Affinage

Showing HEY1 — CHF2 is a alias.

HEY1

Hairy/enhancer-of-split related with YRPW motif protein 1 · UniProt Q9Y5J3

Length
304 aa
Mass
32.6 kDa
Annotated
2026-06-10
100 papers in source corpus 37 papers cited in narrative 37 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

HEY1 is a bHLH-Orange transcriptional repressor that serves as a primary downstream effector of Notch signaling, established by functional RBP-Jkappa sites in its promoter that mediate up-regulation by all four mammalian Notch receptors (PMID:10964718). Beyond Notch, HEY1 is induced by BMP9/Alk1-Smad signaling (PMID:18986983, PMID:25799559), by HIF-1 via a hypoxia response element (PMID:31819034), and by FRA1 in c-Met/HGF signaling (PMID:27134167), integrating multiple developmental and stress inputs. It represses target genes both indirectly through GC-box/SP1-like factors at the VEGFR2 promoter (PMID:16782059) and by direct DNA binding to N-box and other promoter elements of COL2A1/AGGRECAN (PMID:18759300), myogenin and Mef2C (PMID:19917614), IDE (PMID:22036964), DAT1 (PMID:16998899), PINK1 (PMID:31819034), ACY1 (PMID:34002044), and SLC7A11 (PMID:40154588). HEY1 inhibits myogenesis by forming an inactive complex with MyoD and blocking MyoD recruitment to myogenic promoters (PMID:11279181, PMID:19917614), and antagonizes osteogenic and chondrogenic programs through interactions with Runx2 (PMID:15178686, PMID:18986983). Its repressor activity is governed by dimerization state: TRIM28-mediated SUMOylation promotes homodimer formation and DNA binding, whereas deSUMOylation drives HEY1-HES1 heterodimerization and loss of repression (PMID:38166414). Additional post-translational control includes STK38/STK38L phosphorylation at Ser-68, which stabilizes HEY1 but abolishes its enhancement of p53 activity (PMID:27129302), and ubiquitin-mediated degradation by MDM2 and by the KSHV RTA E3 ligase (PMID:19369342, PMID:27129302). In vivo, HEY1 acts redundantly with HEY2 and HeyL to control arterial identity and vascular remodeling (PMID:15107403, PMID:15680351), endocardial EMT for valve and septum formation (PMID:17303760), satellite cell quiescence (PMID:21989910, PMID:30745427), and neural stem cell maintenance (PMID:34772946). In mesenchymal chondrosarcoma, the recurrent HEY1-NCOA2 fusion binds canonical HEY1 target promoters but converts the protein into a transactivator that upregulates PDGFB/PDGFRA and AKT signaling and drives tumorigenesis via Runx2 (PMID:35342947, PMID:37212282).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 2000 High

    Established HEY1 as a direct, bona fide Notch target gene, defining the transcriptional logic that places it downstream of receptor activation.

    Evidence Promoter luciferase assays with activated Notch receptors and RBP-Jkappa site mutagenesis

    PMID:10964718

    Open questions at the time
    • Did not establish HEY1 downstream targets
    • Tested in transfection, not endogenous chromatin context
  2. 2000 High

    Identified the first functional output of HEY1 — repression of VEGFR2 and control of endothelial tube formation — connecting Notch to angiogenic gene control.

    Evidence Gain/loss-of-function in human endothelial cells with capillary tube formation assays

    PMID:11069914 PMID:12453432

    Open questions at the time
    • Direct vs indirect binding to VEGFR2 not resolved at this stage
  3. 2001 High

    Defined HEY1's mechanism in myogenesis as an inactive heterodimeric complex with MyoD, and mapped repression to a C-terminal region independent of bHLH/YRPW motifs.

    Evidence EMSA, co-IP, reporter assays and domain mutagenesis in myogenic conversion assays

    PMID:11279181

    Open questions at the time
    • Did not localize endogenous HEY1 to myogenic promoters (addressed in 2009)
  4. 2004 High

    Demonstrated that HEY1 and HEY2 are essential, redundant in vivo transducers of Notch in cardiovascular development, mediating arterial identity.

    Evidence Single and double knockout mice with arterial marker analysis

    PMID:15107403 PMID:15680351

    Open questions at the time
    • Direct transcriptional targets controlling arterial fate not defined
  5. 2004 Medium

    Extended HEY1's repressive role to osteoblast maturation through direct antagonism of Runx2 downstream of BMP2/Notch.

    Evidence siRNA knockdown with mineralization assays and reporter co-transfection

    PMID:15178686

    Open questions at the time
    • Mechanism of Runx2 inhibition (binding vs sequestration) not fully resolved
  6. 2006 High

    Resolved how HEY1 represses VEGFR2 — indirectly via GC-box/SP1-like proteins requiring an Inr element rather than direct E-box binding — refining the repression mechanism.

    Evidence Promoter deletion/mutation reporters, ChIP and domain mutagenesis in endothelial cells

    PMID:16782059

    Open questions at the time
    • Identity of the SP1-like partner not defined
  7. 2008 High

    Showed direct N-box promoter binding by HEY1 to repress chondrogenic genes COL2A1/AGGRECAN and linked BMP9-Smad induction to osteogenic vs chondrogenic fate choice.

    Evidence ChIP, reporter assays, mutagenesis and in vivo bone formation with Runx2 rescue

    PMID:18759300 PMID:18986983

    Open questions at the time
    • Switch between repressor and corepressor recruitment context-dependent and incompletely mapped
  8. 2009 High

    Demonstrated HEY1 occupies myogenin and Mef2C promoters and reduces MyoD recruitment, shifting the model from MyoD-targeting to promoter-level repression.

    Evidence ChIP for HEY1 and MyoD at endogenous promoters with reporter assays

    PMID:19917614

    Open questions at the time
    • Corepressor complexes recruited at these promoters not identified
  9. 2009 High

    Revealed regulated turnover of HEY1: the viral RTA E3 ligase ubiquitinates and degrades HEY1, disrupting a HEY1/mSin3A repressosome to permit lytic reactivation.

    Evidence Co-IP, ubiquitination assay, proteasome rescue, ChIP and siRNA

    PMID:19369342

    Open questions at the time
    • Cellular E3 ligases for HEY1 not defined here (MDM2 shown later)
  10. 2011 High

    Established HEY1/HeyL as essential for generating quiescent satellite cells, defining a stem-cell maintenance role distinct from differentiation block.

    Evidence Double knockout mice with Pax7/MyoD/Ki67 staining and regeneration assays

    PMID:21989910

    Open questions at the time
    • Direct quiescence target genes not yet defined at this stage
  11. 2016 High

    Uncovered post-translational regulation of HEY1's p53-modulating function via STK38/STK38L phosphorylation at Ser-68 and connected HEY1 to the MDM2-RPL11-p53 axis.

    Evidence MS site identification, phosphomutants, multiple co-IPs and functional readouts

    PMID:27129302

    Open questions at the time
    • Upstream signals controlling STK38/STK38L activity toward HEY1 unknown
  12. 2019 High

    Defined dimer-specific chromatin engagement: HeyL-Hes1 heterodimers bind shared sites with higher affinity than HeyL alone, showing combinatorial control of myogenic suppression.

    Evidence ChIP-seq, co-IP and conditional knockouts with promoter reporters

    PMID:30745427

    Open questions at the time
    • Quantitative genome-wide comparison of HEY1 vs HeyL site selection not resolved
  13. 2019 High

    Placed HEY1 in a hypoxia circuit (HIF-1 induction) that directly represses PINK1 to limit mitochondrial biogenesis and ROS in hepatocellular carcinoma.

    Evidence ChIP for HRE, ChIP-seq for PINK1 target, siRNA and reporter assays

    PMID:31819034

    Open questions at the time
    • Generality of HIF-1-HEY1-PINK1 axis beyond HCC untested
  14. 2024 High

    Identified TRIM28-mediated SUMOylation as the molecular switch governing HEY1 homodimerization, DNA binding, and repression, linking deSUMOylation to proangiogenic HEY1-HES1 heterodimer formation.

    Evidence MS site mapping, ChIP/EMSA/luciferase, dimerization co-IP and SUMO-deficient mutant in vivo vascular models

    PMID:38166414

    Open questions at the time
    • DeSUMOylase responsible for the proangiogenic switch not identified
  15. 2022 High

    Showed the oncogenic HEY1-NCOA2 fusion retains HEY1 promoter targeting but inverts its output to transactivation, upregulating PDGFB/PDGFRA and AKT signaling to drive proliferation.

    Evidence ChIP-seq and RNA-seq in iPSC-derived MSCs with inducible constructs plus proliferation and phospho-AKT readouts

    PMID:35342947 PMID:37212282

    Open questions at the time
    • How NCOA2 fusion recruits coactivators at HEY1 sites mechanistically incomplete

Open questions

Synthesis pass · forward-looking unresolved questions
  • How HEY1 dimerization state, SUMOylation/phosphorylation, and cofactor identity are coordinated to switch between repression and activation across tissues and disease remains unresolved.
  • DeSUMOylase and upstream kinase signals for the dimer switch unknown
  • Genome-wide direct target sets across cell types not unified
  • Mechanism converting fusion-bound promoters to active transcription incomplete

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 9 GO:0003677 DNA binding 6 GO:0098772 molecular function regulator activity 3
Localization
GO:0005634 nucleus 5 GO:0005730 nucleolus 1
Pathway
R-HSA-1266738 Developmental Biology 6 R-HSA-74160 Gene expression (Transcription) 6 R-HSA-162582 Signal Transduction 3 R-HSA-1643685 Disease 3
Partners
HES1ID4MDM2MYODRPL11RUNX2STK38TRIM28

Evidence

Reading pass · 37 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 HEY1 promoter contains two functional RBP-Jkappa binding sites that mediate transcriptional up-regulation by all four activated mammalian Notch receptors, establishing HEY1 as a direct Notch target gene. Cotransfection/promoter luciferase assay with activated Notch receptors; promoter cloning and characterization of RBP-Jkappa binding sites Biochemical and biophysical research communications High 10964718
2000 HESR1 (HEY1) overexpression in endothelial cells down-regulates VEGFR2 mRNA levels and blocks proliferation, migration, and capillary-like network formation; reduction by antisense oligonucleotides also blocks network formation, indicating a required role in endothelial tube formation. Overexpression and antisense knockdown in human endothelial cells; capillary tube formation assay in collagen gels; representational difference analysis to identify HESR1 as induced during network formation The Journal of biological chemistry High 11069914
2001 CHF2 (HEY1) functions as a transcriptional repressor of myogenesis by forming an inactive heterodimeric complex with MyoD; it inhibits MyoD.E47 binding to E-box sites and represses the myogenin promoter. Repression activity maps to a hydrophobic C-terminal region and does not require the bHLH or YRPW motifs. Cotransfection reporter assays; electrophoretic mobility shift assay (EMSA); coimmunoprecipitation; mutational analysis of CHF2 domains; myogenic conversion assay The Journal of biological chemistry High 11279181
2002 Notch signaling activation during endothelial cell network formation induces HESR1 (HEY1) expression and down-regulates VEGFR-2 (KDR); Notch-mediated reduction in VEGFR-2 results in decreased EC proliferation in response to VEGF but not bFGF. Constitutively active Notch 1 or 4 expression in endothelial cells; dominant-negative Notch; RT-PCR for HESR-1 and VEGFR-2; proliferation assays with VEGF vs bFGF Microvascular research Medium 12453432
2003 Hesr1/Hey1 misexpression in developing mouse brain transiently maintains neural precursor cells and increases late-born neurons; Hesr1 inhibits transcription induced by neuronal bHLH genes Mash1 and Math3 in transient transfection assays. In vivo electroporation misexpression in mouse embryonic brain; transient transfection reporter assay showing inhibition of Mash1/Math3-driven transcription The Journal of biological chemistry Medium 12947105
2003 BOIP, a novel protein, interacts specifically with the Orange domain of HRT1/Hey1; this interaction recruits BOIP to the nucleus, indicating the Orange domain mediates protein-protein interactions that regulate Hey1 activity. Yeast two-hybrid screen; subcellular localization by imaging; RNase protection analysis Developmental dynamics Low 14648848
2004 Combined loss of Hey1 and Hey2 causes embryonic lethality with global lack of vascular remodeling and failure of arterial identity (loss of CD44, neuropilin1, ephrin-B2 expression), demonstrating that Hey1/Hey2 are essential downstream transducers of Notch signals in cardiovascular development mediating arterial cell fate. Hey1 and Hey1/Hey2 double knockout mice; in vivo phenotypic analysis; expression analysis of arterial markers in Notch1 and Hey1/Hey2 knockout yolk sacs Genes & development High 15107403
2004 Hey1 completely abrogates Runx2 transcriptional activity via direct interaction; siRNA-mediated inhibition of Hey1 increases osteoblast matrix mineralization, establishing Hey1 as a negative regulator of osteoblast maturation downstream of BMP2-induced Notch signaling. siRNA knockdown of Hey1 in MC3T3 and C2C12 cells; cotransfection reporter assays showing Hey1 interaction with Runx2; osteoblast mineralization assay The Journal of biological chemistry Medium 15178686
2005 Hey1 functions as a corepressor for AF1 in the androgen receptor (AR), inhibiting transcription from androgen-dependent target genes; constitutively active Notch represses AR transactivation; Hey1 colocalizes with AR in prostatic epithelia but is excluded from the nucleus in most prostate cancers. Cotransfection reporter assays; colocalization by immunofluorescence in patient tissue; AR transactivation assays with Notch intracellular domain Molecular and cellular biology Medium 15684393
2005 Hesr1/Hey1 and hesr2/Hey2 double knockout mice recapitulate cardiovascular Notch loss-of-function phenotypes including arterial-venous specification defects, septation defects, and cushion formation defects, demonstrating functional redundancy in mediating Notch signaling in the cardiovascular system. Hesr1/Hesr2 double knockout mouse generation and in vivo phenotypic analysis; genetic epistasis Developmental biology High 15680351
2006 HESR1 (HEY1) represses VEGFR2 transcription in endothelial cells not by directly binding E-boxes but through interactions with GC-box-binding (SP1-like) proteins; the bHLH and Orange domains are sufficient for repression; the C-terminal YRPW motif is not required; repression requires an Inr element and is abolished by addition of a TATA box. Promoter deletion/mutation reporter assays in endothelial cells; ChIP; domain mutagenesis of HESR1 Biochemical and biophysical research communications High 16782059
2006 HESR1 (Hey1) directly binds to the 3' non-coding region of the human dopamine transporter (DAT1) gene and represses its endogenous expression in HEK293 cells; loss of Hesr1 in knockout mice leads to upregulation of DAT and multiple dopamine receptors. Direct binding assay to DAT1 3'UTR region; real-time RT-PCR in Hesr1 knockout mice Journal of neuroscience research Medium 16998899
2007 Combined inactivation of Hey1 and HeyL causes heart malformations including ventricular septal defects and dysplastic valves; atrioventricular explants show impaired epithelial-to-mesenchymal transition (EMT) with reduced MMP-2 expression, demonstrating that Hey1/HeyL control Notch-induced endocardial EMT essential for valve and septum formation. Hey1/HeyL double knockout mice; atrioventricular explant EMT assay; MMP-2 expression analysis; in vivo histology Circulation research High 17303760
2007 Hesr1 (Hey1) and Hesr2 suppress Tbx2 expression at the atrioventricular boundary; forced cardiac expression of Hesr1 reduces or eliminates AV canal with loss of Bmp2 and Tbx2 markers, demonstrating that Hey1/Hey2 directly suppress AV canal-specific gene expression including Tbx2. Forced cardiac expression of Hesr1 in transgenic mice; expression analysis of AV canal markers (Bmp2, Tbx2) by in situ hybridization and RT-PCR Development (Cambridge, England) Medium 17259303
2008 HEY-1 binds to N-box domains in intron 1 of COL2A1 (adjacent to the SOX9 enhancer binding site), repressing COL2A1 and AGGRECAN expression; this repression of chondrogenesis is reversed by TGFbeta3-mediated displacement of corepressor TLE from these sites. ChIP assay showing HEY-1 binding to COL2A1 N-box domains; overexpression reporter; qPCR for COL2A1/AGGRECAN; site-directed mutagenesis of N-box sites Arthritis and rheumatism High 18759300
2008 Hey1 is a direct target of BMP9-induced Smad signaling in mesenchymal stem cells; Hey1 and Runx2 act synergistically in BMP9-induced osteogenic differentiation, with Runx2 functioning downstream of Hey1; Hey1 knockdown diverts cells toward chondrogenic differentiation. ChIP analysis showing Hey1 as direct Smad target; siRNA knockdown; constitutive Hey1 expression; in vivo ectopic bone formation assay; Runx2 rescue of Hey1 knockdown The Journal of biological chemistry High 18986983
2009 Hey1 is recruited to the promoter regions of myogenin and Mef2C in myoblasts; Hey1 expression correlates with reduced MyoD recruitment to these promoters, indicating Hey1 inhibits myogenesis by associating with and repressing key myogenic target gene promoters rather than targeting MyoD's intrinsic transcriptional activity. ChIP assay showing Hey1 at myogenin and Mef2C promoters; ChIP for MyoD in Hey1-expressing cells; reporter assay for MyoD activity The Journal of biological chemistry High 19917614
2009 KSHV RTA E3 ubiquitin ligase interacts with Hey1, ubiquitinates it, and targets it for proteasomal degradation; Hey1 represses the RTA promoter and binds it in association with corepressor mSin3A; RTA-mediated degradation of Hey1 disrupts the Hey1/mSin3A repressosome and contributes to lytic reactivation. Co-immunoprecipitation; ubiquitination assay; proteasome inhibitor rescue; ChIP showing Hey1 and mSin3A at RTA promoter; siRNA knockdown Journal of virology High 19369342
2009 A naturally occurring Leu94Met polymorphism in HEY1 converts it from an AR corepressor to an AR co-activator without affecting intrinsic transcriptional repression; the polymorphism abolishes HEY1-mediated p53 activation, p53-dependent cell-cycle arrest, and chemosensitivity; specific HEY1 motifs control its subcellular localization. Reporter assays comparing WT vs Leu94Met HEY1; cell cycle analysis; drug sensitivity assay; subcellular localization studies with domain mutants Oncogene Medium 19802006
2011 Hesr1 (Hey1) and Hesr3 (HeyL) are co-expressed in satellite cells and are essential for generating undifferentiated quiescent satellite cells during postnatal development; double knockout leads to premature differentiation and age-dependent decline in satellite cell numbers. Hesr1/Hesr3 double knockout mice; immunostaining for Pax7, MyoD, myogenin, Ki67; in vitro satellite cell culture; muscle regeneration assay Development (Cambridge, England) High 21989910
2011 Hey1 (HES/HEY) binds to and represses the insulin-degrading enzyme (IDE) proximal promoter via two functional sites at -379/-372 and -310/-303; this repression promotes extracellular Aβ accumulation; site-directed mutagenesis of these sites reverses Notch-mediated IDE repression. Luciferase reporter assay; site-directed mutagenesis of IDE promoter; transfection of NICD and HEY-1; RT-PCR for IDE mRNA; intracranial injection of JAG-1 in transgenic mice Biochimica et biophysica acta Medium 22036964
2016 HEY1 Ser-68 phosphorylation by STK38 and STK38L stabilizes HEY1 protein but abolishes its ability to enhance p53 transcriptional activity, induce p53-dependent cell cycle arrest, and sensitize cells to chemotherapy; phosphomimetic HEY1-S68D fails to interact with p53, RPL11, and MDM2. HEY1 interacts with MDM2 and is subjected to MDM2-mediated degradation; HEY1 cooperates with RPL11 to inhibit MDM2-mediated p53 degradation. Ribosomal stress causes HEY1 relocalization to nucleolar caps. MALDI-TOF/TOF MS identification of phosphorylation site; phosphomimetic and phosphodeficient mutants; co-immunoprecipitation with STK38, STK38L, MDM2, RPL11, p53; reporter assay; cell cycle analysis; drug sensitivity assay; live imaging of HEY1 relocalization Bioscience reports High 27129302
2016 HEY1 is a direct downstream effector of FRA1 in the c-Met/HGF signaling pathway in liver tumor-initiating cells; CAF-derived HGF activates FRA1 via Erk1/2, which directly drives HEY1 expression to regulate tumor-initiating cell properties. siRNA knockdown of FRA1 and HEY1; chromatin immunoprecipitation; NASH-HCC mouse model; functional tumor-initiating cell assays Cell reports Medium 27134167
2019 Hey1 and HeyL function redundantly and cell-autonomously in muscle stem cells; HeyL forms heterodimeric complexes with Hes1 in living cells; ChIP-seq demonstrates that the HeyL-Hes1 heterodimer binds chromatin sites overlapping Hey1 binding sites with higher affinity than HeyL alone; HeyL and Hes1 act synergistically to suppress myogenic differentiation. Conditional and genetic null mouse models; ChIP-seq; co-IP of HeyL-Hes1 heterodimers; myogenin promoter reporter assay Development (Cambridge, England) High 30745427
2019 HIF-1 induces HEY1 expression via a hypoxia response element (HRE) in the HEY1 locus; HEY1 in turn directly represses PINK1 transcription, reducing mitochondrial biogenesis and ROS levels in HCC cells. ChIP assay identifying HRE in HEY1; transcriptome sequencing; ChIP-seq identifying PINK1 as HEY1 target; siRNA knockdown of HEY1; luciferase reporter assay Cell death & disease High 31819034
2019 BMP9 prevents OPN-type osteoblast differentiation by specifically inducing Hey1, which suppresses OPN expression; Id4 forms complexes with Hey1 to inhibit Hey1's suppressive effects on the Opn promoter; BMP9-induced overexpression of Hey1 overcomes Id4 inhibition. ChIP; immunoprecipitation showing Id4-Hey1 complex; site-directed mutagenesis of Opn promoter; reporter assay; JNK inhibition model The international journal of biochemistry & cell biology Medium 31550547
2021 In the adult mouse brain, Hey1 displays non-oscillatory stationary expression in slowly dividing neural stem-progenitor cells (NPCs), in contrast to the oscillatory expression of Hes1/Hes5 in fast-cycling progenitors; Notch and Hey1 form a module upregulated by cell cycle arrest that contributes to long-term NSC maintenance. Live imaging of Hey1 expression dynamics; genetic manipulation of cell cycle rate and Notch signaling; single-cell analysis of NSC subpopulations Nature communications Medium 34772946
2022 HEY1-NCOA2 fusion protein preferentially binds promoter regions of canonical HEY1 targets (ChIP-seq) but causes transactivation rather than repression of these targets; HEY1-NCOA2 directly targets and upregulates PDGFB and PDGFRA, dramatically increases phospho-AKT (Ser473), and significantly enhances cell proliferation compared to wild-type HEY1 or NCOA2 alone. ChIP-seq; RNA-seq in iPSC-derived MSCs with inducible HEY1-NCOA2, WT HEY1, or WT NCOA2; proliferation assay; Western blot for phospho-AKT The Journal of pathology High 35342947
2024 HEY1 is SUMOylated at conserved lysines by TRIM28 as the E3 SUMO ligase; SUMOylation facilitates HEY1 homodimer formation and preserves its DNA-binding capability at E-box promoter elements, maintaining its function as a repressive transcription factor controlling angiogenic RTKs and Notch pathway genes; proangiogenic stimuli induce HEY1 deSUMOylation, causing HEY1-HES1 heterodimerization and loss of DNA binding and repressive activity. Immunoprecipitation and mass spectrometry identifying SUMOylation sites; ChIP, dual luciferase, and EMSA for promoter binding; co-IP for dimerization; endothelial cell sprouting/migration/proliferation assays; mouse embryonic and postnatal vascular models with endothelial-specific WT or SUMOylation-deficient HEY1 Circulation research High 38166414
2009 Hey1 ubiquitous overexpression causes progressive osteopenia and inhibition of osteoblasts, and increased type X collagen expression with an enlarged hypertrophic zone in the growth plate; Hey1 deficiency causes modest osteopenia and increased osteoclast number/activity, demonstrating complex cell-type specific roles in osteoblasts, osteoclasts, and chondrocytes in vivo. Hey1 global knockout and ubiquitous transgenic overexpression mice; bone histomorphometry; ex vivo osteoclast and osteoblast assays Bone Medium 19857617
2014 Hey1 is required for TrkC-induced apoptosis as a direct interactor of TrkC intracellular domain; Hey1 and TrkC killer-fragment (TrkC-KF) transcriptionally silence MDM2 in the nucleus, contributing to p53 stabilization which then regulates pro-apoptotic factors COBRA1 and BAX. Co-immunoprecipitation identifying Hey1 as TrkC intracellular domain binding partner; nuclear co-localization; MDM2 promoter reporter assay; siRNA knockdown of Hey1; avian neuroblastoma model PLoS biology Medium 29750782
2023 HEY1-NCOA2 expression in embryonic superficial zone cells induces mesenchymal chondrosarcoma in mice; HEY1-NCOA2 binds active enhancers (ChIP-seq) and interacts with Runx2 via NCOA2 C-terminal domains; Runx2 knockdown delays tumor onset, suggesting HEY1-NCOA2 modulates chondrogenic transcription via Runx2 and Runx3. Mouse tumor model with subcutaneous transplantation; ChIP-seq; co-immunoprecipitation of HEY1-NCOA2 with Runx2; Runx2 knockout in tumor model; HDAC inhibitor treatment in vitro and in vivo JCI insight High 37212282
2022 Babam2 interacts with Hey1 to inhibit Nfatc1 transcription, thereby negatively regulating osteoclast formation; Hey1 silencing largely abolishes the inhibitory effects of Babam2 on osteoclastogenesis. Co-immunoprecipitation of Babam2-Hey1 interaction; Hey1 siRNA rescue experiment; Babam2 transgenic mice with bone density and osteoclast activity measurement International journal of biological sciences Medium 35864959
2015 In endothelial cells, BMP9 (via Alk1, not Notch/canonical gamma-secretase signaling) is the serum component responsible for Hey1 and Hey2 transcriptional induction; gamma-secretase inhibition or dominant-negative MAML1 does not prevent serum-induced Hey1 expression, but soluble Alk1 receptor abolishes it. Primary human endothelial cell treatment with serum; gamma-secretase inhibitor; dominant-negative MAML1 expression; soluble Alk1/Alk3 receptor pretreatment; BMP9 stimulation PloS one Medium 25799559
2020 HEY1 directly represses ACY1 gene transcription by binding the ACY1 promoter; lncRNA MAGI2-AS3 binds HEY1 protein and reduces its enrichment at the ACY1 promoter, thus increasing ACY1 expression and inhibiting angiogenesis in renal cell carcinoma. ChIP assay showing HEY1 binding at ACY1 promoter; RNA-binding protein immunoprecipitation (RIP) showing MAGI2-AS3 interaction with HEY1; luciferase reporter assay; siRNA knockdown; xenograft mouse model Cancer gene therapy Medium 34002044
2021 In zebrafish retina, hey1 and id2b are downstream Notch effector genes that differentially regulate Müller glia injury-response threshold and proliferation; epistasis experiments confirm the Dll4/Dlb-Notch3-Hey1/Id2b pathway regulates these processes. Genetic epistasis experiments; Notch inhibition with pathway component knockdown; retinal injury models in zebrafish; chromatin accessibility analysis Glia Medium 34415582
2025 HEY1 directly represses SLC7A11 transcription; EOGT knockdown downregulates HEY1, which in turn reduces SLC7A11 suppression, promoting ferroptosis in HCC cells. ChIP-seq and dual-luciferase reporter assay showing HEY1 binding at SLC7A11 promoter; siRNA knockdown; Western blot; xenograft model Cellular signalling Medium 40154588

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2004 The Notch target genes Hey1 and Hey2 are required for embryonic vascular development. Genes & development 541 15107403
2016 Cancer-Associated Fibroblasts Regulate Tumor-Initiating Cell Plasticity in Hepatocellular Carcinoma through c-Met/FRA1/HEY1 Signaling. Cell reports 275 27134167
2011 Identification of a novel, recurrent HEY1-NCOA2 fusion in mesenchymal chondrosarcoma based on a genome-wide screen of exon-level expression data. Genes, chromosomes & cancer 245 22034177
2000 Comparative analysis of the human and mouse Hey1 promoter: Hey genes are new Notch target genes. Biochemical and biophysical research communications 208 10964718
2004 Coordinated activation of notch, Wnt, and transforming growth factor-beta signaling pathways in bone morphogenic protein 2-induced osteogenesis. Notch target gene Hey1 inhibits mineralization and Runx2 transcriptional activity. The Journal of biological chemistry 190 15178686
2002 Notch activation during endothelial cell network formation in vitro targets the basic HLH transcription factor HESR-1 and downregulates VEGFR-2/KDR expression. Microvascular research 173 12453432
2019 Hypoxia regulates the mitochondrial activity of hepatocellular carcinoma cells through HIF/HEY1/PINK1 pathway. Cell death & disease 158 31819034
2008 Hey1 basic helix-loop-helix protein plays an important role in mediating BMP9-induced osteogenic differentiation of mesenchymal progenitor cells. The Journal of biological chemistry 156 18986983
2005 Mouse hesr1 and hesr2 genes are redundantly required to mediate Notch signaling in the developing cardiovascular system. Developmental biology 150 15680351
2007 Combined loss of Hey1 and HeyL causes congenital heart defects because of impaired epithelial to mesenchymal transition. Circulation research 144 17303760
2003 The basic helix-loop-helix genes Hesr1/Hey1 and Hesr2/Hey2 regulate maintenance of neural precursor cells in the brain. The Journal of biological chemistry 137 12947105
2007 Integrative genomic analyses on HES/HEY family: Notch-independent HES1, HES3 transcription in undifferentiated ES cells, and Notch-dependent HES1, HES5, HEY1, HEY2, HEYL transcription in fetal tissues, adult tissues, or cancer. International journal of oncology 134 17611704
2000 The basic helix-loop-helix transcription factor HESR1 regulates endothelial cell tube formation. The Journal of biological chemistry 128 11069914
2011 Hesr1 and Hesr3 are essential to generate undifferentiated quiescent satellite cells and to maintain satellite cell numbers. Development (Cambridge, England) 124 21989910
2005 Hey1, a mediator of notch signaling, is an androgen receptor corepressor. Molecular and cellular biology 115 15684393
2007 Hesr1 and Hesr2 regulate atrioventricular boundary formation in the developing heart through the repression of Tbx2. Development (Cambridge, England) 103 17259303
2008 Hesr1 and Hesr2 may act as early effectors of Notch signaling in the developing cochlea. Developmental biology 84 18291358
2009 The Notch effector Hey1 associates with myogenic target genes to repress myogenesis. The Journal of biological chemistry 78 19917614
2008 Repression of chondrogenesis through binding of notch signaling proteins HES-1 and HEY-1 to N-box domains in the COL2A1 enhancer site. Arthritis and rheumatism 77 18759300
2017 The NOTCH4-HEY1 Pathway Induces Epithelial-Mesenchymal Transition in Head and Neck Squamous Cell Carcinoma. Clinical cancer research : an official journal of the American Association for Cancer Research 76 29146722
2000 Characterization of the human and mouse HEY1, HEY2, and HEYL genes: cloning, mapping, and mutation screening of a new bHLH gene family. Genomics 69 10860664
2009 Kaposi's sarcoma-associated herpesvirus RTA promotes degradation of the Hey1 repressor protein through the ubiquitin proteasome pathway. Journal of virology 67 19369342
2008 A role for the transcription factor HEY1 in glioblastoma. Journal of cellular and molecular medicine 65 18363832
2001 Regulation of myogenic terminal differentiation by the hairy-related transcription factor CHF2. The Journal of biological chemistry 63 11279181
2009 Ubiquitous overexpression of Hey1 transcription factor leads to osteopenia and chondrocyte hypertrophy in bone. Bone 55 19857617
2014 Hey1 and Hey2 control the spatial and temporal pattern of mammalian auditory hair cell differentiation downstream of Hedgehog signaling. The Journal of neuroscience : the official journal of the Society for Neuroscience 49 25232121
2020 CAFs-derived MFAP5 promotes bladder cancer malignant behavior through NOTCH2/HEY1 signaling. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 46 32293074
2011 Inhibition of the Notch-Hey1 axis blocks embryonal rhabdomyosarcoma tumorigenesis. Clinical cancer research : an official journal of the American Association for Cancer Research 44 21948088
2019 Cell-autonomous and redundant roles of Hey1 and HeyL in muscle stem cells: HeyL requires Hes1 to bind diverse DNA sites. Development (Cambridge, England) 40 30745427
2021 Cell cycle arrest determines adult neural stem cell ontogeny by an embryonic Notch-nonoscillatory Hey1 module. Nature communications 39 34772946
2020 The NOTCH1-HEY1 pathway regulates self-renewal and epithelial-mesenchymal transition of salivary adenoid cystic carcinoma cells. International journal of biological sciences 39 32025208
2014 Latency-associated nuclear antigen of Kaposi sarcoma-associated herpesvirus promotes angiogenesis through targeting notch signaling effector Hey1. Cancer research 39 24523441
2021 Notch signaling via Hey1 and Id2b regulates Müller glia's regenerative response to retinal injury. Glia 38 34415582
2012 Detection of HEY1-NCOA2 fusion by fluorescence in-situ hybridization in formalin-fixed paraffin-embedded tissues as a possible diagnostic tool for mesenchymal chondrosarcoma. Pathology international 37 23252872
2011 Notch signaling proteins HES-1 and Hey-1 bind to insulin degrading enzyme (IDE) proximal promoter and repress its transcription and activity: implications for cellular Aβ metabolism. Biochimica et biophysica acta 37 22036964
2014 Chromosome aberrations and HEY1-NCOA2 fusion gene in a mesenchymal chondrosarcoma. Oncology reports 35 24839999
2015 Serum induces transcription of Hey1 and Hey2 genes by Alk1 but not Notch signaling in endothelial cells. PloS one 34 25799559
2006 HESR1/CHF2 suppresses VEGFR2 transcription independent of binding to E-boxes. Biochemical and biophysical research communications 33 16782059
2018 Nuclear Factor I Represses the Notch Effector HEY1 in Glioblastoma. Neoplasia (New York, N.Y.) 32 30195713
2014 Prostate tumor OVerexpressed-1 (PTOV1) down-regulates HES1 and HEY1 notch targets genes and promotes prostate cancer progression. Molecular cancer 32 24684754
2018 CCN3 and DLL1 co-regulate osteogenic differentiation of mouse embryonic fibroblasts in a Hey1-dependent manner. Cell death & disease 27 30538222
2015 Cyclic stretch enhances bone morphogenetic protein-2-induced osteoblastic differentiation through the inhibition of Hey1. International journal of molecular medicine 27 26647760
2017 Methylation regulates HEY1 expression in glioblastoma. Oncotarget 25 28574840
2004 her7 and hey1, but not lunatic fringe show dynamic expression during somitogenesis in medaka (Oryzias latipes). Gene expression patterns : GEP 24 15261833
2009 HEY1 Leu94Met gene polymorphism dramatically modifies its biological functions. Oncogene 23 19802006
2022 Genomic profiling identifies genes and pathways dysregulated by HEY1-NCOA2 fusion and shines a light on mesenchymal chondrosarcoma tumorigenesis. The Journal of pathology 22 35342947
2022 Mesenchymal chondrosarcoma of the head and neck with HEY1::NCOA2 fusion: A clinicopathologic and molecular study of 13 cases with emphasis on diagnostic pitfalls. Genes, chromosomes & cancer 22 35672279
2021 LncRNA MAGI2-AS3 inhibits tumor progression and angiogenesis by regulating ACY1 via interacting with transcription factor HEY1 in clear cell renal cell carcinoma. Cancer gene therapy 22 34002044
2006 Hesr1 knockout mice exhibit behavioral alterations through the dopaminergic nervous system. Journal of neuroscience research 22 16998899
2018 MiR-769 Inhibits Colorectal Cancer Cell Proliferation and Invasion by Targeting HEY1. Medical science monitor : international medical journal of experimental and clinical research 21 30565566
2010 Expression of the transcription factor HEY1 in glioblastoma: a preliminary clinical study. Tumori 21 20437865
2024 SUMOylation Fine-Tunes Endothelial HEY1 in the Regulation of Angiogenesis. Circulation research 20 38166414
2020 Long noncoding RNA LINC00982 upregulates CTSF expression to inhibit gastric cancer progression via the transcription factor HEY1. American journal of physiology. Gastrointestinal and liver physiology 20 33236952
2020 IMPAD1 functions as mitochondrial electron transport inhibitor that prevents ROS production and promotes lung cancer metastasis through the AMPK-Notch1-HEY1 pathway. Cancer letters 19 32417395
2016 HEY1 functions are regulated by its phosphorylation at Ser-68. Bioscience reports 19 27129302
2006 KSHV RTA induces a transcriptional repressor, HEY1 that represses rta promoter. Biochemical and biophysical research communications 18 16678790
2006 Protective effects of transcription factor HESR1 on retinal vasculature. Microvascular research 18 17028039
2003 Identification of BOIP, a novel cDNA highly expressed during spermatogenesis that encodes a protein interacting with the orange domain of the hairy-related transcription factor HRT1/Hey1 in Xenopus and mouse. Developmental dynamics : an official publication of the American Association of Anatomists 17 14648848
2023 HEY1-NCOA2 expression modulates chondrogenic differentiation and induces mesenchymal chondrosarcoma in mice. JCI insight 16 37212282
2016 Expression of activated Notch1 and Hey1 in papillary thyroid carcinoma. Histopathology 15 27542980
2020 Lidocaine Suppresses Cell Proliferation and Aerobic Glycolysis by Regulating circHOMER1/miR-138-5p/HEY1 Axis in Colorectal Cancer. Cancer management and research 14 32612388
2018 Hey1- and p53-dependent TrkC proapoptotic activity controls neuroblastoma growth. PLoS biology 14 29750782
2002 Isolation and characterization of Xenopus Hey-1: a downstream mediator of Notch signaling. Developmental dynamics : an official publication of the American Association of Anatomists 14 12454931
2017 LDB2 inhibits proliferation and migration in liver cancer cells by abrogating HEY1 expression. Oncotarget 13 29212240
2015 Pharyngeal arch artery defects and lethal malformations of the aortic arch and its branches in mice deficient for the Hrt1/Hey1 transcription factor. Mechanisms of development 13 26577899
2008 Cyclosporine inhibition of angiogenesis involves the transcription factor HESR1. The Journal of surgical research 13 18694572
2022 Babam2 negatively regulates osteoclastogenesis by interacting with Hey1 to inhibit Nfatc1 transcription. International journal of biological sciences 12 35864959
2014 Primary spinal intradural mesenchymal chondrosarcoma with detection of fusion gene HEY1-NCOA2: A paediatric case report and review of the literature. Oncology letters 12 25202377
2012 Theoretical studies on the kinetics and mechanism of the gas-phase reactions of CHF(2)OCHF (2) with OH radicals. Journal of molecular modeling 12 22562169
2020 Importance of endothelial Hey1 expression for thoracic great vessel development and its distal enhancer for Notch-dependent endothelial transcription. The Journal of biological chemistry 11 33454003
2019 Design, synthesis and SAR study of 3rd-generation taxoids bearing 3-CH3, 3-CF3O and 3-CHF2O groups at the C2-benzoate position. Bioorganic chemistry 11 31911305
2016 Pancreatic involvement by mesenchymal chondrosarcoma harboring the HEY1-NCOA2 gene fusion. Human pathology 11 27544802
2021 Hey1 promotes migration and invasion of melanoma cells via GRB2/PI3K/AKT signaling cascade. Journal of Cancer 10 34729100
2020 Reciprocal activation of HEY1 and NOTCH4 under SOX2 control promotes EMT in head and neck squamous cell carcinoma. International journal of oncology 10 33491747
2019 Primary mesenchymal chondrosarcoma of the kidney without HEY1-NCOA2 and IRF2BP2-CDX1 fusion: A case report and review. Oncology letters 10 31897203
2014 Mesenchymal chondrosarcoma diagnosed on FISH for HEY1-NCOA2 fusion gene. Pediatrics international : official journal of the Japan Pediatric Society 10 25336010
2022 Transcription Factor HEY1 Improves Brain Vascular Endothelial Cell Function and Alleviates Ischemic Stroke by Upregulating NOTCH3. Neurochemical research 9 35316462
2019 BMP9 prevents induction of osteopontin in JNK-inactivated osteoblasts via Hey1-Id4 interaction. The international journal of biochemistry & cell biology 9 31550547
2015 The Anti-Adipogenic Potential of COUP-TFII Is Mediated by Downregulation of the Notch Target Gene Hey1. PloS one 9 26719988
2024 Atomoxetine suppresses radioresistance in glioblastoma via circATIC/miR-520d-5p/Notch2-Hey1 axis. Cell communication and signaling : CCS 8 39501373
2022 HEY1-mediated cisplatin resistance in lung adenocarcinoma via epithelial-mesenchymal transition. Medical oncology (Northwood, London, England) 8 36396748
2020 Consecutive Hypoxia Decreases Expression of NOTCH3, HEY1, CC10, and FOXJ1 via NKX2-1 Downregulation and Intermittent Hypoxia-Reoxygenation Increases Expression of BMP4, NOTCH1, MKI67, OCT4, and MUC5AC via HIF1A Upregulation in Human Bronchial Epithelial Cells. Frontiers in cell and developmental biology 8 33015064
2017 Hey1 functions as a positive regulator of odontogenic differentiation in odontoblast‑lineage cells. International journal of molecular medicine 8 29138798
2021 8q21.11 microdeletion syndrome: Delineation of HEY1 as a candidate gene in neurodevelopmental and cardiac defects. Molecular genetics & genomic medicine 7 34549899
2021 Patient-derived xenografts and in vitro model show rationale for imatinib mesylate repurposing in HEY1-NCoA2-driven mesenchymal chondrosarcoma. Laboratory investigation; a journal of technical methods and pathology 7 34837064
2017 Hey1 and Hey2 are differently expressed during mouse tooth development. Gene expression patterns : GEP 7 29155305
2018 Minute mesenchymal chondrosarcoma within osteochondroma: an unexpected diagnosis confirmed by HEY1-NCOA2 fusion. Human pathology 6 29596896
2013 Enhanced prepulse inhibition and low sensitivity to a dopamine agonist in HESR1 knockout mice. Journal of neuroscience research 6 24431082
2022 HOCI Probe CPP Induces the Differentiation of Human Dermal Fibroblasts into Vascular Endothelial Cells through PHD2/HIF-1α/HEY1 Signaling Pathway. Cells 5 36231088
2020 Intracranial Mesenchymal Chondrosarcoma Lacking the Typical Histopathological Features Diagnosed by HEY1-NCOA2 Gene Fusion. NMC case report journal 5 32322450
2017 Role of Jagged1-Hey1 Signal in Angiotensin II-induced Impairment of Myocardial Angiogenesis. Chinese medical journal 5 28139517
2015 Qingyihuaji Formula Inhibits Pancreatic Cancer and Prolongs Survival by Downregulating Hes-1 and Hey-1. Evidence-based complementary and alternative medicine : eCAM 5 26783407
2025 EOGT knockdown promotes ferroptosis and inhibits hepatocellular carcinoma proliferation by regulating SLC7A11 via HEY1. Cellular signalling 4 40154588
2023 Sox9 Inhibits Cochlear Hair Cell Fate by Upregulating Hey1 and HeyL Antagonists of Atoh1. Cells 4 37681879
2016 Reinvestigation of the Unimolecular Reactions of CHF2CHF2: Identification of the 1,1-HF Elimination Component from Addition of :CFCHF2 to trans-2-Butene. The journal of physical chemistry. A 4 27798960
2025 Pediatric mesenchymal chondrosarcoma with archetypal histology in the absence of HEY1::NCOA2 gene fusion: a molecular-morphological paradox. Oral oncology 3 40614571
2023 Inhibition of Pi4kb activity causes malformation of vestibular apparatus in zebrafish by downregulating hey1. Gene 3 38135256
2025 Orbital mesenchymal chondrosarcoma and its specific fusion gene HEY1-NCOA2. BMC ophthalmology 2 40301759
2024 Inhibition of Notch3/Hey1 ameliorates peribiliary hypoxia by preventing hypertrophic hepatic arteriopathy in biliary atresia progression. Histochemistry and cell biology 2 38597939
2024 Dibenzazepine, a γ-Secretase Enzyme Inhibitor, Protects Against Doxorubicin-Induced Cardiotoxicity by Suppressing NF-κB, iNOS, and Hes1/Hey1 Expression. Inflammation 2 39078585

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