Affinage

HEY2

Hairy/enhancer-of-split related with YRPW motif protein 2 · UniProt Q9UBP5

Length
337 aa
Mass
35.8 kDa
Annotated
2026-04-28
75 papers in source corpus 36 papers cited in narrative 35 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

HEY2 is a bHLH transcriptional repressor that serves as a central effector of Notch, FGF, BMP/Alk1, and Hedgehog signaling in cardiovascular development, neural progenitor maintenance, and cochlear cell fate determination. It represses target gene transcription by binding E-box elements and recruiting HDAC1 to promoters of metabolic genes (PGC-1α, CPT1) and ion channel genes (KCNIP2, SCN5A), and it antagonizes the transcriptional activities of GATA4, GATA-6, SRF/myocardin, and Smad3/Smad4 through direct protein–protein interactions, thereby suppressing cardiac hypertrophy, vascular smooth muscle dedifferentiation, and TGF-β signaling (PMID:16603706, PMID:16293227, PMID:39747914, PMID:31396342, PMID:28637782). In the developing heart, Hey2 maintains ventricular chamber identity by suppressing Tbx2 to sustain cardiomyocyte proliferation and regulates atrioventricular canal boundary formation, ventricular septation, and conduction system patterning; its loss causes ventricular septal defects, tetralogy of Fallot, right ventricular hypoplasia, and cardiomyopathy (PMID:12454287, PMID:17259303, PMID:33410138, PMID:24687990). Germline loss-of-function variants in HEY2 cause congenital heart defects including tetralogy of Fallot and thoracic aortic aneurysms in humans (PMID:32820247, PMID:40481234).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 2001 High

    How Hey2 is activated was unknown; demonstration that Notch intracellular domain directly induces HEY2 transcription through RBP-Jκ-dependent promoter activation — even without de novo protein synthesis — established HEY2 as a primary transcriptional target of Notch signaling.

    Evidence Promoter-reporter assays, cycloheximide treatment, RBP-Jκ-deficient cell rescue in smooth muscle cells

    PMID:11741889

    Open questions at the time
    • Whether other pathways independently activate Hey2 was not addressed
    • Chromatin-level regulation of the Hey2 locus not examined
  2. 2002 High

    The in vivo requirement of Hey2 was uncertain; targeted disruption in mice revealed ventricular septal defects, tetralogy of Fallot, tricuspid atresia, and adult cardiomyopathy, establishing Hey2 as essential for cardiac septation and myocardial function.

    Evidence Mouse knockout, histology, echocardiography across multiple independent labs

    PMID:12372253 PMID:12372254 PMID:12454287

    Open questions at the time
    • Whether Hey2 acts cell-autonomously in cardiomyocytes versus other cardiac cell types was unresolved
    • Direct transcriptional targets in heart unknown
  3. 2003 Medium

    The mechanism of Hey2-mediated repression was unclear; discovery that SIRT1 physically associates with HEY2 and participates in its repressive activity revealed that deacetylase recruitment is a key component of Hey2 transcriptional repression.

    Evidence Co-immunoprecipitation (in vitro and in vivo), reporter assays with deacetylase inhibitors

    PMID:12535671

    Open questions at the time
    • Relative contribution of SIRT1-dependent vs. SIRT1-independent deacetylation not quantified
    • No genome-wide target identification
  4. 2004 High

    Whether Hey genes mediate Notch-dependent arterial identity was unknown; combined Hey1/Hey2 knockout recapitulated Notch1/Jagged1 vascular phenotypes with loss of arterial markers (ephrin-B2, neuropilin1), establishing Hey1/Hey2 as essential Notch effectors for arterial-venous specification.

    Evidence Hey1/Hey2 double KO mice, genetic epistasis with Notch1 and Jagged1 knockouts, arterial marker in situ hybridization

    PMID:15107403

    Open questions at the time
    • Whether Hey2 directly represses venous genes or activates arterial genes was not distinguished
    • Endothelial cell-autonomous requirement not tested with conditional KO
  5. 2005 High

    How Hey2 suppresses smooth muscle differentiation was mechanistically unclear; demonstration that HEY2 physically binds SRF and blocks SRF-CArG box interaction revealed a direct protein–protein interference mechanism inhibiting myocardin-induced VSMC gene activation.

    Evidence Co-immunoprecipitation, EMSA, reporter assays in 10T1/2 cells

    PMID:16151017

    Open questions at the time
    • Whether this mechanism operates in vivo during vascular development was not shown
    • Which Hey2 domain mediates SRF interaction was not mapped
  6. 2006 High

    Whether Hey2 modulates cardiac hypertrophy was unknown; transgenic overexpression of Hey2 suppressed phenylephrine-induced hypertrophy by directly binding GATA4 and blocking its DNA binding at hypertrophy gene promoters (ANF, BNP, β-MHC).

    Evidence Transgenic mouse, neonatal myocyte assays, co-immunoprecipitation, reporter assays

    PMID:16603706

    Open questions at the time
    • Whether endogenous Hey2 loss enhances hypertrophy in vivo was not tested
    • Interaction with other GATA family members (GATA-6) in hypertrophy context not explored in this study
  7. 2007 High

    How the AV canal boundary is established was poorly understood; forced Hey2 expression throughout the heart eliminated the AV canal by suppressing Tbx2 and Bmp2, defining Hey2 as a chamber-specific repressor of AV canal identity independent of Notch2.

    Evidence Transgenic misexpression mice, in situ hybridization, Notch2 epistasis

    PMID:17259303

    Open questions at the time
    • Whether Hey2 directly binds the Tbx2 promoter was not shown
    • Whether Hey2 repression of Tbx2 is sufficient or requires cofactors was not addressed
  8. 2008 High

    The upstream transcription factor network controlling Hey2 in endothelial cells was incompletely mapped; Foxc2 was shown to directly bind the Hey2 promoter and cooperate with the Notch transcriptional complex to activate Hey2 expression, integrating VEGF-PI3K/ERK signaling into Hey2 regulation.

    Evidence ChIP, EMSA, promoter-reporter assays, co-immunoprecipitation in endothelial cells

    PMID:18545664

    Open questions at the time
    • Whether Foxc2 is required for Hey2 expression in vivo was not tested
    • Relative contribution of Foxc2 versus RBP-Jκ at the endogenous locus unknown
  9. 2009 High

    Whether Hey2 functions independently of Notch was uncertain in non-vascular contexts; in the cochlea, FGF signaling maintains Hey2 expression in pillar cells independently of Notch, and Hey2 loss sensitizes these cells to Notch inhibition, revealing a Notch-independent FGF–Hey2 axis in auditory cell fate.

    Evidence Mouse knockout, cochlear explant cultures with Notch inhibitor and FGF treatment

    PMID:19154718

    Open questions at the time
    • Whether FGF directly activates Hey2 transcription or acts through intermediary factors was not resolved
    • Whether other Hey family members compensate in cochlea was not fully explored
  10. 2014 High

    Hey2's role in cardiac electrophysiology was unknown; conditional myocardial deletion revealed 50–75% reduction in SCN5A, KCNJ2, and CACNA1C expression with reduced action potential upstroke velocity and conduction system expansion, establishing Hey2 as a transcriptional regulator of cardiac ion channel gene expression.

    Evidence Myocardial-specific conditional KO, patch clamp, qRT-PCR, CCS-LacZ reporter

    PMID:24687990

    Open questions at the time
    • Whether Hey2 directly binds ion channel gene promoters was not shown
    • Whether ion channel phenotype contributes to arrhythmia susceptibility in humans was not tested
  11. 2017 High

    The mechanism behind transmural electrophysiological heterogeneity in the ventricle was unclear; Hey2 haploinsufficiency in mice reduced subepicardial KCNIP2/Ito expression, and human eQTL analysis linked the HEY2 Brugada syndrome risk locus to HEY2–KCNIP2 coexpression, identifying a HEY2→KCNIP2 axis controlling transmural Ito gradient and Brugada syndrome susceptibility.

    Evidence Hey2+/− mice, subepicardial/subendocardial patch clamp, human left ventricular eQTL, genome-wide coexpression analysis

    PMID:28637782

    Open questions at the time
    • Whether HEY2 directly binds the KCNIP2 regulatory region was not demonstrated
    • Functional rescue of Brugada phenotype by KCNIP2 restoration not tested
  12. 2020 High

    Cis-regulatory logic controlling ventricular Hey2 expression was undefined; a conserved distal enhancer requiring T-box (Tbx20) and GATA binding sites — but not NK-2 sites — was identified, revealing Tbx20/GATA as upstream activators at the chromatin level.

    Evidence CRISPR enhancer deletion in mice, site-directed mutagenesis, Tbx20 null mice, in vivo reporter assays

    PMID:32035085

    Open questions at the time
    • Whether additional enhancers control Hey2 expression in other cardiac compartments was not addressed
    • 3D chromatin architecture at the Hey2 locus not characterized in this study
  13. 2020 Medium

    Whether HEY2 variants cause human congenital heart disease was unresolved; germline loss-of-function variants disrupting HEY2 repressor activity were identified in patients with congenital heart defects and thoracic aortic aneurysms, establishing HEY2 as a human disease gene.

    Evidence Genome sequencing, gene-based association (MetaSKAT), reporter assay for functional variant assessment

    PMID:32820247

    Open questions at the time
    • Small cohort size limits genotype–phenotype correlation
    • No animal model rescue of specific human variants performed
    • Mechanism by which loss of HEY2 causes aortic aneurysm not addressed
  14. 2021 High

    How Hey2 controls right ventricular growth was mechanistically unknown; conditional RV-specific deletion showed ectopic Tbx2 induction leading to Mycn downregulation and reduced cardiomyocyte proliferation, defining a Hey2⊣Tbx2⊣Mycn pathway governing RV expansion.

    Evidence Mef2c-AHF-Cre conditional KO, RNA-seq, BrdU incorporation, in situ hybridization

    PMID:33410138

    Open questions at the time
    • Whether Hey2 directly binds the Tbx2 locus or acts indirectly was not resolved
    • Whether the same pathway operates in left ventricle was not tested
  15. 2025 High

    The chromatin mechanism of Hey2-mediated metabolic gene repression was unknown; genome-wide ChIP-seq revealed HEY2 occupancy at PGC-1α, ESRRA, and CPT1 promoters with colocalized HDAC1, mediating histone deacetylation and repression of mitochondrial oxidation genes; this causes impaired respiration, elevated ROS, and cardiomyocyte apoptosis, rescued by PPARGC1A/ESRRA restoration.

    Evidence ChIP-seq, ATAC-seq, Hi-C, CUT&RUN, conditional KO and overexpression in zebrafish and mouse, mitochondrial respiration assays, doxorubicin injury model

    PMID:39747914

    Open questions at the time
    • Whether HDAC1 recruitment is sufficient or whether SIRT1 also participates at metabolic gene loci was not tested
    • Whether metabolic reprogramming contributes to the cardiac phenotypes of Hey2 KO mice was not directly addressed

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: whether HEY2 directly binds the promoters of Tbx2, KCNIP2, and SCN5A or acts through intermediary factors; the structural basis for HEY2 selectivity among its diverse protein partners (GATA4, SRF, Smad3); and whether HEY2 metabolic target repression contributes to congenital heart disease pathogenesis in humans.
  • No crystal or cryo-EM structure of HEY2 or its complexes
  • Direct binding at Tbx2, KCNIP2, SCN5A loci not demonstrated by ChIP
  • Genotype–phenotype correlations in humans limited by small cohort sizes

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 11 GO:0003677 DNA binding 2
Localization
GO:0005634 nucleus 3
Pathway
R-HSA-1266738 Developmental Biology 9 R-HSA-162582 Signal Transduction 7 R-HSA-74160 Gene expression (Transcription) 7 R-HSA-1430728 Metabolism 1 R-HSA-4839726 Chromatin organization 1
Partners
GATA4GATA6HDAC1HEY1SIRT1SMAD3SMAD4SRF

Evidence

Reading pass · 35 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2004 Hey1 and Hey2 are essential downstream transducers of Notch signaling in cardiovascular development; combined loss of Hey1 and Hey2 in mice causes embryonic lethality with global failure of vascular remodeling, and remaining arteries fail to express arterial endothelial markers CD44, neuropilin1, and ephrin-B2, establishing Hey1/Hey2 as mediators of arterial cell fate decision downstream of Notch1/Jagged1 signaling. Mouse knockout (Hey1-/-, Hey2-/-, Hey1/Hey2 double KO), genetic epistasis with Notch1 and Jagged1 knockouts, in situ hybridization for arterial markers Genes & development High 15107403
2002 Hey2 (gridlock ortholog) is required for cardiac morphogenesis; targeted disruption in mice produces ventricular septal defects, tetralogy of Fallot, and tricuspid atresia, establishing Hey2 as an important regulator of cardiac septation and morphogenesis downstream of the Notch/JAG1 pathway. Gene targeting (mouse knockout), histological and morphological analysis Current biology : CB High 12372253 12372254 12454287
2002 Loss of Hey2 (CHF1) in mice causes ventricular septal defects and cardiomyopathy, with surviving adult animals developing impaired myocardial contractility, demonstrating CHF1/Hey2 plays a role in regulation of ventricular septation and normal myocardial function. Targeted gene disruption (mouse KO), histology, echocardiography, survival analysis Proceedings of the National Academy of Sciences of the United States of America High 12454287
2003 SIRT1 physically associates with HEY2 (and HES1) both in vitro and in vivo, and both SIRT1-dependent and SIRT1-independent deacetylase pathways are involved in HEY2-mediated transcriptional repression, demonstrating that the bHLH repressor–Sir2 interaction is conserved from Drosophila to humans. Co-immunoprecipitation (in vitro and in vivo), reporter/transfection assays with deacetylase inhibitors Biochemical and biophysical research communications Medium 12535671
2003 Misexpression of Hesr2/Hey2 in mouse brain transiently maintains neural precursor cells, inhibits transcription induced by neuronal bHLH genes Mash1 and Math3 (in transfection assay), and promotes maintenance of neural progenitors, thereby increasing late-born neurons and subsequently astroglial cells. In utero electroporation (misexpression), transient transfection reporter assays, in situ hybridization The Journal of biological chemistry Medium 12947105
2001 HERP1/HEY2 is a direct primary target gene of Notch signaling in A10 smooth muscle cells: Notch intracellular domain (NICD) activates the HERP1 promoter in an RBP-Jκ-dependent manner, induces endogenous HERP1 mRNA and protein even without de novo protein synthesis, and RBP-Jκ is required for induction. Promoter-reporter assays, co-culture with Notch ligand-expressing cells, cycloheximide treatment, RBP-Jκ-deficient cell rescue experiments, RT-PCR The Journal of biological chemistry High 11741889
2005 HERP1/HEY2 inhibits myocardin-induced vascular smooth muscle cell differentiation by physically interacting with SRF and interfering with SRF binding to CArG-box elements in SMC marker gene promoters. Co-immunoprecipitation, EMSA (electrophoretic mobility shift assay), reporter assays, overexpression in 10T1/2 cells, immunohistochemistry Arteriosclerosis, thrombosis, and vascular biology High 16151017
2004 CHF1/Hey2 deficiency in mice reduces neointima formation after arterial wire injury and impairs VSMC proliferation and PDGF/HB-EGF-induced migration, correlating with decreased Rac1 GTPase activation and reduced levels of the Rac GEF Sos1. Mouse KO, wire injury model, in vitro VSMC migration/proliferation assays, Rac1 activation assay, western blot for Sos1 Arteriosclerosis, thrombosis, and vascular biology High 15345511
2005 Hey1/Hey2 proteins directly homo- and heterodimerize with each other and with other hairy-related bHLH proteins (c-hairy1), as shown by in vitro and in vivo interaction assays, suggesting combinatorial action in the segmentation clock and somite patterning. In vitro and in vivo interaction assays (co-immunoprecipitation/pull-down), in situ hybridization in Dll1 and Notch1 knockout mice Developmental biology Medium 11076679
2006 CHF1/Hey2 overexpression in transgenic mouse myocardium suppresses phenylephrine-induced cardiac hypertrophy; mechanistically, CHF1/Hey2 directly binds GATA4 (by co-immunoprecipitation), inhibits GATA4 binding to its recognition sequence in the ANF promoter, and suppresses GATA4-dependent induction of hypertrophy marker genes (ANF, BNP, β-MHC). Transgenic mouse overexpression, isolated neonatal myocyte assays, co-immunoprecipitation, reporter assays with GATA4 American journal of physiology. Heart and circulatory physiology High 16603706
2005 CHF1/Hey2 suppresses GATA-6-dependent smooth-muscle myosin heavy chain (SM-MHC) promoter activity through direct physical interaction with GATA-6 (co-immunoprecipitation); the bHLH domain of CHF1/Hey2 is required for this transcriptional repression. Co-immunoprecipitation, cotransfection reporter assays, bHLH domain mutational analysis Biochemical and biophysical research communications Medium 16293227
2008 Foxc2 directly activates the Hey2 promoter via conserved Foxc binding elements; Foxc2 physically and functionally interacts with the Notch transcriptional activation complex (Su(H)/NICD) to induce Hey2 promoter activity; VEGF-activated PI3K and ERK pathways modulate Foxc transcriptional activity in Hey2 induction. Promoter-reporter assays, co-immunoprecipitation, chromatin immunoprecipitation (ChIP), EMSA, endothelial cell transfection PloS one High 18545664
2006 Hypoxia induces Dll4 and Hey2 expression via HIF-1α; Hey2 in endothelial progenitor cells represses COUP-TFII (venous identity regulator), promoting arterial cell fate; Hey factors in turn repress HIF-1α-induced gene expression, creating a negative feedback loop in the Dll4-Notch-Hey2 signaling cascade. Hypoxia treatment of cell lines, promoter analysis (HIF-1α binding sites), co-culture/overexpression experiments, quantitative RT-PCR Experimental cell research Medium 17045587
2007 Forced expression of Hesr2/Hey2 throughout the cardiac lineage in mice suppresses Tbx2 and Bmp2 expression and eliminates the atrioventricular (AV) canal, demonstrating that Hey2 directly suppresses Tbx2 to regulate AV boundary formation; this regulation is independent of Notch2 signaling. Myocardial misexpression transgenic mice, in situ hybridization, genetic epistasis Development (Cambridge, England) High 17259303
2005 Combined knockout of Hesr1 and Hesr2/Hey2 in mice is embryonic lethal at E11.5 and recapitulates most cardiovascular phenotypes of disrupted Notch pathway mutants (arterial-venous specification defects, septation, cushion formation), demonstrating functional redundancy between Hey1 and Hey2 as downstream effectors of Notch signaling in cardiovascular development. Mouse double knockout, in situ hybridization, histological analysis, genetic epistasis Developmental biology High 15680351
2009 Hey2 expression in cochlear pillar cells is maintained by FGF signaling independently of Notch; Hey2 blocks hair cell differentiation, and mutation of Hey2 makes pillar cells sensitive to loss of Notch signaling allowing them to differentiate as hair cells, placing Hey2 downstream of FGF but independent of Notch in pillar cell fate maintenance. Mouse knockout, Notch inhibitor treatment, FGF treatment, cochlear explant cultures, cell fate tracing Developmental cell High 19154718
2010 TAp73 promotes long-term neural stem cell maintenance by transcriptionally regulating Hey2; Hey2 downstream of TAp73 prevents premature differentiation of neural precursors, establishing a TAp73→Hey2 transcriptional axis in adult neurogenesis. Mouse KO (TAp73), neural stem cell isolation, overexpression/knockdown of Hey2, BrdU incorporation, differentiation assays Current biology : CB Medium 21074438
2010 In zebrafish, Hey2 is required upstream of Notch for hematopoietic stem cell (HSC) formation in the dorsal aorta; Hey2 expression is induced downstream of cloche/Scl and maintained by Hedgehog and VEGF signaling; knockdown of Hey2 reduces Notch receptor expression in aortic angioblasts, and Notch activation rescues HSC formation in hey2 morphants. Zebrafish morpholino knockdown, Notch activation (genetic rescue), in situ hybridization, epistasis analysis Blood High 20511544
2011 CHF1/Hey2 regulates MMP10 expression through multiple E-box elements in the MMP10 promoter; loss/knockdown of CHF1/Hey2 increases MMP10 expression and activity in VSMCs; mutation of E-boxes abolishes repression and unmasks an activator function for CHF1/Hey2. KO/siRNA knockdown, promoter-reporter assays, E-box mutagenesis, MMP10 activity assays Biochemical and biophysical research communications Medium 22079635
2012 Conditional myocardial knockout of CHF1/Hey2 causes abnormalities in calcium handling after pressure overload, mediated by increased FKBP12.6 expression; treatment with FK506 (which inhibits FKBP12.6 association with ryanodine receptor) restored contractile function in KO cardiomyocytes, linking CHF1/Hey2 to EC coupling via FKBP12.6. Conditional myocardial KO mice, aortic banding, isolated cardiomyocyte calcium transient measurements, FK506 pharmacological rescue, quantitative RT-PCR American journal of physiology. Heart and circulatory physiology High 22408025
2013 Hey2 regulates bone remodeling: conditional osteoblast-specific Hey2 deletion increases trabecular bone volume and suppresses alkaline phosphatase (ALPL) activity; Hey2 transgenic overexpression in osteoblasts decreases osteoblast activity, increases bone resorption, and induces IL-6 (promoting osteoclastogenesis) in a sex-dependent manner. Conditional KO (Osx-Cre and Oc-Cre), transgenic overexpression, bone histomorphometry, ALPL activity assays, osteoclastogenesis co-culture assay The Journal of biological chemistry Medium 23782701
2013 COUP-TFII directly binds the Hey2 promoter and downregulates Hey2 expression in arterial endothelial cells, as shown by ChIP, EMSA, and promoter analysis; Hey2 in turn regulates EphrinB2 expression downstream, placing Hey2 as part of the COUP-TFII→Hey2→EphrinB2 arteriovenous specification hierarchy. ChIP, EMSA, promoter analysis, lentiviral overexpression/shRNA knockdown in human endothelial cells, qRT-PCR Basic research in cardiology Medium 23744056
2014 Conditional double knockout of Hey1 and Hey2 in prosensory cochlear cells causes premature upregulation of the pro-hair cell factor Atoh1 and premature hair cell differentiation, establishing Hey1/Hey2 as suppressors of Atoh1 in cochlear progenitor maintenance; this prosensory expression and its graded downregulation is controlled by Hedgehog signaling in a largely FGFR-dependent manner. Conditional double knockout (Hey1/Hey2), in situ hybridization, immunofluorescence, FGFR pharmacological inhibition The Journal of neuroscience : the official journal of the Society for Neuroscience High 25232121
2014 Myocardial-specific deletion of CHF1/Hey2 results in 50% reduction in cardiomyocyte action potential dV/dT, 50-75% reduction in SCN5A, KCNJ2, and CACNA1C ion channel subunit gene expression, increased delayed afterdepolarizations, and ~3-fold expansion of cardiac conduction system tissue, linking CHF1/Hey2 to transcriptional regulation of cardiac ion channel genes. Myocardial-specific conditional KO, patch clamp electrophysiology, qRT-PCR for ion channel gene expression, CCS-LacZ reporter cross FASEB journal High 24687990
2015 Serum/BMP9 induces Hey1 and Hey2 transcription in endothelial cells through Alk1 (BMP receptor) signaling independently of canonical Notch (gamma-secretase or dominant-negative MAML1 did not prevent induction), identifying BMP/Alk1 as a Notch-independent upstream activator of Hey2 in endothelial cells. Gamma-secretase inhibition, dominant-negative MAML1 expression, soluble Alk1/Alk3 receptor treatment, BMP9 stimulation, qRT-PCR PloS one Medium 25799559
2017 HEY2 controls normal transmural electrophysiological gradient in the ventricle: Hey2+/- mice show reduced expression of Kcnip2 and Kcnd2 (Ito subunits) in subepicardium, diminished transmural Ito differences and J-wave amplitude; in humans, Brugada syndrome risk allele at rs9388451 associates with increased HEY2 expression, and HEY2 coexpression with KCNIP2 is the strongest genome-wide correlate, identifying a HEY2→KCNIP2 ion channel patterning axis. Heterozygous KO mice, patch-clamp electrophysiology (subepicardial vs. subendocardial cardiomyocytes), surface ECG, genome-wide coexpression analysis, eQTL analysis in human LV samples Circulation research High 28637782
2017 Hey2 overexpression is sufficient to induce endothelial-to-mesenchymal transition (EndoMT) in HUVECs; endothelial-specific conditional deletion of Hey2 in mice reduces EndoMT frequency and mitigates radiation-induced proctitis, demonstrating a causal role for Hey2 in driving EndoMT. siRNA knockdown and plasmid overexpression in HUVECs, Cre-LoxP endothelial-specific KO mice, irradiation model, immunocytochemistry, western blot, qPCR Scientific reports Medium 28694461
2018 HEY2 is a key mediator of NKX2-5 function during human cardiomyogenesis: NKX2-5 deletion in hESCs impairs cardiomyogenesis and HEY2 expression; molecular profiling and genetic rescue experiments demonstrate HEY2 acts downstream of NKX2-5 in the cardiac transcriptional network to enable VCAM1 activation and PDGFRα downregulation. hESC gene deletion (NKX2-5 null), molecular profiling, genetic rescue (HEY2 overexpression), action potential recording, gene expression analysis Nature communications High 29636455
2018 Notch signaling and Nrg1/ErbB2 regulate Hey2 expression level (but not pattern) in myocardium/endocardium; FGF signaling regulates Hey2 expression pattern in early myocardium and also regulates Hey2 level in a Notch1-dependent manner; Hey2 is expressed in endocardial cells of AV canal, outflow tract, and base of trabeculae in addition to compact myocardium. RNAscope in situ hybridization, Hey2-CreERT2 knockin lineage tracing, pathway disruption (Notch, FGF, Nrg1/ErbB2 inhibition/KO) Scientific reports Medium 29422515
2019 HEY2 forms complexes with Smad3 and Smad4 and represses Smad3/Smad4 transcriptional activity, thereby inhibiting TGF-β-induced growth arrest and c-Myc downregulation in hepatocellular carcinoma cells; HEY2 overexpression suppresses TGF-β biological responses while HEY2 knockdown enhances them. Co-immunoprecipitation, siRNA knockdown and overexpression, reporter assays, western blot, qRT-PCR American journal of translational research Medium 31396342
2020 A distal Hey2 enhancer conserved in mouse and human drives ventricular free-wall myocyte-specific expression; this enhancer requires conserved T-box and Gata binding sites (not NK-2 sites), and Tbx20 is required for enhancer activity in embryonic ventricles; Tbx20 cooperates with cardiac GATA proteins to control the ventricular enhancer. Enhancer deletion in mice (CRISPR), in vivo reporter assays, site-directed mutagenesis of binding sites, Tbx20 null mice, luciferase reporter assays Developmental biology High 32035085
2020 Germline loss-of-function variants in HEY2 functional domains disrupt its repressive activity (shown by reporter gene assay) and cause congenital heart defects and thoracic aortic aneurysms in humans, with heterozygous carriers showing cardiovascular defects at high penetrance. Genome sequencing, gene-based association test (MetaSKAT), reporter/expression assays for variant functional consequences Genetics in medicine Medium 32820247
2021 Hey2 conditional KO in the right ventricle/outflow tract (Mef2c-AHF-Cre) causes right ventricular hypoplasia; RNA-seq reveals ectopic induction of Tbx2 in the RV chamber myocardium, leading to reduced Mycn expression and decreased S-phase cells, establishing a Hey2→Tbx2→Mycn pathway controlling RV cardiomyocyte proliferation. Conditional KO (Mef2c-AHF-Cre), RNA-seq, in situ hybridization, BrdU incorporation, histology Development, growth & differentiation High 33410138
2025 HEY2 enriches at promoters of metabolic genes (Ppargc1/PGC-1α, Esrra, Cpt1) and colocalizes with HDAC1 to effectuate histone deacetylation and transcriptional repression of mitochondrial oxidation genes; HEY2-induced impairment of mitochondrial respiration causes elevated ROS and cardiomyocyte apoptosis; restoration of PPARGC1A/ESRRA rescues bioenergetic deficits, defining an HEY2/HDAC1–Ppargc1/Cpt1 transcriptional module controlling cardiac energy metabolism. Genome-wide ChIP-seq, ATAC-seq, Hi-C, CUT&RUN; conditional KO and overexpression in zebrafish and mouse; mitochondrial respiration assays; doxorubicin cardiac injury model Nature communications High 39747914
2025 A novel HEY2 missense variant (p.Glu57Asp) completely disrupts HEY2 repressive transcriptional activity in a reporter gene assay and segregates with non-syndromic Tetralogy of Fallot in a family, confirming that HEY2 repressor function is required for normal conotruncal cardiac development. Sanger sequencing, gene reporter assay (loss of repression), family segregation analysis European journal of human genetics Medium 40481234

Source papers

Stage 0 corpus · 75 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 538 15107403
2013 Common variants at SCN5A-SCN10A and HEY2 are associated with Brugada syndrome, a rare disease with high risk of sudden cardiac death. Nature genetics 418 23872634
2009 Hey2 regulation by FGF provides a Notch-independent mechanism for maintaining pillar cell fate in the organ of Corti. Developmental cell 213 19154718
2006 Hypoxia-mediated activation of Dll4-Notch-Hey2 signaling in endothelial progenitor cells and adoption of arterial cell fate. Experimental cell research 177 17045587
2002 Tetralogy of fallot and other congenital heart defects in Hey2 mutant mice. Current biology : CB 159 12372254
2005 Mouse hesr1 and hesr2 genes are redundantly required to mediate Notch signaling in the developing cardiovascular system. Developmental biology 150 15680351
2002 Ventricular septal defect and cardiomyopathy in mice lacking the transcription factor CHF1/Hey2. Proceedings of the National Academy of Sciences of the United States of America 145 12454287
2008 Foxc transcription factors directly regulate Dll4 and Hey2 expression by interacting with the VEGF-Notch signaling pathways in endothelial cells. PloS one 142 18545664
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
2000 Oscillating expression of c-Hey2 in the presomitic mesoderm suggests that the segmentation clock may use combinatorial signaling through multiple interacting bHLH factors. Developmental biology 136 11076679
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 132 17611704
2002 Mouse gridlock: no aortic coarctation or deficiency, but fatal cardiac defects in Hey2 -/- mice. Current biology : CB 129 12372253
2003 Human Sir2-related protein SIRT1 associates with the bHLH repressors HES1 and HEY2 and is involved in HES1- and HEY2-mediated transcriptional repression. Biochemical and biophysical research communications 122 12535671
2007 Hesr1 and Hesr2 regulate atrioventricular boundary formation in the developing heart through the repression of Tbx2. Development (Cambridge, England) 103 17259303
2018 NKX2-5 regulates human cardiomyogenesis via a HEY2 dependent transcriptional network. Nature communications 89 29636455
2005 HERP1 inhibits myocardin-induced vascular smooth muscle cell differentiation by interfering with SRF binding to CArG box. Arteriosclerosis, thrombosis, and vascular biology 89 16151017
2001 HERP1 is a cell type-specific primary target of Notch. The Journal of biological chemistry 87 11741889
2004 Transcription factor CHF1/Hey2 regulates neointimal formation in vivo and vascular smooth muscle proliferation and migration in vitro. Arteriosclerosis, thrombosis, and vascular biology 86 15345511
2004 Targeted disruption of hesr2 results in atrioventricular valve anomalies that lead to heart dysfunction. Circulation research 85 15297376
2008 Hesr1 and Hesr2 may act as early effectors of Notch signaling in the developing cochlea. Developmental biology 84 18291358
2001 The basic helix-loop-helix gene hesr2 promotes gliogenesis in mouse retina. The Journal of neuroscience : the official journal of the Society for Neuroscience 79 11160397
2010 TAp73 acts via the bHLH Hey2 to promote long-term maintenance of neural precursors. Current biology : CB 72 21074438
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
2018 MicroRNA-98 reduces amyloid β-protein production and improves oxidative stress and mitochondrial dysfunction through the Notch signaling pathway via HEY2 in Alzheimer's disease mice. International journal of molecular medicine 64 30365070
2008 Hey2 functions in parallel with Hes1 and Hes5 for mammalian auditory sensory organ development. BMC developmental biology 58 18302773
2017 The Brugada Syndrome Susceptibility Gene HEY2 Modulates Cardiac Transmural Ion Channel Patterning and Electrical Heterogeneity. Circulation research 56 28637782
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
2006 Transcription factor CHF1/Hey2 suppresses cardiac hypertrophy through an inhibitory interaction with GATA4. American journal of physiology. Heart and circulatory physiology 48 16603706
2015 Sox7 controls arterial specification in conjunction with hey2 and efnb2 function. Development (Cambridge, England) 44 25834021
2010 Hey2 acts upstream of Notch in hematopoietic stem cell specification in zebrafish embryos. Blood 41 20511544
2019 microRNA-599 promotes apoptosis and represses proliferation and epithelial-mesenchymal transition of papillary thyroid carcinoma cells via downregulation of Hey2-depentent Notch signaling pathway. Journal of cellular physiology 35 31565805
2018 LncRNA PRNCR1 interacts with HEY2 to abolish miR-448-mediated growth inhibition in non-small cell lung cancer. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 34 30257372
2015 Serum induces transcription of Hey1 and Hey2 genes by Alk1 but not Notch signaling in endothelial cells. PloS one 34 25799559
2004 Phenotypic variability in Hey2 -/- mice and absence of HEY2 mutations in patients with congenital heart defects or Alagille syndrome. Mammalian genome : official journal of the International Mammalian Genome Society 30 15389319
2018 Notch signaling regulates Hey2 expression in a spatiotemporal dependent manner during cardiac morphogenesis and trabecular specification. Scientific reports 29 29422515
2018 Hey2 regulates the size of the cardiac progenitor pool during vertebrate heart development. Development (Cambridge, England) 27 30355727
2016 HEY2, a target of miR-137, indicates poor outcomes and promotes cell proliferation and migration in hepatocellular carcinoma. Oncotarget 24 27191260
2017 Endothelial Hey2 deletion reduces endothelial-to-mesenchymal transition and mitigates radiation proctitis in mice. Scientific reports 23 28694461
2010 The bHLH transcription factor CHF1/Hey2 regulates susceptibility to apoptosis and heart failure after pressure overload. American journal of physiology. Heart and circulatory physiology 22 20382855
2025 The transcriptional repressor HEY2 regulates mitochondrial oxidative respiration to maintain cardiac homeostasis. Nature communications 19 39747914
2018 microRNA-146a and Hey2 form a mutual negative feedback loop to regulate the inflammatory response in chronic apical periodontitis. Journal of cellular biochemistry 19 30125982
2014 Myocardial deletion of transcription factor CHF1/Hey2 results in altered myocyte action potential and mild conduction system expansion but does not alter conduction system function or promote spontaneous arrhythmias. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 19 24687990
2005 CHF1/Hey2 suppresses SM-MHC promoter activity through an interaction with GATA-6. Biochemical and biophysical research communications 17 16293227
2022 Berberine inhibited the formation of metastasis by intervening the secondary homing of colorectal cancer cells in the blood circulation to the lung and liver through HEY2. Phytomedicine : international journal of phytotherapy and phytopharmacology 16 35802997
2019 Attenuation of PRRX2 and HEY2 enables efficient conversion of adult human skin fibroblasts to neurons. Biochemical and biophysical research communications 16 31255287
2013 Impact of Hey2 and COUP-TFII on genes involved in arteriovenous differentiation in primary human arterial and venous endothelial cells. Basic research in cardiology 15 23744056
2013 Hairy and Enhancer of Split-related with YRPW motif (HEY)2 regulates bone remodeling in mice. The Journal of biological chemistry 15 23782701
2007 Transcription factor CHF1/Hey2 regulates the global transcriptional response to platelet-derived growth factor in vascular smooth muscle cells. Physiological genomics 15 17327490
2020 Expression of Hey2 transcription factor in the early embryonic ventricles is controlled through a distal enhancer by Tbx20 and Gata transcription factors. Developmental biology 14 32035085
2017 SEL1L-dependent Substrates Require Derlin2/3 and Herp1/2 for Endoplasmic Reticulum-associated Degradation. Cell structure and function 14 28552883
2020 Germline variants in HEY2 functional domains lead to congenital heart defects and thoracic aortic aneurysms. Genetics in medicine : official journal of the American College of Medical Genetics 13 32820247
2016 Common Variant Near HEY2 Has a Protective Effect on Ventricular Fibrillation Occurrence in Brugada Syndrome by Regulating the Repolarization Current. Circulation. Arrhythmia and electrophysiology 12 26729854
2015 Duplication of HEY2 in cardiac and neurologic development. American journal of medical genetics. Part A 12 25832314
2021 A role of Hey2 transcription factor for right ventricle development through regulation of Tbx2-Mycn pathway during cardiac morphogenesis. Development, growth & differentiation 11 33410138
2012 Transcription factor CHF1/Hey2 regulates EC coupling and heart failure in mice through regulation of FKBP12.6. American journal of physiology. Heart and circulatory physiology 11 22408025
2010 Transcription factor CHF1/Hey2 regulates coronary vascular maturation. Mechanisms of development 11 20619341
2009 CHF1/Hey2 promotes physiological hypertrophy in response to pressure overload through selective repression and activation of specific transcriptional pathways. Omics : a journal of integrative biology 11 20001863
2005 ZFPM2/FOG2 and HEY2 genes analysis in nonsyndromic tricuspid atresia. American journal of medical genetics. Part A 10 15643620
2020 Sox2-dependent maintenance of mouse oligodendroglioma involves the Sox2-mediated downregulation of Cdkn2b, Ebf1, Zfp423, and Hey2. Glia 9 32975900
2014 BMP signaling participates in late phase differentiation of the retina, partly via upregulation of Hey2. Developmental neurobiology 9 24890415
2013 Hesr2 knockout mice develop aortic valve disease with advancing age. Arteriosclerosis, thrombosis, and vascular biology 8 23288164
2010 Transcription Factor CHF1/Hey2 Regulates Specific Pathways in Serum Stimulated Primary Cardiac Myocytes: Implications for Cardiac Hypertrophy. Current genomics 8 21119893
2023 Hey2 enhancer activity defines unipotent progenitors for left ventricular cardiomyocytes in juxta-cardiac field of early mouse embryo. Proceedings of the National Academy of Sciences of the United States of America 7 37669370
2017 Hey1 and Hey2 are differently expressed during mouse tooth development. Gene expression patterns : GEP 7 29155305
2022 HIF-2α Inhibits Ameloblast Differentiation via Hey2 in Tooth Development. Journal of dental research 6 35912776
2019 A Novel Somatic Variant in HEY2 Unveils an Alternative Splicing Isoform Linked to Ventricular Septal Defect. Pediatric cardiology 6 30955100
2019 HEY2 acting as a co-repressor with smad3 and smad4 interferes with the response of TGF-beta in hepatocellular carcinoma. American journal of translational research 6 31396342
2011 Regulation of MMP10 expression by the transcription factor CHF1/Hey2 is mediated by multiple E boxes. Biochemical and biophysical research communications 5 22079635
2024 MicroRNA-181b-5p/HEY2 axis is involved in the progress of deep venous thrombosis via mediating vascular endothelial injury. Hematology (Amsterdam, Netherlands) 3 39495146
2023 Genetic lineage tracing in skin reveals predominant expression of HEY2 in dermal papilla during telogen and that HEY2+ cells contribute to the regeneration of dermal cells during wound healing. Experimental dermatology 2 37649203
2011 Effects of hepatocyte growth factor-mediated activation of Dll4-Notch-Hey2 signaling pathway. Chinese medical journal 2 21362320
2025 Super-enhancers and Mef2c: Novel regulators of cardiac hypertrophy via the Hey2/Notch/p38 signaling pathway. European journal of pharmacology 1 40441591
2025 A novel heterozygous pathogenic variant in HEY2 led to a familial form of non-syndromic Tetralogy of Fallot. European journal of human genetics : EJHG 1 40481234
2024 Notch-1/2 receptors and Jagged-1 ligand, but not HERP-1 transcription factor, are immunohistochemically expressed in the epithelial lining of periapical cysts. Journal of clinical and experimental dentistry 0 38314334
2020 Notch-HEY2 signaling pathway contributes to the differentiation of CD34+ hematopoietic-like stem cells from adult peripheral blood insulin-producing cells after the treatment with platelet-derived mitochondria. Molecular biology reports 0 32997309