChIP, reporter assays for DAX1
Implicated ERRbeta in tumor-suppressive transcriptional control in breast cancer through FST/BCAS2 and cyclin D1 regulation.
Evidence ChIP cloning, supershift, CoIP, reporter assays in breast cancer cells
Defined a context-specific ESRRB program in trophoblast stem cells with distinct interactome (Lsd1, Integrator) and target genes, separating its TSC and ESC roles.
Evidence ChIP-seq, mass spectrometry interactome, Fgf inhibition, loss-of-function in TS cells
Established ESRRB as a mitotic bookmarking factor, explaining how transcriptional identity is propagated through cell division.
Evidence ChIP-seq in synchronized mitotic cells, FRAP, single-molecule tracking, motif analysis
Connected ESRRB to metabolic reprogramming, showing it activates OXPHOS required for efficient acquisition of naive pluripotency.
Evidence Reprogramming assays, metabolic flux analysis, pathway inhibition with Esrrb/Zic3
Mechanistically defined ESRRB as a pioneer factor and placed it downstream of LIF/Jak, while demonstrating functional equivalence to Nanog in germ cell development.
Evidence ATAC-seq/bisulfite/ChIP-seq pioneer assay; Jak-inhibitor rescue; Esrrb-at-Nanog-locus knockin rescue with fertility endpoint
PMID:27601327 PMID:29212799 PMID:29320730 PMID:29910149 PMID:30275266
Revealed post-translational and signalling-integrated control of ESRRB and direct enhancer regulation of Bmp4 in extraembryonic ectoderm linking it to PGC development.
Evidence Chemical proteomics/mutagenesis for S25 O-GlcNAcylation; ChIP-seq, reporter, CRISPR enhancer deletion at Bmp4
PMID:30299501 PMID:31315026 PMID:31492838
Defined ESRRB protein turnover via SCF/NEDDylation in cancer and a Wnt-Esrrb axis controlling diapause-associated epiblast organization.
Evidence MLN4924 stabilization with ChIP for p300 recruitment; 3D epiblast model with Wnt and Esrrb manipulation
Showed ESRRB and Nr5a2 jointly control core pluripotency-factor binding, and refined its roles in trophoblast conversion, germline entry, and oocyte-like chromatin decondensation.
Evidence Esrrb/Nr5a2 double KO with ChIP-seq; CDX2 ChIP/mutagenesis with OCT4 CoIP; Otx2 epistasis; H1foo CoIP/ChIP-seq
PMID:34023782 PMID:34397088 PMID:34616727 PMID:34971561
Linked ESRRB to cell-cycle-coupled fate output (G2/M-driven XEN differentiation) and identified a function in gamma motor neuron physiology.
Evidence Cell-cycle reporter/scRNA-seq/ATAC-seq with KO/OE; conditional KO with electrophysiology and gait analysis plus chick gain-of-function
Defined ESRRB as required and sufficient for the naive-to-formative transition and as a stoichiometry-dependent fate switch with NANOG, plus a cancer-promoting SMAD7/MYC feedback circuit.
Evidence CRISPR KO/OE with ChIP-seq and organoid/PGCLC assays; NANOG:ESRRB titration with modeling; CRISPR KO/OE with ChIP and xenografts in cervical cancer
PMID:37106060 PMID:37350664 PMID:37633265
Established a PTM code directing ESRRB genome occupancy, with ERK phosphorylation at S42/S43 and lactylation at K228/K232 toggling pluripotency versus XEN fate and target binding.
Evidence Phosphoproteomics, phosphomimetic/lactylation-site mutagenesis, ChIP-seq, self-renewal and XEN differentiation assays
PMID:38473939 PMID:39261511 PMID:39919750
Showed ESRRB co-opts MIR SINE enhancers and YY1 to build 3D enhancer networks for naive gene expression, and reopened the question of an endogenous metal ligand.
Evidence Hi-C/HiChIP/CRISPR-TE proteomics/enhancer deletion; cell-based reporter, ChIP, docking for calcium/cadmium activation
| Year | Finding | Method | Journal | Conf | PMIDs |
|---|---|---|---|---|---|
| 1997 | Targeted disruption of Estrrb in mice causes severely impaired placental formation, with abnormal chorion development, overabundance of trophoblast giant cells, and severe deficiency of diploid trophoblast, leading to embryonic death at E10.5. The phenotype is rescued by aggregation with tetraploid wild-type cells contributing exclusively to extra-embryonic tissues, demonstrating that ERR-beta functions cell-autonomously in the chorion. | Gene knockout (targeted disruption), tetraploid rescue aggregation | Nature | High | 9285590 |
| 1997 | Human ESRRB gene maps to chromosome 14q24.3 and murine Estrrb maps to mouse chromosome 12, established by FISH and interspecific backcross analysis. | Fluorescence in situ hybridization (FISH), interspecific backcross analysis | Genomics | High | 9344655 |
| 2005 | GSK4716 and GSK9089 were identified as the first small molecule agonists of ERRbeta (and ERRgamma); in cell-based reporter assays, GSK4716 mimics the protein ligand PGC-1alpha in activating human ERRbeta and ERRgamma transcriptional activity. | Ligand binding assay, cell-based reporter gene assay | Journal of medicinal chemistry | Medium | 15857113 |
| 2007 | ERR-beta (NR3B2) controls the fate and function of endolymph-producing cells (strial marginal cells and vestibular dark cells) in the inner ear; Nr3b2-/- strial marginal cells fail to express multiple ion channel and transporter genes and show partial transformation toward adjacent Pendrin-expressing epithelial cell fate, with secondary loss of strial capillaries. | Gene knockout, transcriptome comparison (WT vs Nr3b2-/- stria vascularis), immunohistochemistry | Developmental cell | High | 17765677 |
| 2007 | Short-form human ERRbeta (SFhERRbeta) potently represses the transcriptional activity of Nrf2 on antioxidant response element (ARE)-mediated gene expression. This repression occurs through physical interaction with Nrf2 (not by competing for ARE binding or reducing Nrf2 protein levels), and SFhERRbeta alters the subcellular localization of Nrf2. Deletion mutant analysis showed ERRbeta interacts with Nrf2 through multiple sites. | Reporter gene assay, co-immunoprecipitation, confocal immunofluorescence, deletion mutant analysis | Molecular and cellular endocrinology | Medium | 17920186 |
| 2008 | ESRRB binds directly to two ERRE sites in the proximal 5'-UTR of the mouse Oct4 gene, one adjacent to a NANOG binding site. Both ESRRB and NANOG are required for Oct4 promoter activity in ES cells. ESRRB and NANOG interact physically through their DNA-binding domains, and this interaction reciprocally modulates their transcriptional activities. Stable transfection of Esrrb is sufficient to sustain ES cell characteristics in the absence of LIF. | Reporter gene assay, ChIP, co-immunoprecipitation, stable transfection, LIF withdrawal assay | The Journal of biological chemistry | High | 18957414 |
| 2008 | Loss-of-function mutations in ESRRB (frameshift, missense in DNA-binding domain and ligand-binding domain) cause autosomal recessive nonsyndromic hearing impairment DFNB35. Esrrb is expressed during inner ear development and present postnatally in the cochlea. Molecular modeling indicates mutations affect structural integrity of the DNA-binding and ligand-binding domains. | Linkage mapping, mutation analysis, RNA in situ hybridization, immunohistochemistry, molecular modeling | American journal of human genetics | High | 18179891 |
| 2009 | The orphan nuclear receptor Esrrb functions in conjunction with Oct4 and Sox2 to reprogram mouse embryonic fibroblasts (MEFs) to induced pluripotent stem cells (iPS cells), replacing the requirement for Klf transcription factors. Esrrb-reprogrammed cells share ES cell expression and epigenetic signatures, are pluripotent in vitro and in vivo, contribute to chimeras, and are germline-transmissible. In ES cells, Esrrb targets genes involved in self-renewal and pluripotency. | Retroviral reprogramming, gene expression profiling, epigenetic analysis, in vivo teratoma, chimera generation, germline transmission | Nature cell biology | High | 19136965 |
| 2010 | ERRbeta is selectively expressed in rod photoreceptors. Overexpression of ERRbeta induces rod-specific gene expression in wild-type and Nrl-/- retinas. Loss of ERRbeta causes rod dysfunction and degeneration; inverse agonists trigger rapid rod degeneration rescued by constitutively active ERRbeta mutants. ERRbeta coordinates expression of multiple genes that are rate-limiting regulators of ATP generation and consumption in photoreceptors. Enhancing ERRbeta activity rescues photoreceptor defects from loss of Crx. | Gene knockout, overexpression, inverse agonist treatment, constitutively active mutant rescue, gene expression analysis | Proceedings of the National Academy of Sciences of the United States of America | High | 20534447 |
| 2012 | Esrrb is a direct transcriptional target of Nanog. Nanog binds directly to the Esrrb locus, enhances RNA Pol II binding, and stimulates Esrrb transcription. Overexpression of Esrrb maintains LIF-independent self-renewal and pluripotency even in Nanog-/- ESCs. Esrrb can reprogram Nanog-/- EpiSCs and rescue stalled reprogramming in Nanog-/- pre-iPSCs. Deletion of Esrrb abolishes Nanog's ability to confer LIF-independent self-renewal, placing Esrrb functionally downstream of Nanog. | ChIP, RNA Pol II ChIP, genetic epistasis (Nanog-/- ESCs/EpiSCs/pre-iPSCs), overexpression, LIF-withdrawal assay | Cell stem cell | High | 23040477 |
| 2012 | Esrrb is repressed by Tcf3 downstream of Gsk3. Knockdown or knockout of Esrrb eliminates ESC response to Gsk3 inhibition, causing loss of pluripotency markers and colony-forming capability. Forced Esrrb expression phenocopies Gsk3 inhibition or Tcf3 deletion by suppressing differentiation and sustaining self-renewal. Esrrb is thus necessary and sufficient to mediate self-renewal downstream of Gsk3 inhibition; LIF/Stat3 regulates ESCs independently in parallel. | shRNA knockdown, gene knockout, forced expression, genome localization (ChIP-seq), transcriptome analysis, genetic epistasis | Cell stem cell | High | 23040478 |
| 2012 | Ncoa3 (a coactivator) is required to mediate Esrrb function in ESCs. Ncoa3 interacts with Esrrb via Esrrb's ligand-binding domain and bridges Esrrb to RNA Polymerase II complexes. Ncoa3 is critical for both induction and maintenance of pluripotency, shares overlapping gene regulatory functions with Esrrb, and cooperates genome-wide with the Oct4-Sox2-Nanog circuitry at active enhancers to upregulate self-renewal genes. | Co-immunoprecipitation (domain mapping), ChIP-seq, microarray, knockdown/knockout functional assays | Genes & development | High | 23019124 |
| 2013 | Dax1 interacts with Esrrb; the interaction is mediated through LXXLL motifs of Dax1 and the activation- and ligand-binding domains of Esrrb. Esrrb directly binds to ERRE1 in the Dax1 promoter and enhances Dax1 expression in an Oct3/4-independent manner. Dax1 represses Esrrb transcriptional activity. Oct3/4, Dax1, and Esrrb have competitive inhibition capacity for each complex, forming a regulatory loop. | Co-immunoprecipitation (domain mapping), promoter-reporter assay, ChIP, overexpression/knockdown | Molecular and cellular biology | Medium | 23508100 |
| 2013 | Esrrb and Sox2 co-bind DNA at a novel constrained composite motif (Esrrb-Sox motif, gap of 2-8 bp). The Esrrb-Sox2 complex regulates gene expression differences between ESCs and epiblast stem cells; knockdown of both factors downregulates Klf4, Klf5, Jam2, Pecam1, and Nr0b1. Esrrb-Sox2 composite binding elements are conserved across eutherian and metatherian mammals. | ChIP-seq motif discovery (co-motif analysis), shRNA knockdown, gene expression analysis | Stem cells | Medium | 23169531 |
| 2014 | Overexpressed ERRbeta induces FST-mediated apoptosis in breast cancer cells and enhances E-cadherin expression via FST upregulation. ERRbeta-mediated BCAS2 upregulation inhibits FST transcription through downregulation of beta-catenin/TCF4 recruitment to the FST promoter, and downregulates cyclin D1 to block G1-S transition. ERRbeta was identified as a co-regulator of ERalpha by co-immunoprecipitation. | ChIP cloning, gel supershift assay, co-immunoprecipitation, western blot, confocal microscopy, reporter assay | British journal of cancer | Medium | 24667650 |
| 2015 | In trophoblast stem (TS) cells, Esrrb is a downstream target of Fgf signalling and drives TS cell self-renewal by directly binding and regulating TS cell-specific transcription factors Elf5 and Eomes. In TS cells (unlike ES cells), Esrrb interacts with the histone demethylase Lsd1 and with the RNA Polymerase II-associated Integrator complex, as determined by mass spectrometry-based interactome analysis. | ChIP-seq, mass spectrometry (interactome), Fgf signaling inhibition, gene expression analysis, loss-of-function | Nature communications | High | 26206133 |
| 2016 | Esrrb remains bound to key regulatory regions during mitosis in mouse ESCs. Mitotic Esrrb binding is highly dynamic, driven by specific recognition of its DNA-binding motif, and is associated with early transcriptional reactivation of target genes after mitosis. Esrrb thus functions as a mitotic bookmarking factor. | ChIP-seq in synchronized mitotic cells, live-cell imaging (FRAP), motif analysis, single-molecule tracking | Nature cell biology | High | 27723719 |
| 2016 | Esrrb directly binds to ERRE2 in the Gata6 promoter and activates Gata6 transcription. Dax1 represses this Esrrb-driven activation without directly binding ERRE2, by interacting with Esrrb. Ncoa3 enhances Esrrb transcriptional activity at the Gata6 promoter. Dax1 also associates with Ncoa3 and represses its activity. | Biotin DNA pulldown, ChIP, promoter-reporter assay, co-immunoprecipitation | Biochemical and biophysical research communications | Medium | 27601327 |
| 2017 | Esrrb and Zic3 synergistically enhance reprogramming efficiency to naive pluripotency by regulating cellular metabolic pathways. Esrrb activates oxidative phosphorylation (OXPHOS), which is essential for efficient reprogramming, while Zic3 represses OXPHOS. Both cooperatively activate glycolytic metabolism independently of HIF factors. Esrrb-mediated OXPHOS activation is also critical for conversion of primed PSCs to naive state. | Retroviral transduction (reprogramming assay), metabolic flux analysis, gene expression analysis, pathway inhibition | Cell metabolism | Medium | 28467928 |
| 2018 | Esrrb acts as a pioneer factor during reprogramming of epiblast stem cells to naive pluripotency: it binds to silenced enhancers containing stable nucleosomes and hypermethylated DNA that are inaccessible to Oct4, Sox2, and Nanog. Esrrb binding is accompanied by local loss of DNA methylation, LIF-dependent engagement of p300, and nucleosome displacement, leading to recruitment of core pluripotency factors within approximately 2 days. | ATAC-seq, bisulfite sequencing, ChIP-seq (Esrrb, p300, histone marks), EpiSC-to-naive reprogramming assay | Cell stem cell | High | 29910149 |
| 2018 | Esrrb downregulation precedes and marks commitment to differentiation from naive pluripotency. In Esrrb-negative ESCs, Class I regulatory elements (associated with naive pluripotency genes) lose both NANOG and OCT4 binding, while Class II elements retain OCT4 but lose NANOG binding, identifying mechanistically distinct classes of regulatory element that cumulatively restrict potency during exit from naive pluripotency. | Fluorescent reporter sorting, ChIP-seq in sorted ESC subpopulations, transcriptome analysis | The EMBO journal | High | 30275266 |
| 2018 | Esrrb expression during reprogramming is regulated downstream of the LIF/Jak signaling pathway. Overexpression of Esrrb resumes reprogramming halted by Jak inhibition in pre-iPSCs, generating pluripotent iPSCs. Neither Nanog overexpression nor Wnt stimulation can substitute for LIF/Jak activity in inducing Esrrb expression during reprogramming. | Jak inhibitor treatment, Esrrb overexpression rescue, gene expression analysis | Biology open | Medium | 29212799 |
| 2018 | Esrrb complementation (knockin of Esrrb at the Nanog locus) rescues PGC numbers to wild-type levels and results in fertile adult mice in a Nanog-null background, demonstrating that Esrrb can functionally replace Nanog in germ cell development. Nanog-null PGCs show decreased proliferation and increased apoptosis; induced Esrrb expression restores PGCLC numbers as efficiently as Nanog. | Germline knockout, knockin complementation, in vitro PGCLC differentiation, proliferation/apoptosis assays | Cell reports | High | 29320730 |
| 2019 | ESRRB is an O-GlcNAcylated protein in mouse ESCs. OGT (O-GlcNAc transferase) O-GlcNAcylates ESRRB at serine 25. This modification stabilizes ESRRB protein, promotes its transcriptional activity, and facilitates its interactions with OCT4 and NANOG, which is important for mESC self-renewal and pluripotency. | Metabolic glycan labeling with chemical reporters (1,3-Pr2GalNAz), proteomics, site-directed mutagenesis, co-immunoprecipitation, transcriptional reporter assay, protein stability assay | Nature communications | High | 31492838 |
| 2019 | Esrrb directly regulates Bmp4 in the extraembryonic ectoderm (ExE) through binding to an enhancer at the Bmp4 locus (identified by ChIP-seq and luciferase reporter assay). Loss of either Esrrb or this enhancer (CRISPR deletion) reduces Bmp4 expression in the ExE and decreases PGC numbers, placing Esrrb upstream of Bmp4 in PGC development regulation. | Microarray (Esrrb-null vs WT ExE), ChIP-seq, luciferase reporter assay, CRISPR/Cas9 enhancer deletion | Developmental biology | High | 31315026 |
| 2019 | Esrrb directly binds and activates TSC-specific target genes including Cdx2, Eomes, Sox2, Fgfr4, and Bmp4 in trophoblast stem cells. Precise Esrrb levels are critical for TSC stemness; depletion causes rapid differentiation and loss of hemorrhagic lesion-forming ability in vivo. Esrrb overexpression can facilitate MEF-to-iTSC conversion and can substitute for Eomes. | Knockdown/overexpression, ChIP, in vivo implantation assay, reprogramming assay | Journal of molecular cell biology | Medium | 30299501 |
| 2020 | ERRbeta is targeted for proteasomal degradation in breast cancer via the SCF E3 ubiquitin ligase complex, activated by NEDDylation of Cullin subunits. Inhibition of NEDDylation with MLN4924 restores ERRbeta expression. Restored ERRbeta recruits the coactivator p300 to promoters of target genes p21Cip1/Waf1 and E-cadherin to upregulate their expression. | In vitro/in vivo MLN4924 treatment, western blot (protein stability), ChIP (p300 recruitment), gene expression analysis | Cell death & disease | Medium | 32839427 |
| 2020 | The canonical Wnt/beta-catenin pathway and its downstream factor Esrrb are identified as the key signaling cascade regulating tissue-scale organization of the murine pluripotent lineage during embryonic diapause. Autocrine Wnt activity controls epiblast morphogenesis and long-term maintenance during diapause via Esrrb, though this circuit is dispensable for pre-implantation embryonic development. | 3D in vitro epiblast model, Wnt pathway inhibition/activation, Esrrb manipulation, live imaging | Nature communications | Medium | 33127892 |
| 2021 | ESRRB directly regulates CDX2 by binding to its promoter region. Mutational analysis of ESRRB showed the N-terminus zinc finger domain is indispensable for regulation of TSC markers (KRT8, KRT18, CDX2). ESRRB cooperates with OCT4 for conversion from pluripotent to trophoblast-like state. | ChIP (promoter binding), site-directed mutagenesis (domain analysis), overexpression, co-immunoprecipitation | Frontiers in cell and developmental biology | Medium | 34616727 |
| 2021 | The conjunct activity of Esrrb and Nr5a2 (two orphan nuclear receptors) parallels the importance of Oct4 and Sox2 for naive ESC self-renewal. By co-occupying a large common set of regulatory elements, Esrrb and Nr5a2 together control the binding of Oct4, Sox2, and Nanog to DNA. Double knockout causes collapse of the pluripotency network and ESC differentiation. | Double knockout (Esrrb/Nr5a2), ChIP-seq, transcriptome analysis, rescue experiments | Development | High | 34397088 |
| 2021 | NANOG mediates Otx2 downregulation required for PGCLC induction. Esrrb, a direct Nanog target, does not downregulate Otx2 when overexpressed in EpiLCs and cannot promote PGCLC specification. However, ESRRB expression in Otx2+/- EpiLCs rescues PGCLC emergence, placing Esrrb downstream of Nanog's Otx2-repression function in germline entry. | Forced expression, genetic epistasis (Otx2 heterozygosity rescue), in vitro PGCLC differentiation assay, gene expression analysis | Stem cell reports | Medium | 34971561 |
| 2021 | H1foo (oocyte-specific linker histone) physically interacts with Esrrb. Esrrb is required for H1foo-dependent chromatin decondensation at specific target loci. ChIP-seq shows H1foo enrichment at oocyte-specific gene TSS regions in ESCs overexpressing H1foo, and this localization depends on Esrrb. | ChIP-seq, co-immunoprecipitation, chromatin accessibility assay, knockdown | Biochemical and biophysical research communications | Medium | 34023782 |
| 2022 | ERR2 and ERR3 (ERRbeta and ERRgamma) are required in motor neurons for gamma motor neuron functional properties (low firing thresholds, high firing rates) necessary for proprioceptive movement control. Selective loss of ERR2/ERR3 in motor neurons generates morphologically normal gamma motor neurons that lack characteristic functional properties, disrupting gait and precision movements. Gain-of-function in chick suggests ERR2/ERR3 operate via transcriptional activation of neural activity modulators. | Conditional knockout, gain-of-function (chick), electrophysiology, gait analysis, gene expression analysis | PLoS biology | High | 36542664 |
| 2022 | Esrrb is upregulated during G2/M phase of the cell cycle in ESCs and drives extraembryonic endoderm (XEN) differentiation. G1 cells overexpressing Esrrb gain the ability to produce XEN cells, while ESRRB-KO ESCs lose the potential to differentiate into XEN. ESRRB is associated with XEN poised enhancers in its active chromatin state. | Cell-cycle reporter system, scRNA-seq, ESRRB KO, overexpression, ATAC-seq (enhancer analysis) | Stem cell reports | Medium | 35594859 |
| 2023 | ESRRB is required and sufficient to activate formative genes during the naive-to-formative epiblast transition. Genetic inactivation of Esrrb leads to illegitimate expression of mesendoderm and extra-embryonic markers, impaired formative gene expression, failure to self-organize in 3D, and impaired ability to generate formative stem cells and primordial germ cells. ESRRB occupies key formative gene loci in naive cells and throughout the formative state. | CRISPR knockout, forced expression, ChIP-seq, 3D organoid self-organization assay, PGCLC differentiation, transcriptome analysis | Nature cell biology | High | 37106060 |
| 2023 | ESRRB activates SMAD7 transcription directly (a TGFbeta pathway inhibitor), which blocks phosphorylation and nuclear translocation of SMAD2/3, thereby downregulating CDKN1A and upregulating CCNA2 and MYC in cervical cancer. MYC in turn transactivates ESRRB and upregulates SMAD7, forming a positive feedback loop. ESRRB knockout causes G0-G1 arrest and reduces tumor growth in vivo. | CRISPR/Cas9 knockout, forced expression, ChIP, luciferase reporter, phospho-western blot, xenograft tumor assay | Cancer research | Medium | 37350664 |
| 2023 | The stoichiometry of NANOG and ESRRB determines cell fate: when both are expressed, ESRRB supports pluripotency; when NANOG is absent, ESRRB supports a bistable culture with primitive endoderm identity. The bipartite ESRRB activity depends on cooperative DNA co-binding with NANOG, and quantitative titration of their ratio allows tuning of differentiation output. | Forced expression titration, reporter cell lines, mathematical modeling, gene expression analysis | Cell systems | Medium | 37633265 |
| 2024 | ERK phosphorylates ESRRB on Serine 42 and 43. Dephosphorylation of ESRRB facilitates its binding to pluripotency gene loci and enhances ESC self-renewal activity, while phosphorylation of ESRRB increases its binding to extraembryonic endoderm (XEN) gene loci and promotes XEN differentiation. This PTM switch thus differentially directs ESRRB genome occupancy and cell fate. | Quantitative phosphoproteomics, site-directed mutagenesis (S42/S43A and S42/S43D phosphomimetics), ChIP-seq, ESC self-renewal and XEN differentiation assays | Stem cell reports | High | 39919750 |
| 2024 | Esrrb is lactylated at K228 and K232. Lactylation of Esrrb (regulated by intracellular lactate from glycolysis) enhances its activity in promoting ESC self-renewal in the absence of LIF and XEN differentiation by increasing Esrrb binding at target genes. | Site-directed mutagenesis (K228/K232 lactylation sites), ChIP, protein activity assay, LIF-withdrawal self-renewal assay, XEN differentiation assay | International journal of molecular sciences | Medium | 38473939 |
| 2024 | A novel splicing variant (c.397+2T>G) in ESRRB causes exon 4 skipping, premature stop codon, and nonsense-mediated decay. A missense variant (p.Arg382Cys) in the ligand-binding domain disrupts key intramolecular interactions causing protein instability, reduces transcriptional activity, and alters expression of downstream target genes essential for inner ear function. | Splicing assay, NMD analysis, protein stability assay, transcriptional activity reporter assay, gene expression analysis of downstream targets | Scientific reports | Medium | 39261511 |
| 2025 | In the naïve pluripotent state, ESRRB co-opts MIR (mammalian-wide interspersed repeat) SINE enhancers for naïve-specific gene expression. ESRRB and MIR enhancer interactions form chromatin loops building networks of enhancers and super-enhancers regulating pluripotency genes. Loss of an ESRRB-bound MIR enhancer impairs self-renewal. ESRRB co-binds MIR elements with the structural protein YY1. | Hi-C, H3K27ac HiChIP, CRISPR-guided TE proteomics, CRISPR enhancer deletion, ChIP-seq | Genome biology | Medium | 40296153 |
| 2025 | Calcium and cadmium activate ESRRB transcriptional activity in breast cancer cells. Treatment with calcium or cadmium enhances ESRRB nuclear localization, increases RNA polymerase II recruitment to ERREs, and enhances cell stemness and proliferation pathways. Mutational analysis and molecular docking identified potential metal interaction sites within the ESRRB ligand-binding domain, suggesting calcium may act as a natural ligand. | Cell-based transcriptional reporter, confocal microscopy (nuclear localization), ChIP (RNA Pol II at ERRE), site-directed mutagenesis, molecular docking | International journal of molecular sciences | Low | 41516107 |
| Year | Title | Journal | Citations | PMID |
|---|---|---|---|---|
| 2009 | Reprogramming of fibroblasts into induced pluripotent stem cells with orphan nuclear receptor Esrrb. | Nature cell biology | 360 | 19136965 |
| 1997 | Placental abnormalities in mouse embryos lacking the orphan nuclear receptor ERR-beta. | Nature | 341 | 9285590 |
| 2012 | Esrrb is a pivotal target of the Gsk3/Tcf3 axis regulating embryonic stem cell self-renewal. | Cell stem cell | 324 | 23040478 |
| 2012 | Esrrb is a direct Nanog target gene that can substitute for Nanog function in pluripotent cells. | Cell stem cell | 270 | 23040477 |
| 2008 | Esrrb activates Oct4 transcription and sustains self-renewal and pluripotency in embryonic stem cells. | The Journal of biological chemistry | 130 | 18957414 |
| 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 | 121 | 24693477 |
| 2016 | Mitotic binding of Esrrb marks key regulatory regions of the pluripotency network. | Nature cell biology | 120 | 27723719 |
| 2019 | Next-generation unnatural monosaccharides reveal that ESRRB O-GlcNAcylation regulates pluripotency of mouse embryonic stem cells. | Nature communications | 103 | 31492838 |
| 2007 | Estrogen-related receptor beta/NR3B2 controls epithelial cell fate and endolymph production by the stria vascularis. | Developmental cell | 98 | 17765677 |
| 2015 | Fgf and Esrrb integrate epigenetic and transcriptional networks that regulate self-renewal of trophoblast stem cells. | Nature communications | 94 | 26206133 |
| 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 | 93 | 15857113 |
| 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 |
| 2010 | The orphan nuclear hormone receptor ERRbeta controls rod photoreceptor survival. | Proceedings of the National Academy of Sciences of the United States of America | 71 | 20534447 |
| 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 |
| 2017 | Esrrb, an estrogen-related receptor involved in early development, pluripotency, and reprogramming. | FEBS letters | 67 | 28834535 |
| 2018 | Esrrb Unlocks Silenced Enhancers for Reprogramming to Naive Pluripotency. | Cell stem cell | 64 | 29910149 |
| 2017 | Hybrid Cellular Metabolism Coordinated by Zic3 and Esrrb Synergistically Enhances Induction of Naive Pluripotency. | Cell metabolism | 62 | 28467928 |
| 2014 | Significant association of full-thickness rotator cuff tears and estrogen-related receptor-β (ESRRB). | Journal of shoulder and elbow surgery | 50 | 25219474 |
| 2020 | Wnt/Beta-catenin/Esrrb signalling controls the tissue-scale reorganization and maintenance of the pluripotent lineage during murine embryonic diapause. | Nature communications | 49 | 33127892 |
| 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 |
| 2023 | Esrrb guides naive pluripotent cells through the formative transcriptional programme. | Nature cell biology | 26 | 37106060 |
| 2014 | Role of estrogen related receptor beta (ESRRB) in DFN35B hearing impairment and dental decay. | BMC medical genetics | 25 | 25023176 |
| 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 |
| 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 | 21 | 30299501 |
| 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 |
| 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 |
| 2017 | Identification of novel inverse agonists of estrogen-related receptors ERRγ and ERRβ. | Bioorganic & medicinal chemistry | 17 | 28189393 |
| 2015 | ERRβ splice variants differentially regulate cell cycle progression. | Cell cycle (Georgetown, Tex.) | 17 | 25496115 |
| 2020 | Modulation of estrogen-related receptors subtype selectivity: Conversion of an ERRβ/γ selective agonist to ERRα/β/γ pan agonists. | Bioorganic chemistry | 16 | 32683181 |
| 2019 | Esrrb function is required for proper primordial germ cell development in presomite stage mouse embryos. | Developmental biology | 16 | 31315026 |
| 2024 | Glycolysis-Stimulated Esrrb Lactylation Promotes the Self-Renewal and Extraembryonic Endoderm Stem Cell Differentiation of Embryonic Stem Cells. | International journal of molecular sciences | 15 | 38473939 |
| 2017 | Naive-like ESRRB+ iPSCs with the Capacity for Rapid Neural Differentiation. | Stem cell reports | 15 | 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 |
| 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 | 11 | 34616727 |
| 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 |
| 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 |
| 2025 | Tetramethyl bisphenol F exposure induces human ovarian granulosa cell senescence and mouse ovarian damage by regulating ESRRB signalling. | Ecotoxicology and environmental safety | 5 | 40014986 |
| 2023 | Nilaparvata lugens ERR2 regulates moulting and ovary development is related to hormone signalling. | Insect molecular biology | 5 | 36861367 |
| 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 | 5 | 37222961 |
| 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 |
| 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 |
| 2025 | ERK phosphorylates ESRRB to regulate the self-renewal and differentiation of mouse embryonic stem cells. | Stem cell reports | 2 | 39919750 |
| 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 | Multi-omics analysis of early reperfused ischemic heart reveals ERRβ/γ activation protects against acute myocardial infarction injury. | Journal of advanced research | 1 | 41429340 |
| 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 | Calcium and Cadmium Activate ESRRB to Mediate Cell Stemness and Pluripotency. | International journal of molecular sciences | 0 | 41516107 |
No submissions yet.