Affinage

HES1

Transcription factor HES-1 · UniProt Q14469

Length
280 aa
Mass
29.5 kDa
Annotated
2026-04-28
100 papers in source corpus 41 papers cited in narrative 41 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

HES1 is a bHLH transcriptional repressor that functions as a central effector of Notch signaling to maintain progenitor and stem cell identity across neural, hematopoietic, endocrine, and muscle lineages by repressing proneural genes (Ascl1/Mash1) and cell cycle inhibitors (p27Kip1, p57, p21) (PMID:7909512, PMID:15870295, PMID:16899237, PMID:10615124). HES1 recruits Groucho/TLE corepressors whose chromatin association is enhanced by CK2-mediated hyperphosphorylation, and it also represses transcription at the elongation step by blocking P-TEFb recruitment to target genes such as CXCL1 (PMID:11756536, PMID:27322654). HES1 expression oscillates with an approximately 2-hour period driven by a delayed negative autoregulatory feedback loop tuned by miR-9-mediated mRNA decay and Usp22/Usp27x-mediated protein stabilization, and the distinction between oscillatory versus sustained HES1 expression differentially controls proliferation versus quiescence through opposing effects on p21 via the Dusp7-ERK axis (PMID:12932324, PMID:23134481, PMID:25846153, PMID:37200191). Beyond developmental contexts, HES1 directly represses immune and stress-response genes including CYLD, GADD34, VEGF-C/WDFY1, and GABAB1, and its protein stability is regulated by RASSF1A-SNURF/RNF4-mediated ubiquitin-dependent degradation (PMID:20832754, PMID:29491143, PMID:31015298, PMID:34897944).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1994 High

    Establishing HES1 as a neural differentiation repressor resolved the question of whether mammalian hairy/Enhancer-of-split homologs functionally inhibit neurogenesis, as shown by persistent HES1 expression blocking neuronal and glial differentiation in neural precursors.

    Evidence Retroviral HES1 transduction in mouse embryonic neural precursor cells in vivo and in vitro

    PMID:7909512

    Open questions at the time
    • Mechanism of repression (DNA binding vs. protein sequestration) not yet distinguished
    • Identity of direct transcriptional targets unknown
  2. 2000 High

    Multi-tissue knockout analyses established HES1 as a general gatekeeper of progenitor cell differentiation across endoderm, retina, and CNS boundary regions, resolving whether its anti-differentiation function was neural-specific.

    Evidence Hes1-null and Hes1/Hes3 double-null mouse analyses in pancreas, gut, retina, and midbrain-hindbrain boundary; retroviral gain-of-function

    PMID:10615124 PMID:10839357 PMID:11500373 PMID:16728479

    Open questions at the time
    • Direct transcriptional targets in each tissue not yet identified
    • Relationship between HES1 and cell cycle exit mechanisms unresolved
  3. 2000 High

    Domain dissection revealed that HES1 possesses two independent repression mechanisms — the WRPW/Groucho-dependent pathway and a helix 3/4 domain-dependent DNA-binding-dependent pathway — answering how HES1 could repress diverse targets including p21.

    Evidence Tetracycline-inducible HES1 domain mutants in PC12 cells with reporter assays and BrdU incorporation

    PMID:10913198

    Open questions at the time
    • Identity of the helix 3/4 domain corepressor unknown
    • How the two repression modes are coordinated in vivo unresolved
  4. 2002 High

    Discovery that HES1 interaction with Groucho/TLE triggers CK2-mediated TLE hyperphosphorylation and chromatin association provided the first mechanistic link between HES1 binding and corepressor activation.

    Evidence Co-immunoprecipitation, in vitro CK2 kinase assay, chromatin fractionation, and pharmacological CK2 inhibition

    PMID:11756536

    Open questions at the time
    • Whether CK2 phosphorylation is required in vivo not tested
    • How target specificity is achieved through TLE unknown
  5. 2003 Medium

    Mathematical modeling demonstrated that HES1's ~2-hour expression oscillations arise from delayed negative autoregulatory feedback without additional pathway components, framing HES1 as a biological clock.

    Evidence Delay differential equation modeling fitted to experimental Hes1 mRNA/protein dynamics

    PMID:12932324

    Open questions at the time
    • Model not yet validated by perturbation of delay parameters in cells
    • Post-transcriptional regulators of oscillation period not identified
  6. 2005 High

    Identification of p27Kip1 and subsequently p57 as direct HES1 targets via class C site binding resolved how HES1 couples transcriptional repression to cell cycle control in progenitors.

    Evidence ChIP and reporter assays for p27Kip1 and p57 promoters; Hes1-KO and Hes1/p57-double-KO mouse phenotypes

    PMID:15870295 PMID:16899237

    Open questions at the time
    • Whether HES1 represses all CKIs simultaneously or selectively in different tissues unclear
    • Chromatin state at CKI promoters under HES1 control not characterized
  7. 2007 High

    Discovery that Id proteins physically interact with HES1 to release its autorepression without blocking its other targets explained how neural stem cells sustain high HES1 levels while maintaining its repressive activity on differentiation genes.

    Evidence Co-immunoprecipitation; Id overexpression in chick hindbrain; Id1/Id3 double-KO mouse with precocious neurogenesis

    PMID:17681138

    Open questions at the time
    • Structural basis of Id–HES1 interaction not resolved
    • Whether Id–HES1 modulation occurs in non-neural tissues unknown
  8. 2010 High

    Linking HES1 to NF-κB pathway maintenance in T-ALL through direct CYLD repression revealed a non-developmental oncogenic function, answering how Notch sustains IKK activation in leukemia.

    Evidence ChIP for HES1 at CYLD locus; CYLD re-expression rescue; T-ALL cell lines and animal models

    PMID:20832754

    Open questions at the time
    • Whether CYLD repression by HES1 operates in normal T cells unknown
    • Additional immune targets of HES1 not yet surveyed genome-wide
  9. 2012 High

    Demonstration that miR-9 targets the HES1 3′-UTR and is required for Hes1 oscillations in neural stem cells established a post-transcriptional layer essential for the HES1 oscillatory clock.

    Evidence Luciferase 3′-UTR reporter; miR-9 knockdown blocking oscillations and neuronal differentiation in mouse brain

    PMID:23134481

    Open questions at the time
    • Whether other miRNAs contribute to HES1 oscillation tuning not tested
    • How miR-9 itself oscillates relative to HES1 not fully resolved
  10. 2015 High

    Identification of Usp22, Usp27x, and Usp51 as deubiquitinases that stabilize HES1 protein revealed the ubiquitin-dependent turnover mechanism governing oscillation period and amplitude.

    Evidence MS-based interactome from mouse ES cells; in vitro deubiquitination assays; cycloheximide chase; in vivo knockdown in developing brain

    PMID:25846153

    Open questions at the time
    • Identity of the E3 ubiquitin ligase(s) for HES1 turnover not yet defined at this point
    • Whether DUB activity itself oscillates unknown
  11. 2016 High

    Discovery that HES1 represses inflammatory genes by blocking P-TEFb recruitment and RNA Pol II Ser2 phosphorylation established a post-initiation repression mechanism distinct from classical promoter silencing.

    Evidence ChIP for P-TEFb and Pol II Ser2P at CXCL1 locus in Hes1 conditional KO macrophages; inflammatory arthritis model

    PMID:27322654

    Open questions at the time
    • Whether elongation block is the primary mechanism at all HES1 targets unknown
    • Structural basis of P-TEFb exclusion by HES1 not resolved
  12. 2019 High

    Live imaging in adult neural and muscle stem cells demonstrated that oscillatory versus sustained HES1 expression differentially controls quiescence vs. differentiation, reframing HES1 dynamics as a fate-determining signal rather than a simple on/off switch.

    Evidence Live-cell Hes1/Ascl1/MyoD reporters; conditional Hes1 KO in adult NSCs and muscle stem cells; compound Hes1/3/5 knockouts

    PMID:30862660 PMID:30862661

    Open questions at the time
    • How oscillation amplitude is sensed by downstream targets mechanistically unclear
    • Whether oscillation dynamics differ between tissue stem cell types not systematically compared
  13. 2021 High

    Identification of RASSF1A as a scaffold for SNURF/RNF4-mediated HES1 ubiquitination and degradation provided the missing E3 ligase pathway controlling HES1 protein turnover and explained how the Notch-HES1 axis can be uncoupled independently of Hippo.

    Evidence Co-immunoprecipitation of RASSF1A, SNURF/RNF4, and HES1; ubiquitination assays; proteasome inhibitor experiments

    PMID:34897944

    Open questions at the time
    • Whether SNURF/RNF4 is the sole E3 for HES1 or acts redundantly with others unclear
    • In vivo significance in stem cell oscillation context not tested
  14. 2023 High

    Resolving the paradox of how oscillatory HES1 promotes proliferation while sustained HES1 induces quiescence, this study showed sustained HES1 represses Dusp7, elevating p-ERK which induces p21 — the opposite of oscillatory HES1's direct p21 repression — establishing dynamics-dependent pathway switching.

    Evidence Conditional oscillatory vs. sustained Hes1 expression in mouse NSCs; Dusp7 and p-ERK analysis; p21 reporter assays

    PMID:37200191

    Open questions at the time
    • Whether Dusp7-ERK switching operates in non-neural stem cells unknown
    • How transcriptional dynamics are decoded at the chromatin level remains unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key open questions include the structural basis for HES1's dual repression mechanisms (promoter silencing vs. elongation block), the full genome-wide catalog of direct targets across tissues, and how oscillation dynamics are decoded by downstream chromatin and signaling networks to produce binary fate outcomes.
  • No crystal structure of HES1 in complex with corepressors or DNA
  • Systematic comparison of HES1 oscillation parameters across tissue stem cell types lacking
  • How HES1 dynamics-dependent pathway switching (e.g., Dusp7-ERK vs. direct p21 repression) is specified at the molecular level remains unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 13 GO:0003677 DNA binding 10
Localization
GO:0005634 nucleus 6
Pathway
R-HSA-1266738 Developmental Biology 8 R-HSA-1640170 Cell Cycle 5 R-HSA-162582 Signal Transduction 4 R-HSA-168256 Immune System 3 R-HSA-5357801 Programmed Cell Death 3
Partners
ID1PARP1RASSF1ARNF4RUNX2TLE1USP22USP27X
Complex memberships
HES1–Groucho/TLE corepressor complex

Evidence

Reading pass · 41 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1994 HES-1 is a bHLH transcriptional repressor that, when persistently expressed via retroviral transduction in neural precursor cells, prevents neuronal and glial differentiation and keeps cells in the ventricular/subventricular zone, establishing HES-1 as a negative regulator of neural differentiation. Retroviral transduction of HES-1 into mouse embryonic neural precursor cells in vivo and in vitro; immunostaining for neuronal/glial markers The EMBO journal High 7909512
1994 The human HES1 gene (HRY) is encoded by four exons and maps to chromosome 3q28-q29; its predicted amino acid sequence differs from the rat homolog at only four positions, confirming orthology. Genomic cloning, sequencing, and fluorescence in situ hybridization (FISH) Genomics High 8020957
1999 Hes1 is required cell-autonomously for the expansion of early T cell precursors at the CD4-CD8- double-negative stage in the thymus; Hes1-null fetal liver cells transferred into RAG2-null hosts fail to generate mature T cells due to defects in both TCR-independent and TCR-dependent thymocyte expansion. Hes1-null mouse genetics; fetal liver cell transfer into RAG2-null hosts; flow cytometric analysis of thymocyte populations Genes & development High 10323870
2000 Hes1 promotes formation of Müller glia in the retina; retroviral overexpression of Hes1 drives glial marker expression in retinal progenitors, while misexpression of a dominant-negative Hes1 reduces glial number. Retroviral transduction of Hes1 and dominant-negative Hes1 in retinal progenitors; cotransfection reporter assays linking Rax to Hes1 regulatory regions Neuron High 10839357
2000 Hes6, a related bHLH protein, acts as an inhibitor of Hes1: Hes6 alone does not bind DNA but suppresses Hes1-mediated transcriptional repression and relieves Hes1 inhibition of Mash1-E47 heterodimers, thereby promoting neuronal differentiation. Mutation of the loop region of Hes1 and Hes6 shows the loop is functionally important for their distinct activities. Transcriptional reporter assays; retroviral misexpression in developing retina; domain swap mutagenesis Development (Cambridge, England) High 10851137
2000 Hes1 operates as a general negative regulator of endodermal endocrine differentiation; Hes1-deficient mice display severe pancreatic hypoplasia due to accelerated differentiation of glucagon-expressing post-mitotic endocrine cells, with upregulation of multiple bHLH components driving precocious and excessive endocrine differentiation in stomach and gut. Hes1 knockout mouse analysis; histology and marker expression in pancreas, stomach and gut Nature genetics High 10615124
2000 HES-1 represses transcription through its helix 3-helix 4 (H3/4) domain independently of its WRPW corepressor-recruitment motif; the H3/4 domain mediates DNA-binding-dependent transcriptional repression and is required for inhibition of NGF-induced differentiation, cell growth arrest, and direct repression of the p21 promoter in PC12 cells. Tetracycline-inducible expression of HES-1 domain mutants in PC12 cells; transcription reporter assays; BrdU incorporation; PCNA measurement Molecular and cellular biology High 10913198
2001 Hes1 and Hes3 redundantly prevent premature differentiation of isthmic organizer cells; in Hes1/Hes3 double-null mice the midbrain and anterior hindbrain are missing because organizer cells prematurely differentiate into neurons and lose expression of Fgf8, Wnt1, and Pax2/5. Hes1/Hes3 double-knockout mouse genetics; in situ hybridization and immunostaining for organizer markers The EMBO journal High 11500373
2002 Hes1 interaction with Groucho/TLE corepressors induces hyperphosphorylation of TLE proteins by protein kinase CK2, which promotes TLE association with chromatin and enhances transcriptional repression; pharmacological inhibition of CK2 reduces TLE hyperphosphorylation, chromatin association, and repression activity. Co-immunoprecipitation; in vitro kinase assay with purified CK2; chromatin fractionation; pharmacological CK2 inhibition; transcription reporter assays Molecular and cellular biology High 11756536
2002 Hes-1 can act as either a transcriptional repressor or activator in a cell-type-specific manner: it represses the human acid alpha-glucosidase (GAA) promoter in HepG2 cells but activates the same element in human fibroblasts, as demonstrated by site-directed mutagenesis of the Hes-1 binding site and Hes-1 overexpression assays. Transfection reporter assays; site-directed mutagenesis; Hes-1 overexpression in fibroblasts vs. HepG2 cells Biochemical and biophysical research communications Medium 11855828
2003 Mathematical modeling informed by experimental data shows that oscillatory Hes1 mRNA and protein expression (period ~2 h) is driven by transcriptional time delays in a short negative autoregulatory feedback loop, without requiring additional pathway components. Mathematical/computational modeling using delay differential equations fitted to experimental Hes1 expression data Current biology : CB Medium 12932324
2005 Hes1 directly represses p27Kip1 transcription by binding to class C sites in the p27Kip1 promoter, thereby promoting progenitor cell proliferation; conditional Hes1 expression in HeLa cells reduces p27Kip1 mRNA and protein and increases growth rate, while Hes1-deficient mice show increased p27Kip1 transcripts in thymus, liver, and brain. Tetracycline-inducible Hes1 expression; promoter-reporter assays; ChIP/DNA binding; qRT-PCR; Hes1 knockout mouse analysis Molecular and cellular biology High 15870295
2006 Persistent and high-level Hes1 expression in boundary cells of the developing CNS constitutively represses Mash1, forming neuron-free boundaries that act as organizing centers; in Hes1/Hes3/Hes5 triple-null mice, proneural genes are ectopically expressed in boundaries causing ectopic neurogenesis and loss of organizing centers. Triple-null mouse genetics; retroviral Hes1 misexpression; in situ hybridization for Mash1 and proneural genes Development (Cambridge, England) High 16728479
2006 Hes1 directly represses p57 (Cdkn1c) in pancreatic progenitors to maintain their cell cycle progression and self-renewal; inactivation of Hes1 upregulates p57, causing cell cycle arrest and precocious differentiation, and p57/Hes1 double-null embryos show progenitor expansion without apoptosis. Hes1 and p57/Hes1 double-knockout mouse genetics; promoter-reporter assays; BrdU labeling; flow cytometry Developmental biology High 16899237
2007 Id proteins (Id1–3) physically interact with Hes1 protein and release Hes1 negative autoregulation, thereby sustaining Hes1 expression levels in early neural stem cells without interfering with Hes1's ability to regulate other target genes; loss of Id1/Id3 reduces Hes1 expression and leads to precocious neurogenesis. Co-immunoprecipitation; Id2 overexpression in chick hindbrain; Id1/Id3 double-KO mouse analysis; Id1-3 RNAi in chick embryos Developmental cell High 17681138
2007 Serum-induced STAT3 oscillations regulate Hes1 expression by controlling its protein half-life, and loss of Hes1 oscillations causes G1 phase retardation; STAT oscillations are driven by delayed negative feedback via SOCS3, and coupled STAT-Hes1 oscillations are required for efficient cell cycle progression. Live-cell reporter assays; luciferase oscillation measurement; siRNA knockdown of Hes1 and Stat3; cell cycle analysis by FACS Proceedings of the National Academy of Sciences of the United States of America High 17592117
2007 Hes1 co-expressed with Runx2 in osteoblasts increases Runx2 protein stability (half-life), augments Runx2-DNA complex formation at target sites, and accelerates osteoblast differentiation including upregulation of osteopontin and type I collagen. Co-expression and retroviral overexpression in osteoblasts; Western blot for protein levels; cycloheximide chase; ChIP; osteogenic marker gene expression Biochemical and biophysical research communications Medium 18162173
2008 The glucocorticoid receptor (GR) directly represses Hes1 promoter activity by recruiting histone deacetylase (HDAC) activities to the Hes1 gene; liver-specific disruption of GR induces Hes1 expression and reduces hepatic steatosis, and genetic restoration of Hes1 in steatotic animals normalizes hepatic triglyceride levels. Liver-specific GR knockout mice; chromatin immunoprecipitation (ChIP) for GR and HDAC at Hes1 promoter; Hes1 adenoviral restoration; triglyceride measurements Cell metabolism High 18762022
2010 Hes1, acting as a transcriptional repressor downstream of oncogenic Notch1, sustains IKK activation in T-ALL by directly repressing the deubiquitinase CYLD, a negative regulator of the IKK complex, thereby maintaining NF-κB pathway activation. Human T-ALL cell lines and animal models; ChIP for Hes1 at CYLD locus; CYLD re-expression rescue experiments; IKK inhibition in vivo Cancer cell High 20832754
2010 In embryonic stem cells, Hes1 expression oscillates with a period of ~3–5 h; sustained Hes1 expression inhibits Notch signaling rather than acting as its effector, causing ES cells to prefer the mesodermal over the neural fate by suppressing Notch. Live-cell fluorescence reporter for Hes1 oscillations in mouse ES cells; sustained Hes1 expression constructs; differentiation assays Genes to cells : devoted to molecular & cellular mechanisms Medium 20545770
2010 Hes1 inhibits cycling of hematopoietic progenitor cells in a DNA-binding-dependent manner, associated with upregulation of p21Cip1/Waf1; a mutant Hes1 lacking the DNA-binding domain fails to inhibit cell cycling, indicating that HES1's anti-proliferative effect in HSPCs requires direct DNA binding. Lentiviral transduction of wild-type and DNA-binding-domain-deleted Hes1 mutant in human CD34+ and mouse HSPCs; cell cycle analysis; in vivo repopulation assays Stem cells (Dayton, Ohio) High 16513761
2010 The Notch target Hes1 binds the Gli1 first intron and represses Gli1 transcription (Hedgehog pathway), as shown by chromatin immunoprecipitation in GBM neurosphere lines; this cross-pathway repression may underlie resistance to Notch inhibition. Chromatin immunoprecipitation (ChIP) for Hes1 at Gli1 first intron; gamma-secretase inhibitor treatment; combined Notch + Hedgehog inhibitor assays Clinical cancer research Medium 21169257
2011 HES1 physically interacts with PARP1 in B-cell ALL; this interaction inhibits HES1 transcriptional function and induces PARP1 activation, self-ADP ribosylation, NAD+ consumption, ATP depletion, and AIF nuclear translocation, leading to apoptosis in a cell-type-specific manner. Co-immunoprecipitation of HES1 and PARP1; PARP1 activity assays; NAD+/ATP measurement; AIF translocation imaging; B-ALL vs. T-ALL comparison Blood High 21224467
2012 miR-9 directly binds the 3'-UTR of Hes1 mRNA (seed sequence complementarity confirmed), negatively regulates Hes1 protein levels, and is required for oscillatory Hes1 mRNA expression in neural stem cells; miR-9 knockdown inhibits Hes1 oscillations and blocks neuronal differentiation. Luciferase 3'-UTR reporter assays; miR-9 overexpression and knockdown in developing mouse brain; Hes1 protein and mRNA quantification; cell cycle analysis Genes to cells : devoted to molecular & cellular mechanisms High 23134481
2015 Deubiquitinases Usp27x, Usp22, and Usp51 directly deubiquitinate and stabilize Hes1 protein; Usp22 knockdown shortens Hes1 half-life and delays its oscillation, enhancing neuronal differentiation, while Usp27x mis-expression reduces neuronal differentiation. Hes1 immunoprecipitation from mouse ES cells with MS identification of interacting deubiquitinases; in vitro deubiquitination assays; cycloheximide chase; in vivo knockdown in developing mouse brain The FEBS journal High 25846153
2015 The transcription factor Hes1 directly represses PUMA/BBC3 (a proapoptotic BH3-only factor) in T-ALL, as demonstrated by ChIP; loss of Hes1 in T-ALL cells decreases survival, establishing HES1 as a critical mediator of NOTCH1-induced leukemogenesis through suppression of apoptosis. ChIP for HES1 at BBC3/PUMA locus; shRNA knockdown of HES1 in T-ALL cell lines and in vivo leukemia model; gene expression analysis Blood High 25784680
2015 Insm1 binds the Hes1 promoter and represses Hes1 expression in pulmonary neuroendocrine cells; in Insm1-mutant mice, Hes1 is upregulated in neuroendocrine cells, blocking their terminal differentiation and interfering with Ascl1 maintenance. ChIP of Insm1 at Hes1 promoter; Insm1 knockout mouse analysis; immunostaining for Hes1 and Ascl1 Developmental biology High 26453796
2015 OR1A1 activation induces cAMP/PKA/CREB signaling that upregulates HES-1, which then acts as a corepressor of PPARγ in hepatocytes, reducing triglyceride synthesis; this was shown by PKA inhibition, CREB phosphorylation assays, and OR1A1 loss-of-function. cAMP measurement; PKA activity assay; CREB phosphorylation Western blot; HES-1 siRNA knockdown; triglyceride and lipid accumulation assays The international journal of biochemistry & cell biology Medium 25817041
2016 Hes1 suppresses inflammatory gene expression (specifically CXCL1) by inhibiting recruitment of the positive transcription elongation complex P-TEFb, thereby preventing phosphorylation of RNA polymerase II at Ser2 and blocking productive elongation — a post-initiation mechanism of transcriptional repression. ChIP for P-TEFb, RNA Pol II Ser2P at CXCL1 locus; Hes1 conditional knockout macrophages; neutrophil recruitment assays in vivo; inflammatory arthritis model Nature immunology High 27322654
2016 CREB and Sirt1 antagonistically regulate Hes1 promoter activity in neural stem cells in response to glucose availability: low glucose promotes CREB binding and Hes1 expression/proliferation, while high glucose promotes Sirt1-dependent repression of the Hes1 promoter, leading to impaired proliferation. ChIP for CREB and Sirt1 at Hes1 promoter; CREB-deficient NSC cultures; Sirt1 pharmacological inhibition; glucose manipulation; proliferation assays Cell reports High 26804914
2017 HES1 directly binds the IGF2BP2 promoter and promotes IGF2BP2 expression; IGF2BP2 then recognizes and stabilizes m6A-modified GLUT1 mRNA, enhancing aerobic glycolysis in colorectal cancer cells. ChIP-PCR and dual-luciferase reporter for HES1 at IGF2BP2 promoter; m6A-RIP for GLUT1 mRNA; GLUT1 mRNA stability assays; HES1 knockdown/overexpression with metabolic readouts Cell death discovery Medium 37957183
2018 HES1 binds the GADD34 promoter and represses its transcription; depletion of HES1 upregulates GADD34 during ER stress and increases cell death, identifying HES1 as a pro-survival repressor of the pro-apoptotic UPR gene GADD34. ChIP for HES1 at GADD34 promoter; HES1 siRNA knockdown in mouse and human cells; ER stress-induced cell death assays; GADD34 reporter assays The Journal of biological chemistry High 29491143
2019 In quiescent adult neural stem cells, Hes1 levels remain oscillatory but with elevated peaks and troughs that continuously suppress Ascl1 expression; inactivation of Hes1 and related genes upregulates Ascl1 and increases neurogenesis, causing premature NSC depletion. Conversely, sustained Hes1 expression maintains quiescence by repressing Ascl1. Conditional Hes1 knockout mice; live-cell Hes1/Ascl1 reporters; quantitative imaging of oscillation dynamics in adult brain; Hes1/Hes3/Hes5 compound knockouts Genes & development High 30862661
2019 Hes1 drives oscillatory MyoD expression in activated muscle stem cells; ablation of the Hes1 oscillator disrupts stable MyoD oscillations, leading to sustained MyoD expression, increased differentiation, impaired muscle stem cell maintenance, and defective muscle growth and repair. Live-cell MyoD and Hes1 reporters in single fibers and primary cultures; Hes1 conditional knockout in muscle stem cells; postnatal muscle growth and regeneration assays Genes & development High 30862660
2019 Hes1 positively regulates VEGF-C transcription through direct genomic occupancy (genome-wide ChIP-seq); VEGF-C then suppresses WDFY1 (a TLR signaling adaptor), attenuating type I IFN production; Hes1-deficient mice show heightened IFN signatures and enhanced antiviral resistance. Genome-wide Hes1 ChIP-seq; Hes1 conditional knockout mice; VEGF-C and WDFY1 expression analysis; encephalomyocarditis virus challenge; lupus nephritis model The Journal of experimental medicine High 31015298
2019 Hes1 modulates Shh responsiveness and ciliogenesis in hair follicle stem cells; epithelial Hes1 deletion impairs Smoothened ciliary accumulation upon Shh stimulation and delays anagen initiation; Smoothened agonist rescues anagen defects in Hes1-deficient follicles. Epithelial-specific Hes1 conditional knockout; ciliogenesis assays in primary keratinocytes; Smoothened ciliary localization imaging; Shh pathway reporter; depilation-induced hair regeneration assays Stem cells (Dayton, Ohio) High 31721388
2021 RASSF1A acts as a scaffold for the SUMO-targeted E3 ubiquitin ligase SNURF/RNF4 to target HES1 for ubiquitin-mediated proteasomal degradation; RASSF1A directly uncouples the NOTCH-HES1 axis independently of the Hippo pathway. Co-immunoprecipitation of RASSF1A, SNURF/RNF4, and HES1; ubiquitination assays; proteasome inhibitor experiments; HES1 protein stability assays; tumor cell differentiation assays EMBO reports High 34897944
2022 Notch/Hes1 signaling in myeloid cells downregulates lactate transporter MCT2 transcription, reducing intracellular lactate, which destabilizes the transcription factor c-Jun via FBW7 ubiquitin ligase-mediated degradation; lactate interacts with c-Jun to protect it from degradation, linking Notch-Hes1 to myeloid differentiation through lactate-c-Jun axis. LC-MS identification of c-Jun as intracellular lactate sensor; CRISPR-Cas9 gene disruption; ChIP for Hes1 at MCT2 locus; myeloid-specific Notch/RBP-J conditional activation; in vivo tumor models Cell reports High 35263597
2022 Hes1 directly binds the GABAB1 receptor (Gabbr1) promoter in medial prefrontal cortex neurons and represses its transcription; Notch1-Hes1 signaling thereby negatively regulates GABAB1 receptor expression and modulates neuronal activity and methamphetamine-induced behavioral sensitization. ChIP for Hes1 at GABAB1 promoter; genetic and pharmacological Notch1 manipulation in mouse mPFC; GABAB receptor pharmacology; locomotor sensitization behavioral assays Molecular psychiatry High 35732696
2022 HES1 transcriptionally activates immunoglobulin-binding protein 1 (IGBP1) expression, which in turn promotes PP6 (protein phosphatase 6) expression and inhibits its ubiquitination; L-menthol prevents proteasomal degradation of HES1, restoring this HES1-IGBP1-PP6 axis in keratinocytes and ameliorating psoriasis-like inflammation. Target identification with phenotypic screen; ChIP for HES1 at IGBP1 promoter; HES1 stability and proteasome inhibitor assays; IGBP1 and PP6 expression rescue experiments; imiquimod mouse model Nature communications High 36535970
2023 Oscillatory Hes1 expression directly represses p21 (Cdkn1a) to promote neural stem cell proliferation, whereas sustained Hes1 overexpression paradoxically upregulates p21 by repressing Dusp7 (an ERK phosphatase), increasing p-ERK which induces p21; thus the dynamics of Hes1 expression differentially control NSC proliferation through p21. Conditional oscillatory vs. sustained Hes1 expression in mouse NSCs; p21 promoter reporter assays; Dusp7 expression analysis; p-ERK measurement; cell cycle and proliferation assays Cell reports High 37200191

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2000 Control of endodermal endocrine development by Hes-1. Nature genetics 924 10615124
2000 rax, Hes1, and notch1 promote the formation of Müller glia by postnatal retinal progenitor cells. Neuron 421 10839357
2003 Oscillatory expression of Hes1, p53, and NF-kappaB driven by transcriptional time delays. Current biology : CB 401 12932324
1994 Persistent expression of helix-loop-helix factor HES-1 prevents mammalian neural differentiation in the central nervous system. The EMBO journal 339 7909512
2010 The Notch/Hes1 pathway sustains NF-κB activation through CYLD repression in T cell leukemia. Cancer cell 237 20832754
2000 The bHLH gene Hes6, an inhibitor of Hes1, promotes neuronal differentiation. Development (Cambridge, England) 215 10851137
2005 Hes1 directly controls cell proliferation through the transcriptional repression of p27Kip1. Molecular and cellular biology 181 15870295
2006 Persistent and high levels of Hes1 expression regulate boundary formation in the developing central nervous system. Development (Cambridge, England) 177 16728479
1999 The bHLH gene Hes1 is essential for expansion of early T cell precursors. Genes & development 177 10323870
2007 Id sustains Hes1 expression to inhibit precocious neurogenesis by releasing negative autoregulation of Hes1. Developmental cell 158 17681138
2015 Hes1: a key role in stemness, metastasis and multidrug resistance. Cancer biology & therapy 149 25781910
2010 The Notch target Hes1 directly modulates Gli1 expression and Hedgehog signaling: a potential mechanism of therapeutic resistance. Clinical cancer research : an official journal of the American Association for Cancer Research 143 21169257
2019 High Hes1 expression and resultant Ascl1 suppression regulate quiescent vs. active neural stem cells in the adult mouse brain. Genes & development 130 30862661
2006 p57 and Hes1 coordinate cell cycle exit with self-renewal of pancreatic progenitors. Developmental biology 130 16899237
2004 Dual roles for the Notch target gene Hes-1 in the differentiation of 3T3-L1 preadipocytes. Molecular and cellular biology 128 15060169
2002 HES-1 preserves purified hematopoietic stem cells ex vivo and accumulates side population cells in vivo. Blood 128 12406868
2000 The bHLH gene Hes1 regulates differentiation of multiple cell types. Molecules and cells 128 10774739
2001 Hes1 and Hes3 regulate maintenance of the isthmic organizer and development of the mid/hindbrain. The EMBO journal 127 11500373
2008 The glucocorticoid receptor controls hepatic dyslipidemia through Hes1. Cell metabolism 120 18762022
2007 Ultradian oscillations of Stat, Smad, and Hes1 expression in response to serum. Proceedings of the National Academy of Sciences of the United States of America 105 17592117
2006 HES1 inhibits cycling of hematopoietic progenitor cells via DNA binding. Stem cells (Dayton, Ohio) 98 16513761
2012 MicroRNA9 regulates neural stem cell differentiation by controlling Hes1 expression dynamics in the developing brain. Genes to cells : devoted to molecular & cellular mechanisms 95 23134481
2005 Multiple requirements for Hes 1 during early eye formation. Developmental biology 93 16038893
2000 HES-1 repression of differentiation and proliferation in PC12 cells: role for the helix 3-helix 4 domain in transcription repression. Molecular and cellular biology 89 10913198
2014 Hes1 is involved in the self-renewal and tumourigenicity of stem-like cancer cells in colon cancer. Scientific reports 87 24492635
2005 Regulation of the Notch target gene Hes-1 by TGFalpha induced Ras/MAPK signaling in human neuroblastoma cells. Experimental cell research 86 16120441
2022 Notch-mediated lactate metabolism regulates MDSC development through the Hes1/MCT2/c-Jun axis. Cell reports 75 35263597
2016 The transcriptional repressor Hes1 attenuates inflammation by regulating transcription elongation. Nature immunology 75 27322654
2017 HES1 Promotes Colorectal Cancer Cell Resistance To 5-Fu by Inducing Of EMT and ABC Transporter Proteins. Journal of Cancer 73 28928869
2010 Hes1 regulates embryonic stem cell differentiation by suppressing Notch signaling. Genes to cells : devoted to molecular & cellular mechanisms 73 20545770
2004 Expression of Hairy/Enhancer of Split genes, Hes1 and Hes5, during murine nephron morphogenesis. Gene expression patterns : GEP 71 15465493
2006 Hes1 is required for pituitary growth and melanotrope specification. Developmental biology 70 17367776
2016 HES1 in immunity and cancer. Cytokine & growth factor reviews 68 27066918
2019 Oscillations of MyoD and Hes1 proteins regulate the maintenance of activated muscle stem cells. Genes & development 65 30862660
2016 A CREB-Sirt1-Hes1 Circuitry Mediates Neural Stem Cell Response to Glucose Availability. Cell reports 60 26804914
2016 Hes1: the maestro in neurogenesis. Cellular and molecular life sciences : CMLS 57 27233500
2015 Activation of OR1A1 suppresses PPAR-γ expression by inducing HES-1 in cultured hepatocytes. The international journal of biochemistry & cell biology 53 25817041
2011 Notch/HES1-mediated PARP1 activation: a cell type-specific mechanism for tumor suppression. Blood 53 21224467
2004 Roles of the bHLH gene Hes1 in retinal morphogenesis. Brain research 53 15033430
2002 Role for Hes1-induced phosphorylation in Groucho-mediated transcriptional repression. Molecular and cellular biology 53 11756536
2005 Hairy Enhancer of Split-1 (HES-1), a Notch1 effector, inhibits the growth of carcinoid tumor cells. Surgery 50 16360401
2015 Deubiquitinating enzymes regulate Hes1 stability and neuronal differentiation. The FEBS journal 49 25846153
2010 HES1 (hairy and enhancer of split 1) is a determinant of bone mass. The Journal of biological chemistry 49 21084301
2012 The micro-RNA 199b-5p regulatory circuit involves Hes1, CD15, and epigenetic modifications in medulloblastoma. Neuro-oncology 48 22411914
2013 Hes1 and Hes5 regulate vascular remodeling and arterial specification of endothelial cells in brain vascular development. Mechanisms of development 46 23871867
2008 Premature differentiation and aberrant movement of pituitary cells lacking both Hes1 and Prop1. Developmental biology 46 18996108
2015 Hes1, an important gene for activation of hepatic stellate cells, is regulated by Notch1 and TGF-β/BMP signaling. World journal of gastroenterology 45 25624721
2015 Insm1 controls the differentiation of pulmonary neuroendocrine cells by repressing Hes1. Developmental biology 44 26453796
2016 Tigecycline Inhibits Glioma Growth by Regulating miRNA-199b-5p-HES1-AKT Pathway. Molecular cancer therapeutics 41 26823491
2021 HES1 and HES4 have non-redundant roles downstream of Notch during early human T-cell development. Haematologica 39 31919081
2015 Therapeutic targeting of HES1 transcriptional programs in T-ALL. Blood 39 25784680
2007 Hes1 stimulates transcriptional activity of Runx2 by increasing protein stabilization during osteoblast differentiation. Biochemical and biophysical research communications 37 18162173
2019 Hes1 regulates anagen initiation and hair follicle regeneration through modulation of hedgehog signaling. Stem cells (Dayton, Ohio) 34 31721388
2016 Notch-Hes-1 axis controls TLR7-mediated autophagic death of macrophage via induction of P62 in mice with lupus. Cell death & disease 34 27537524
2014 CPEB1 modulates differentiation of glioma stem cells via downregulation of HES1 and SIRT1 expression. Oncotarget 34 25216517
2020 Hes1 deficiency causes hematopoietic stem cell exhaustion. Stem cells (Dayton, Ohio) 33 32129527
2021 IL-6 and IL-8, secreted by myofibroblasts in the tumor microenvironment, activate HES1 to expand the cancer stem cell population in early colorectal tumor. Molecular carcinogenesis 32 33544929
1994 Genomic cloning and chromosomal localization of HRY, the human homolog to the Drosophila segmentation gene, hairy. Genomics 32 8020957
2020 MYEOV increases HES1 expression and promotes pancreatic cancer progression by enhancing SOX9 transactivity. Oncogene 31 32879444
2017 The doublesex-related Dmrta2 safeguards neural progenitor maintenance involving transcriptional regulation of Hes1. Proceedings of the National Academy of Sciences of the United States of America 31 28655839
2023 HES1 promotes aerobic glycolysis and cancer progression of colorectal cancer via IGF2BP2-mediated GLUT1 m6A modification. Cell death discovery 30 37957183
2023 Differential cell-cycle control by oscillatory versus sustained Hes1 expression via p21. Cell reports 29 37200191
2020 Simultaneous Requirements for Hes1 in Retinal Neurogenesis and Optic Cup-Stalk Boundary Maintenance. The Journal of neuroscience : the official journal of the Society for Neuroscience 29 31949107
2015 Astragaloside IV protects cardiomyocytes from anoxia/reoxygenation injury by upregulating the expression of Hes1 protein. Canadian journal of physiology and pharmacology 29 27070866
2013 The role of dimerisation and nuclear transport in the Hes1 gene regulatory network. Bulletin of mathematical biology 29 23686434
2016 Hes1 Controls Exocrine Cell Plasticity and Restricts Development of Pancreatic Ductal Adenocarcinoma in a Mouse Model. The American journal of pathology 28 27639167
2009 Hes1 potentiates T cell lymphomagenesis by up-regulating a subset of notch target genes. PloS one 28 19688092
2012 miR-1-mediated induction of cardiogenesis in mesenchymal stem cells via downregulation of Hes-1. BioMed research international 27 23509692
2016 Loss of Hes1 Differentiates Sessile Serrated Adenoma/Polyp From Hyperplastic Polyp. The American journal of surgical pathology 26 26448192
2018 microRNA-203 Modulates Wound Healing and Scar Formation via Suppressing Hes1 Expression in Epidermal Stem Cells. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 25 30261495
2014 Control of hair cell development by molecular pathways involving Atoh1, Hes1 and Hes5. Gene 25 25550047
2011 Notch signalling is off and is uncoupled from HES1 expression in Ewing's sarcoma. The Journal of pathology 25 21984123
2022 Targeting the transcription factor HES1 by L-menthol restores protein phosphatase 6 in keratinocytes in models of psoriasis. Nature communications 24 36535970
2014 Regulation of a Notch3-Hes1 pathway and protective effect by a tocopherol-omega alkanol chain derivative in muscle atrophy. The Journal of pharmacology and experimental therapeutics 24 25326132
2012 The expression of NOTCH2, HES1 and SOX9 during mouse retinal development. Gene expression patterns : GEP 24 23277114
2002 Hes-1, a known transcriptional repressor, acts as a transcriptional activator for the human acid alpha-glucosidase gene in human fibroblast cells. Biochemical and biophysical research communications 24 11855828
2022 Dysregulation of SIRT3 SUMOylation Confers AML Chemoresistance via Controlling HES1-Dependent Fatty Acid Oxidation. International journal of molecular sciences 23 35955415
2012 PDX-1/Hes-1 interactions determine cholangiocyte proliferative response to injury in rodents: possible implications for sclerosing cholangitis. Journal of hepatology 22 23207146
2024 Curcumin pretreatment attenuates myocardial ischemia/reperfusion injury by inhibiting ferroptosis, autophagy and apoptosis via HES1. International journal of molecular medicine 21 39364745
2021 The NOTCH-HES-1 axis is involved in promoting Th22 cell differentiation. Cellular & molecular biology letters 20 33622250
2010 Mouse microRNA-124 regulates the expression of Hes1 in P19 cells. Frontiers in bioscience (Elite edition) 20 20036862
2022 Medial prefrontal cortex Notch1 signalling mediates methamphetamine-induced psychosis via Hes1-dependent suppression of GABAB1 receptor expression. Molecular psychiatry 19 35732696
2019 Hes1 attenuates type I IFN responses via VEGF-C and WDFY1. The Journal of experimental medicine 19 31015298
2017 Inhibition of Notch1/Hes1 signaling pathway improves radiosensitivity of colorectal cancer cells. European journal of pharmacology 19 29126793
2010 Hes1/Hes5 gene inhibits differentiation via down-regulating Hash1 and promotes proliferation in cervical carcinoma cells. International journal of gynecological cancer : official journal of the International Gynecological Cancer Society 19 21495212
2008 TGF-alpha induces upregulation and nuclear translocation of Hes1 in glioma cell. Cell biochemistry and function 19 18636433
2021 Melatonin attenuates aortic oxidative stress injury and apoptosis in STZ-diabetes rats by Notch1/Hes1 pathway. The Journal of steroid biochemistry and molecular biology 18 34224859
2010 Hes1 regulates formations of the hypophyseal pars tuberalis and the hypothalamus. Cell and tissue research 18 20431921
2019 SP promotes cell proliferation in esophageal squamous cell carcinoma through the NK1R/Hes1 axis. Biochemical and biophysical research communications 17 31109645
2022 HES1 promoter activation dynamics reveal the plasticity, stemness and heterogeneity in neuroblastoma cancer stem cells. Journal of cell science 16 36321463
2019 HES1, two programs: promoting the quiescence and proliferation of adult neural stem cells. Genes & development 16 31043492
2005 Overexpression of HES-1 is not sufficient to impose T-cell differentiation on human hematopoietic stem cells. Blood 16 16322473
1998 Genetic elements regulating HES-1 induction in Wnt-1-transformed PC12 cells. Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research 15 9790494
2021 ETV4 transcriptionally activates HES1 and promotes Stat3 phosphorylation to promote malignant behaviors of colon adenocarcinoma. Cell biology international 14 34270850
2021 RASSF1A disrupts the NOTCH signaling axis via SNURF/RNF4-mediated ubiquitination of HES1. EMBO reports 14 34897944
2020 Hes1 Is Essential in Proliferating Ductal Cell-Mediated Development of Intrahepatic Cholangiocarcinoma. Cancer research 14 33067264
2019 Synchronization of Hes1 oscillations coordinates and refines condensation formation and patterning of the avian limb skeleton. Mechanisms of development 14 30867133
2018 Hairy and enhancer of split 1 (HES1) protects cells from endoplasmic reticulum stress-induced apoptosis through repression of . The Journal of biological chemistry 14 29491143
2017 Elimination of GPR146-mediated antiviral function through IRF3/HES1-signalling pathway. Immunology 14 28464285
2013 Jagged-1-HES-1 signaling inhibits the differentiation of TH17 cells via ROR gammat. Journal of biological regulators and homeostatic agents 14 23489689