Affinage

BHLHE41

Class E basic helix-loop-helix protein 41 · UniProt Q9C0J9

Length
482 aa
Mass
50.5 kDa
Annotated
2026-06-09
100 papers in source corpus 41 papers cited in narrative 41 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

BHLHE41 (DEC2/SHARP1) is a basic helix-loop-helix transcriptional repressor that integrates circadian, hypoxic, and differentiation signals to control gene expression across diverse cell lineages (PMID:12397359, PMID:17487425, PMID:22801492). It binds class B E-boxes (CACGTG) as a homodimer and represses transcription through two separable routes: a C-terminal domain that recruits HDAC1 in an HDAC-dependent manner and the bHLH domain that represses HDAC-independently, in part by heterodimerizing with and inactivating partner factors such as MyoD and E47 (PMID:12657651, PMID:17487425, PMID:11278948). Beyond direct DNA occupancy, it suppresses targets by competing for E-box or SP1 sites and by direct protein-protein interaction with activating factors including CLOCK/BMAL1, HIF-1α/HIF-2α, C/EBPα/β, RXRα, SREBP-1c, SP1, and Smad3 (PMID:12397359, PMID:18838394, PMID:19029947, PMID:19786558, PMID:22801492, PMID:26391953), frequently coupled to recruitment of co-repressors HDAC1 and the methyltransferase G9a, the latter deposited at target promoters in a manner gated by SUMOylation of two conserved lysines and reversed by SENP1 (PMID:23087213, PMID:23637228, PMID:24942744, PMID:20821348). As a core clock component it is induced by CLOCK/BMAL1 and RORα through E-boxes and ROREs and feeds back to repress its own and Per promoters, regulating circadian period and sleep length—a human P385R mutation causes familial short sleep, acting through derepression of prepro-orexin (PMID:15147242, PMID:19679812, PMID:29531056, PMID:22244086). It promotes proteasomal degradation of HIF-1α/HIF-2α independently of pVHL to suppress hypoxia-driven angiogenesis and breast cancer metastasis (PMID:18233956, PMID:22801492, PMID:24918449). Functionally, it blocks skeletal muscle and adipocyte differentiation (PMID:15448136, PMID:19029947), and is required for TH2 commitment, B-1a cell development, and alveolar macrophage self-renewal and identity (PMID:19881507, PMID:28250425, PMID:31414712).

Mechanistic history

Synthesis pass · year-by-year structured walk · 21 steps
  1. 2001 High

    Establishing BHLHE41's domain architecture and intrinsic repressor activity defined how it acts mechanistically distinct from WRPW-containing bHLH factors.

    Evidence Molecular cloning, sequence analysis and GAL4 fusion reporter dissection with TSA inhibition

    PMID:11162494 PMID:11278948

    Open questions at the time
    • No structural model of the HLH or Orange domains
    • Identity of the C-terminal HDAC-recruiting surface not mapped at residue level
  2. 2002 High

    Showing BHLHE41 represses CLOCK/BMAL1-driven Per1 transactivation placed it as a negative arm of the molecular clock and raised whether it acts by competition or protein binding.

    Evidence Luciferase reporter assays and protein interaction studies in cell culture

    PMID:12397359

    Open questions at the time
    • Relative contribution of E-box competition vs Bmal1 binding not resolved
    • No in vivo clock phenotype in this study
  3. 2002 High

    Demonstrating direct HIF-1α induction of BHLHE41 via HREs connected hypoxia signaling to this repressor's expression.

    Evidence Luciferase reporters with HIF-1α and EMSA of HRE binding

    PMID:12354771

    Open questions at the time
    • Did not address BHLHE41's reciprocal effect on HIF
  4. 2003 High

    Defining E-box homodimer binding plus direct MyoD/E-protein and SP1 interactions established multiple parallel repression mechanisms, and reciprocal DEC1-DEC2 cross-regulation revealed an interlocking repressor network.

    Evidence EMSA, ChIP, Co-IP, reporter assays and inducible DEC1 overexpression

    PMID:12624110 PMID:12657651

    Open questions at the time
    • Stoichiometry of homodimer vs heterodimer occupancy at endogenous loci unknown
  5. 2004 High

    Identifying CLOCK/BMAL1 and CLOCK/BMAL2 activation of Dec2 through E-boxes plus Dec2 autorepression closed a negative-feedback loop, and parallel work extended the repressor to muscle and lipid-metabolic targets.

    Evidence Reporter and gel-retardation assays, Clock mutant mice, C2C12 myoblast Co-IP and rescue, hepatic CYP7A reporter/EMSA

    PMID:15066123 PMID:15147242 PMID:15448136

    Open questions at the time
    • In vivo significance of CYP7A repression not tested in animals
    • Whether autoregulation operates at all peripheral clocks unknown
  6. 2007 High

    Domain-resolved dissection separated HDAC1-dependent repression at class B E-boxes from HDAC-independent MyoD-heterodimer repression at class A E-boxes, clarifying two mechanistic modes.

    Evidence Gel retardation, GAL4 fusion analysis and structure-function mutagenesis

    PMID:17487425

    Open questions at the time
    • Cofactors recruited in the HDAC-independent mode not fully defined
  7. 2008 High

    BHLHE41 was shown to interact directly with HIF-1α and inhibit its DNA binding, and to repress additional targets (MLH1, SREBP-1c) via E-box binding and HDAC-dependent mechanisms, broadening its regulatory reach.

    Evidence Co-IP, ChIP, EMSA, reporter assays and siRNA in multiple cell systems

    PMID:18233956 PMID:18345027 PMID:18838394

    Open questions at the time
    • Whether HIF inhibition was via DNA-binding competition or protein degradation not yet distinguished (resolved 2012)
  8. 2008 High

    Genetic mouse models established BHLHE41 as a bona fide in vivo clock regulator controlling period and entrainment, with context-dependent dual repressor/coactivator behavior.

    Evidence Single and double Sharp-1/Sharp-2 mutant mice with circadian behavior and phase-shift assays

    PMID:18648504

    Open questions at the time
    • Molecular basis of coactivator function unexplained
  9. 2009 High

    BHLHE41 was placed as a node controlling lineage differentiation and nuclear-receptor signaling, acting as an RXRα corepressor and a positive regulator of TH2 commitment.

    Evidence Dec2-deficient mice, TH2 differentiation and asthma models, ChIP, LXXLL-motif mutagenesis, Co-IP

    PMID:19786558 PMID:19881507

    Open questions at the time
    • Direct vs indirect activation of JunB/GATA-3 in vivo not fully separated
  10. 2009 High

    A human DEC2 missense mutation causally linked to short sleep, validated in transgenic mice, established the gene's role in sleep-length regulation.

    Evidence Family genetics and transgenic mouse EEG/activity recording

    PMID:19679812

    Open questions at the time
    • Downstream effector of the sleep phenotype not identified in this study (later orexin)
  11. 2010 High

    Direct HDAC1 recruitment to the cyclin D1 promoter upon bexarotene treatment defined a co-repressor recruitment mechanism for cell-cycle control.

    Evidence Co-IP, ChIP, reporter assays, siRNA and TSA inhibition

    PMID:20821348

    Open questions at the time
    • Generality of HDAC1 recruitment across other targets not established here
  12. 2012 High

    BHLHE41 was shown to drive proteasomal degradation of HIF-1α/HIF-2α independent of pVHL and ubiquitination, recasting it as a metastasis suppressor and a HIF-presenting factor.

    Evidence Co-IP, proteasomal degradation assays, in vitro invasion and in vivo metastasis models with gain/loss of function

    PMID:22801492

    Open questions at the time
    • Biochemical mechanism of ubiquitin-independent proteasome targeting unresolved
    • Structural basis of HIF presentation unknown
  13. 2012 High

    Identification of G9a as a direct partner depositing H3K9me2 and methylating MyoD established a chromatin-modifying axis for the muscle-differentiation block, and RORα was defined as a distinct nuclear-receptor activator of Dec2.

    Evidence Co-IP, ChIP for H3K9me2, siRNA, G9a inhibition; EMSA/ChIP/reporter for RORα

    PMID:22244086 PMID:23087213

    Open questions at the time
    • Whether G9a recruitment generalizes beyond muscle loci not tested in this study
  14. 2013 High

    SUMOylation at K240/K255 was shown to gate co-repressor G9a recruitment and full repressor activity, defining a post-translational switch controlling BHLHE41 function.

    Evidence SUMO site mutagenesis, ChIP for G9a and H3K9me2, SENP1 co-expression and differentiation assays

    PMID:23637228

    Open questions at the time
    • E3 SUMO ligase for BHLHE41 not identified
    • Stimulus controlling SUMOylation dynamics unknown
  15. 2013 Medium

    BHLHE41 was linked to additional signaling and cancer pathways via Smad3 interaction and a GLI-driven repression of MLH1, expanding its regulatory and disease relevance.

    Evidence Co-IP and muscle-regeneration knockout model; GLI target screening, promoter reporters, double knockdown, TALEN editing

    PMID:24165159 PMID:24357723

    Open questions at the time
    • Smad3 interaction supported by single-lab Co-IP
    • Direct vs indirect MLH1 repression via GLI axis not fully separated
  16. 2014 Medium

    Mechanistic links between SUMO/SENP1 regulation and adipogenesis, hypoxia signaling, EMT, sleep, and metabolic induction were consolidated, including the orexin effector of short sleep and insulin-driven SHARP-1 induction.

    Evidence SENP1-KO MEFs, Co-IP/ChIP, transgenic mice with orexin-antagonist rescue, reporter assays, pharmacological/dominant-negative dissection of insulin signaling

    PMID:24446161 PMID:24942744 PMID:25083013 PMID:25446074 PMID:29531056 PMID:39

    Open questions at the time
    • Several mechanisms rest on single-lab evidence
    • Tissue-specificity of insulin-induced PEPCK repression not validated in vivo
  17. 2017 High

    Genetic models established BHLHE41 (with paralog BHLHE40) as essential for B-1a cell development and self-renewal through repression of cell-cycle and BCR-signaling inhibitors.

    Evidence Bhlhe41/Bhlhe40 double knockout mice, flow cytometry, expression profiling and BCR rescue

    PMID:28250425

    Open questions at the time
    • Direct DNA-binding map in B-1a cells not generated here
  18. 2018 High

    BHLHE41 was identified as a context-dependent oncogenic driver in MLL-AF6 AML where it binds active chromatin and activates survival genes, contrasting with its canonical repressor role.

    Evidence ChIP-seq, knockdown/overexpression, mouse leukemia model and human AML samples; HDAC4-Sharp1 satellite cell axis by KO/RNA-seq/rescue

    PMID:29472596 PMID:29692408

    Open questions at the time
    • Molecular determinant of activator vs repressor mode unknown
    • Cofactors enabling gene activation in AML not defined
  19. 2019 High

    Genome-wide DNA-binding and knockout studies established BHLHE40/41-mediated repression of lineage-inappropriate genes in alveolar macrophages and direct repression of Sohlh1 in germ cells, extending its identity-control role across tissues.

    Evidence Knockout mice, competitive transplantation, ChIP-seq, RNA-seq; scRNA-seq and spermatogonial transplantation

    PMID:30988352 PMID:31414712

    Open questions at the time
    • Direct BHLHE41 (vs BHLHE40) binding contribution in macrophages not separately resolved
    • Germ-cell findings single-lab
  20. 2020 Medium

    Functional genomics positioned BHLHE40/41 in negative-feedback opposition to TFEB, protecting cells from lysosomal cell death.

    Evidence Genome-wide CRISPR screen and lysosomal death assays

    PMID:33176151

    Open questions at the time
    • Direct vs indirect counter-regulation of TFEB targets not dissected
    • Single-lab screen
  21. 2022 Medium

    Epitranscriptomic control by METTL3 (m6A) and an upstream CIC-PER2 circuit were shown to set BHLHE41 levels, coupling it to MDSC migration via CXCL1 and to B-1a development.

    Evidence m6A-seq, RNA-seq, cytokine arrays, depletion/inhibitor experiments, syngeneic and humanized mice; B-cell-specific Cic-null mice

    PMID:35172136 PMID:35700773

    Open questions at the time
    • Whether CXCL1 is a direct BHLHE41 target not fully established
    • CIC-PER2 axis single-lab epistasis

Open questions

Synthesis pass · forward-looking unresolved questions
  • The structural and biochemical basis for BHLHE41's switch between transcriptional repressor and activator, and for its ubiquitin-independent presentation of HIF to the proteasome, remains unresolved.
  • No experimental structure of BHLHE41 or its complexes
  • Mechanism distinguishing repressor vs activator chromatin states unknown
  • Biochemical reconstitution of HIF degradation not achieved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 6 GO:0003677 DNA binding 5 GO:0098772 molecular function regulator activity 5
Localization
GO:0005634 nucleus 3
Pathway
R-HSA-1266738 Developmental Biology 5 R-HSA-1643685 Disease 4 R-HSA-9909396 Circadian clock 4 R-HSA-168256 Immune System 3 R-HSA-4839726 Chromatin organization 3 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-8953897 Cellular responses to stimuli 3
Partners
BMAL1CEBPBE47G9AHDAC1HIF1AMYODRXRA

Evidence

Reading pass · 41 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 DEC2 (BHLHE41) represses Clock/Bmal1-induced transactivation of the Per1 promoter through direct protein-protein interactions with Bmal1 and/or competition for E-box elements, functioning as a negative regulator of the mammalian molecular clock. Transcription reporter (luciferase) assays and protein-protein interaction studies in cell culture Nature High 12397359
2001 DEC2 (BHLHE41) is a bHLH transcription factor lacking the WRPW motif for Groucho corepressor interaction, contains an Orange domain, and dimerizes via its HLH domain; it was mapped to human chromosome 12p11.23-p12.1. Molecular cloning, sequence analysis, chromosomal mapping Biochemical and biophysical research communications Medium 11162494
2002 DEC2 gene transcription is directly induced by HIF-1α through functional hypoxia response elements (HREs) in its promoter that bind HIF-1α and HIF-1β, demonstrating direct transcriptional regulation by hypoxia. Luciferase reporter assays with HIF-1α, gel mobility shift assays (EMSA) identifying HRE binding The Journal of biological chemistry High 12354771
2003 DEC1 negatively regulates DEC2 expression by binding to an E-box motif in the DEC2 proximal promoter through direct DNA binding; DNA-binding-defective DEC1 mutants lose this repressive activity. Co-transfection reporter assays, stable transfectants with tetracycline-inducible DEC1, deletion and site-directed mutagenesis of DEC2 promoter The Journal of biological chemistry High 12624110
2003 mSharp-1/DEC2 binds E-box motifs (CANNTG) as a homodimer and represses transcription through: (1) occupancy of E-box sites by homodimers, (2) direct physical interaction with MyoD and E proteins, and (3) interaction with transcriptional activator Sp1 to impair Sp1-induced transcription. Gel mobility shift assays, chromatin immunoprecipitation (ChIP), co-immunoprecipitation, luciferase reporter assays The Journal of biological chemistry High 12657651
2004 Dec2 gene transcription is regulated by the molecular clock: Clock/Bmal1 and Clock/Bmal2 heterodimers activate Dec2 via two CACGTG E-boxes in its promoter, while Dec2 itself binds these E-boxes to repress its own transcription (negative autoregulatory feedback). Cry and Per also suppress Clock/Bmal-induced Dec2 transcription. Luciferase reporter assays, gel retardation assays, Clock mutant mouse analysis The Biochemical journal High 15147242
2004 Sharp-1/DEC2 inhibits skeletal muscle differentiation by interacting with MyoD and E-proteins (E47), reducing their DNA binding and transactivation from MyoD-dependent E-box sites; re-expression of MyoD~E47 rescues the differentiation block, placing myogenic bHLH factors downstream of Sharp-1. C2C12 myoblast overexpression, co-immunoprecipitation, gene expression analysis, genetic rescue experiment The Journal of biological chemistry High 15448136
2004 DEC2 suppresses transcription of the cholesterol 7α-hydroxylase gene (CYP7A), CYP8B, and CYP51 in liver by binding to the E-box (CACATG) in the CYP7A promoter, opposing the activating effect of D-site binding protein (DBP). Transfection reporter assays, electrophoretic mobility shift assays (EMSA) Genes to cells Medium 15066123
2007 DEC2 represses transcription through multiple mechanisms at E-box elements: (1) preferential binding to class B E-boxes (CACGTG) as a homodimer, (2) repression via C-terminal domain recruiting HDAC1 in an HDAC-dependent manner, and (3) repression at class A E-boxes (MyoD targets) via heterodimer formation with MyoD through basic and HLH domains in an HDAC-independent manner. Gel retardation assays, luciferase reporter assays, GAL4 fusion domain analysis, structure-function mutagenesis International journal of molecular medicine High 17487425
2008 DEC2 binds directly to HIF-1α (co-immunoprecipitation) but not ARNT1, and decreases HIF-1α binding to the HRE in the VEGF promoter, thereby suppressing VEGF gene expression under hypoxic conditions. Co-immunoprecipitation, ChIP assay, luciferase reporter assays, DEC2 knockdown Genes to cells High 18233956
2008 DEC2 represses the MLH1 promoter by directly binding to an E-box-like motif in the MLH1 promoter, an effect that is inhibited by the HDAC inhibitor trichostatin A, suggesting histone deacetylase-dependent repression mechanism. Co-transfection reporter assay, EMSA, ChIP assay, siRNA knockdown Oncogene High 18345027
2008 DEC2 inhibits SREBP-1c-induced transcription by competing with SREBP-1c for E-box binding in the SREBP-1c promoter and/or by direct protein-protein interaction with SREBP-1c protein; DEC2 is the major initiator of hypoxic repression of SREBP-1c while DEC1/Stra13 substitutes in prolonged hypoxia. Reporter assays, Co-IP/protein interaction studies, siRNA knockdown of DEC2 and Stra13 Nucleic acids research Medium 18838394
2008 SHARP1/DEC2 interacts with and inhibits transcriptional activity of both C/EBPβ and C/EBPα, and enhances association of C/EBPβ with HDAC1, leading to retention of HDAC1 and histone methyltransferase G9a at C/EBPα and PPARγ2 promoters and inhibition of adipogenesis. Protein interaction studies (Co-IP), ChIP assays, overexpression in adipocyte differentiation model, pharmacological rescue with troglitazone EMBO reports High 19029947
2009 DEC2 is required for initial TH2 lineage commitment in CD4+ T cells; DEC2 directly binds to and activates transcription of JunB and GATA-3 genes, and GATA-3 in turn induces DEC2 expression creating a feed-forward regulatory circuit. Dec2-deficient mouse model, in vitro TH2 differentiation assays, asthma model, ChIP/transcriptional activation assays Nature immunology High 19881507
2009 DEC2 functions as a corepressor of retinoid X receptor (RXRα): DEC2 directly interacts with RXRα (interaction enhanced by ligand), represses ligand-dependent RXRα transactivation, modifies RXRα-cofactor interactions, and an LXXLL motif in DEC2 is necessary for RXRα repression. DEC2 also represses LXR target genes in hepatocytes. Transfection reporter assays, Co-IP, ChIP assays, siRNA knockdown, DEC2 deletion/point mutants Molecular pharmacology High 19786558
2009 A human missense mutation in DEC2 (hDEC2-P385R) is associated with familial short sleep phenotype; transgenic mice carrying this mutation showed increased vigilance time and less sleep, establishing DEC2 as a transcriptional repressor regulating sleep length. Human genetics (family study), transgenic mouse model with EEG/activity recording Science High 19679812
2001 SHARP-1 represses transcription via two independent domains: (1) a C-terminal domain that represses via a histone deacetylase (HDAC)-dependent mechanism (sensitive to trichostatin A), and (2) the bHLH domain that represses via an HDAC-independent mechanism. SHARP-1 represses transcription from the M1 muscarinic acetylcholine receptor gene promoter. GAL4 fusion reporter assays, trichostatin A pharmacological inhibition, overexpression reporter assays The Journal of biological chemistry High 11278948
2012 SHARP1/DEC2 (BHLHE41) suppresses breast cancer metastasis by directly binding to HIF-1α and HIF-2α and promoting their proteasomal degradation, serving as the HIF-presenting factor to the proteasome. This process is independent of pVHL, hypoxia, and the ubiquitination machinery. Co-IP demonstrating SHARP1-HIF interaction, proteasomal degradation assays, in vitro migration/invasion assays, in vivo metastasis models, gain- and loss-of-function Nature High 22801492
2012 G9a lysine methyltransferase directly interacts with Sharp-1 and enhances its ability to transcriptionally repress the myogenin promoter; Sharp-1 overexpression leads to G9a-dependent H3K9me2 and MyoD methylation at muscle gene promoters, and G9a inhibition rescues the Sharp-1-imposed differentiation block. Co-IP demonstrating Sharp-1/G9a interaction, ChIP for H3K9me2, siRNA knockdown, pharmacological inhibition of G9a Molecular biology of the cell High 23087213
2013 Sharp-1 associates directly with Smad3 (co-immunoprecipitation), and overexpression of Sharp-1 inhibits TGF-β- and Smad3-mediated expression of extracellular matrix genes in myofibroblasts, placing Sharp-1 as a regulator of TGF-β signaling in muscle regeneration. Co-IP, in vitro overexpression, knockout mouse model of injury-induced muscle regeneration, decorin treatment rescue Journal of cell science Medium 24357723
2013 Sumoylation of Sharp-1 at two conserved lysine residues (K240 and K255) is required for its full transcriptional repression activity and inhibition of myogenic differentiation; sumoylation acts as a signal for recruitment of the co-repressor G9a and associated H3K9me2 mark at muscle promoters. SUMO site mutagenesis (K240R, K255R), ChIP for G9a and H3K9me2, SENP1 co-expression, myogenic differentiation assays The Journal of biological chemistry High 23637228
2014 SENP1 (SUMO-specific protease 1) is a specific de-SUMOylation protease for Sharp-1; SENP1-mediated de-SUMOylation of Sharp-1 releases Sharp-1 repression of PPARγ transcription, thereby promoting adipocyte differentiation. SENP1 knockout mouse embryonic fibroblasts, de-SUMOylation assays, adipocyte differentiation assays The Journal of biological chemistry Medium 24942744
2014 DEC2 suppresses prepro-orexin (Hcrt) promoter activity through cis-acting E-box elements; the short-sleep mutant DEC2-P384R has reduced repressor activity and decreased binding affinity to the prepro-orexin promoter due to weakened interaction with other transcription factors, resulting in increased orexin expression. Cell culture reporter assay, transgenic mouse model, orexin receptor antagonist treatment rescue, promoter binding assays Proceedings of the National Academy of Sciences High 29531056
2014 A novel BHLHE41 variant (Y362H) reduces the ability of BHLHE41 to suppress CLOCK/BMAL1 and NPAS2/BMAL1 transactivation in vitro, and is associated with reduced sleep duration and resistance to sleep deprivation; random mutagenesis identified additional variants affecting CLOCK/BMAL1 suppression. Cell-based luciferase reporter assay for CLOCK/BMAL1 transactivation suppression, sequencing of BHLHE41 gene in sleep-phenotyped cohorts Sleep Medium 25083013
2015 BHLHE41 competes with transcription factor SP1 for DNA binding to regulate TWIST1 gene transcription; BHLHE41 suppresses transcription of EMT effectors SNAI1, SNAI2, and TWIST1 in endometrial cancer cells. Luciferase reporter assays, promoter deletion analysis, siRNA knockdown, invasion assays Molecular and cellular biology Medium 26391953
2014 DEC2 represses Twist1 transcription by directly binding to a consensus E-box (CACGTG) in the Twist1 promoter, as demonstrated by site-directed mutagenesis abolishing DEC2 response and ChIP confirming direct binding. Luciferase reporter assays, site-directed mutagenesis of E-box, ChIP assay, siRNA knockdown Biochemical and biophysical research communications High 25446074
2008 Sharp-1/DEC2 is expressed in the suprachiasmatic nucleus and peripheral tissues with circadian oscillation; Sharp-1 and Sharp-2 regulate period length, tissue-specific clock gene expression, and entrainment to external cues in vivo; in a context-specific manner, SHARP-1 can serve dual functions as both repressor and co-activator of mammalian clock gene expression. Sharp-1 and Sharp-2 single and double mutant mice, circadian behavior recording, light-pulse phase-shifting experiments, jet-lag paradigm PloS one High 18648504
2010 DEC2 (BHLHE41) interacts with HDAC1 (co-immunoprecipitation), and bexarotene treatment causes recruitment of both DEC2 and HDAC1 to the cyclin D1 promoter (ChIP), repressing cyclin D1 transcription; HDAC inhibitor TSA reverses repression, and DEC2 siRNA knockdown abolishes repression. Co-immunoprecipitation, ChIP, luciferase reporter assay, siRNA knockdown, TSA pharmacological inhibition Breast cancer research and treatment High 20821348
2012 RORα activates Dec1 and Dec2 expression through novel ROR response elements (ROREs) identified in the Dec1 and Dec2 promoters, but REVERBα does not repress Dec2 via these elements (unlike its effect on Bmal1), indicating distinct regulation of Dec2 by nuclear receptors. Luciferase reporter assays, EMSA, ChIP assays for RORα binding to DEC2 promoter Genes to cells Medium 22244086
2015 DEC2-E4BP4 form a heterodimer that binds to the EE element (direct repeat of E-box-like sequences) in the Per2 promoter and represses Per2 transcription, identifying this heterodimer as a key repressor of the Per2 feedback loop. Reporter assays, protein-protein interaction studies, promoter binding assays Frontiers in neurology Medium 26257703
2017 Bhlhe41 is essential for B-1a cell development and self-renewal; Bhlhe41 directly represses cell-cycle regulators and inhibitors of BCR signaling while enabling pro-survival cytokine signaling, as determined by Bhlhe41-/- Bhlhe40-/- double knockout mice showing severely reduced B-1a cells with abnormal phenotype and altered BCR repertoire. Bhlhe41/Bhlhe40 double knockout mouse model, flow cytometry, gene expression analysis, pre-rearranged BCR rescue experiment Nature immunology High 28250425
2018 SHARP1 is an oncogenic driver in MLL-AF6 AML; its expression is directly regulated by MLL-AF6/DOT1L; SHARP1 binds to transcriptionally active chromatin and activates genes critical for cell survival and key oncogenic MLL-AF6 targets; genetic deletion in mice delays leukemia development while sparing normal hematopoiesis. MLL-AF6 AML cell lines, SHARP1 knockdown/overexpression, ChIP-seq, mouse leukemia model, human AML samples Nature communications High 29692408
2019 Bhlhe40 and Bhlhe41 are required for alveolar macrophage self-renewal and identity; genome-wide characterization of Bhlhe40 DNA binding showed direct repression of lineage-inappropriate genes in alveolar macrophages; knockout cells showed decreased proliferation and downregulation of AM signature genes. Bhlhe40/Bhlhe41 knockout mice, competitive bone marrow transplantation, ChIP-seq, RNA-seq The EMBO journal High 31414712
2019 Dec2 directly represses Sohlh1 (a spermatogonial differentiation factor) transcription in neonatal germ cells; Dec2 deficiency in mice reduces undifferentiated spermatogonia and impairs spermatogonial stem cell engraftment efficiency. Single-cell RNA-seq, Dec2 knockout mice, spermatogonial transplantation assay Scientific reports Medium 30988352
2020 BHLHE40 and BHLHE41 act in negative feedback opposition to TFEB; genes counter-regulated by TFEB and BHLHE40/41 were identified, with BHLHE40/41 protecting cells from lysosomal cell death when TFEB drives their expression. Genome-wide CRISPR library screen, transcriptional response assays, lysosomal cell death assays Cell reports Medium 33176151
2022 METTL3 promotes BHLHE41 expression in an m6A-dependent manner (epitranscriptomic regulation); BHLHE41 subsequently induces CXCL1 transcription to enhance MDSC migration; BHLHE41 depletion abolishes the METTL3-driven MDSC migration effect, establishing the m6A-BHLHE41-CXCL1/CXCR2 axis. m6A sequencing, RNA sequencing, cytokine arrays, BHLHE41 siRNA depletion, CXCR2 inhibitor treatment, syngeneic mouse models, CD34+ humanized mice Gastroenterology High 35700773
2022 In the CIC-PER2-BHLHE41 axis regulating B-1a cell development, CIC suppresses postnatal B-1a cells by repressing Per2; CIC deficiency mediates Per2 derepression which inhibits CRY-mediated transcriptional repression of Bhlhe41, thereby upregulating Bhlhe41 levels and promoting B-1a cell formation. B-cell-specific Cic-null mice, BCR signaling analysis, genetic pathway analysis Cell reports Medium 35172136
2013 GLI1/GLI2 activate BHLHE41/DEC2/SHARP1 expression through a GLI-binding site in its promoter; activated BHLHE41 then suppresses MLH1 expression in pancreatic cancer cells, establishing a GLI1-BHLHE41-MLH1 pathway that impairs DNA mismatch repair. GLI1 target gene screening, promoter reporter assays with GLI-binding site, double knockdown of GLI1/GLI2, TALEN-based MLH1 gene modification, immunohistochemistry Cancer research Medium 24165159
2018 HDAC4 regulates Sharp1 expression in satellite cells; HDAC4 conditional knockout leads to upregulation of Sharp1 (and P21), which blocks satellite cell differentiation. Reducing Sharp1 expression in HDAC4 KO satellite cells rescues the differentiation block, placing Sharp1 downstream of HDAC4. Tamoxifen-inducible conditional HDAC4 knockout in Pax7+ cells, RNA-sequencing, shRNA-mediated Sharp1 reduction rescue experiment Scientific reports Medium 29472596
2014 SHARP1 physically interacts with HIF-1α in endometrial cancer cells; SHARP1 overexpression decreases HIF-1α protein levels and reduces expression of HIF-1α target genes (VEGFA, ANGPTL4, CA9) under hypoxia, suppressing hypoxia-induced angiogenesis. Co-immunoprecipitation, western blotting, siRNA knockdown, in vivo xenograft model PloS one Medium 24918449
2014 Insulin induces SHARP-1 gene expression at the transcriptional level via both PI3-K/aPKCλ/JNK and PI3-K/Rac/JNK signaling pathways; new protein synthesis is required for induction; and overexpressed SHARP-1 specifically represses PEPCK promoter activity. Pharmacological inhibitors (LY294002, wortmannin, staurosporine), dominant-negative aPKCλ and Rac1 overexpression, actinomycin D and cycloheximide treatment, promoter-reporter assays Hormone and metabolic research Medium 24446161

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Dec1 and Dec2 are regulators of the mammalian molecular clock. Nature 569 12397359
2009 The transcriptional repressor DEC2 regulates sleep length in mammals. Science (New York, N.Y.) 241 19679812
2022 METTL3 Inhibits Antitumor Immunity by Targeting m6A-BHLHE41-CXCL1/CXCR2 Axis to Promote Colorectal Cancer. Gastroenterology 211 35700773
2012 SHARP1 suppresses breast cancer metastasis by promoting degradation of hypoxia-inducible factors. Nature 211 22801492
2002 Identification of functional hypoxia response elements in the promoter region of the DEC1 and DEC2 genes. The Journal of biological chemistry 196 12354771
2003 DEC1 negatively regulates the expression of DEC2 through binding to the E-box in the proximal promoter. The Journal of biological chemistry 102 12624110
2017 Essential role for the transcription factor Bhlhe41 in regulating the development, self-renewal and BCR repertoire of B-1a cells. Nature immunology 92 28250425
2001 Molecular cloning and characterization of DEC2, a new member of basic helix-loop-helix proteins. Biochemical and biophysical research communications 91 11162494
2014 A novel BHLHE41 variant is associated with short sleep and resistance to sleep deprivation in humans. Sleep 90 25083013
2014 DEC1/STRA13/SHARP2 and DEC2/SHARP1 coordinate physiological processes, including circadian rhythms in response to environmental stimuli. Current topics in developmental biology 89 25248482
2016 DEC1 and DEC2 Crosstalk between Circadian Rhythm and Tumor Progression. Journal of Cancer 88 26819638
2008 Disturbed clockwork resetting in Sharp-1 and Sharp-2 single and double mutant mice. PloS one 86 18648504
2019 Bhlhe40 and Bhlhe41 transcription factors regulate alveolar macrophage self-renewal and identity. The EMBO journal 81 31414712
2008 Human mismatch repair gene, MLH1, is transcriptionally repressed by the hypoxia-inducible transcription factors, DEC1 and DEC2. Oncogene 80 18345027
2009 Requirement for the basic helix-loop-helix transcription factor Dec2 in initial TH2 lineage commitment. Nature immunology 78 19881507
2004 Expression of the gene for Dec2, a basic helix-loop-helix transcription factor, is regulated by a molecular clock system. The Biochemical journal 76 15147242
2008 Basic-helix-loop-helix (bHLH) transcription factor DEC2 negatively regulates vascular endothelial growth factor expression. Genes to cells : devoted to molecular & cellular mechanisms 72 18233956
2004 Sharp-1/DEC2 inhibits skeletal muscle differentiation through repression of myogenic transcription factors. The Journal of biological chemistry 72 15448136
2003 mSharp-1/DEC2, a basic helix-loop-helix protein functions as a transcriptional repressor of E box activity and Stra13 expression. The Journal of biological chemistry 67 12657651
2010 Anti-apoptotic effect of the basic helix-loop-helix (bHLH) transcription factor DEC2 in human breast cancer cells. Genes to cells : devoted to molecular & cellular mechanisms 62 20236182
2018 DEC2 modulates orexin expression and regulates sleep. Proceedings of the National Academy of Sciences of the United States of America 60 29531056
2004 Rhythmic expression of DEC1 and DEC2 in peripheral tissues: DEC2 is a potent suppressor for hepatic cytochrome P450s opposing DBP. Genes to cells : devoted to molecular & cellular mechanisms 59 15066123
2008 Stra13/DEC1 and DEC2 inhibit sterol regulatory element binding protein-1c in a hypoxia-inducible factor-dependent mechanism. Nucleic acids research 57 18838394
2009 The basic helix-loop-helix proteins differentiated embryo chondrocyte (DEC) 1 and DEC2 function as corepressors of retinoid X receptors. Molecular pharmacology 51 19786558
2007 Transcriptional repression by the basic helix-loop-helix protein Dec2: multiple mechanisms through E-box elements. International journal of molecular medicine 51 17487425
2011 Basic helix-loop-helix transcription factors DEC1 and DEC2 regulate the paclitaxel-induced apoptotic pathway of MCF-7 human breast cancer cells. International journal of molecular medicine 46 21327324
2020 TFEB Transcriptional Responses Reveal Negative Feedback by BHLHE40 and BHLHE41. Cell reports 45 33176151
2013 GLI1 interferes with the DNA mismatch repair system in pancreatic cancer through BHLHE41-mediated suppression of MLH1. Cancer research 45 24165159
2018 HDAC4 regulates satellite cell proliferation and differentiation by targeting P21 and Sharp1 genes. Scientific reports 44 29472596
2015 Regulation of the Mechanism of TWIST1 Transcription by BHLHE40 and BHLHE41 in Cancer Cells. Molecular and cellular biology 43 26391953
2008 SHARP1/DEC2 inhibits adipogenic differentiation by regulating the activity of C/EBP. EMBO reports 41 19029947
2012 G9a mediates Sharp-1-dependent inhibition of skeletal muscle differentiation. Molecular biology of the cell 40 23087213
2005 Tissue-specific disruption of rhythmic expression of Dec1 and Dec2 in clock mutant mice. Journal of biological rhythms 40 16267380
2023 A transient wave of Bhlhe41+ resident macrophages enables remodeling of the developing infarcted myocardium. Cell reports 39 37751357
2015 DEC2 expression is positively correlated with HIF-1 activation and the invasiveness of human osteosarcomas. Journal of experimental & clinical cancer research : CR 37 25884381
2010 The rexinoid bexarotene represses cyclin D1 transcription by inducing the DEC2 transcriptional repressor. Breast cancer research and treatment 36 20821348
2014 Stra13 and Sharp-1, the non-grouchy regulators of development and disease. Current topics in developmental biology 34 25248481
2016 Functional characterization of the 12p12.1 renal cancer-susceptibility locus implicates BHLHE41. Nature communications 33 27384883
2009 Dec2 promotes Th2 cell differentiation by enhancing IL-2R signaling. Journal of immunology (Baltimore, Md. : 1950) 33 19880450
2001 The basic helix-loop-helix protein, sharp-1, represses transcription by a histone deacetylase-dependent and histone deacetylase-independent mechanism. The Journal of biological chemistry 33 11278948
2012 BHLH transcription factor DEC2 regulates pro-apoptotic factor Bim in human oral cancer HSC-3 cells. Biomedical research (Tokyo, Japan) 31 22572381
2014 Mice lacking the circadian modulators SHARP1 and SHARP2 display altered sleep and mixed state endophenotypes of psychiatric disorders. PloS one 30 25340473
2015 Differentially Expressed in Chondrocytes 2 (DEC2) Increases the Expression of IL-1β and Is Abundantly Present in Synovial Membrane in Rheumatoid Arthritis. PloS one 29 26710124
2016 DEC2 suppresses tumor proliferation and metastasis by regulating ERK/NF-κB pathway in gastric cancer. American journal of cancer research 27 27648362
2014 SHARP1 suppresses angiogenesis of endometrial cancer by decreasing hypoxia-inducible factor-1α level. PloS one 27 24918449
2014 Small ubiquitin-like modifier (SUMO) protein-specific protease 1 de-SUMOylates Sharp-1 protein and controls adipocyte differentiation. The Journal of biological chemistry 27 24942744
2012 The basic helix-loop-helix transcription factor DEC2 inhibits TGF-β-induced tumor progression in human pancreatic cancer BxPC-3 cells. International journal of molecular medicine 27 22735690
2011 Berberine exerts anti-adipogenic activity through up-regulation of C/EBP inhibitors, CHOP and DEC2. Biochemical and biophysical research communications 27 21893041
2004 Dec1 and Dec2 expression is disrupted in the suprachiasmatic nuclei of Clock mutant mice. Journal of biological rhythms 26 15038852
2014 Involvement of c-Myc in the proliferation of MCF-7 human breast cancer cells induced by bHLH transcription factor DEC2. International journal of molecular medicine 25 25524285
2007 Differential regulation of DEC2 among hypoxia-inducible genes in endometrial carcinomas. Oncology reports 25 17342330
2021 A deficiency of Dec2 triggers periodontal inflammation and pyroptosis. Journal of periodontal research 24 33641180
2012 Regulation of basic helix-loop-helix transcription factors Dec1 and Dec2 by RORα and their roles in adipogenesis. Genes to cells : devoted to molecular & cellular mechanisms 24 22244086
2021 Inhibition of DEC2 is necessary for exiting cell dormancy in salivary adenoid cystic carcinoma. Journal of experimental & clinical cancer research : CR 23 33990215
2020 MicroRNA-16 directly binds to DEC2 and inactivates the TLR4 signaling pathway to inhibit lupus nephritis-induced kidney tissue hyperplasia and mesangial cell proliferation. International immunopharmacology 23 32795896
2015 Enhanced memory consolidation in mice lacking the circadian modulators Sharp1 and -2 caused by elevated Igf2 signaling in the cortex. Proceedings of the National Academy of Sciences of the United States of America 23 26100875
2013 p63, Sharp1, and HIFs: master regulators of metastasis in triple-negative breast cancer. Cancer research 23 23913939
2018 The basic helix-loop-helix transcription factor SHARP1 is an oncogenic driver in MLL-AF6 acute myelogenous leukemia. Nature communications 22 29692408
2014 Suppression of the epithelial-mesenchymal transition by SHARP1 is linked to the NOTCH1 signaling pathway in metastasis of endometrial cancer. BMC cancer 22 24997474
2019 Smad3 Suppresses Epithelial Cell Migration and Proliferation via the Clock Gene Dec1, Which Negatively Regulates the Expression of Clock Genes Dec2 and Per1. The American journal of pathology 20 30664860
2013 Sumoylation of the basic helix-loop-helix transcription factor sharp-1 regulates recruitment of the histone methyltransferase G9a and function in myogenesis. The Journal of biological chemistry 20 23637228
2019 Overexpression of BHLHE41, correlated with DNA hypomethylation in 3'UTR region, promotes the growth of human clear cell renal cell carcinoma. Oncology reports 18 30816499
2019 BHLHE41 promotes U87 and U251 cell proliferation via ERK/cyclinD1 signaling pathway. Cancer management and research 18 31616182
2016 Basic helix-loop-helix transcription factor DEC2 functions as an anti-apoptotic factor during paclitaxel-induced apoptosis in human prostate cancer cells. International journal of molecular medicine 18 27840924
2008 BHLHB3: a candidate tumor suppressor in lung cancer. Oncogene 18 18223678
2013 Sharp-1 regulates TGF-β signaling and skeletal muscle regeneration. Journal of cell science 17 24357723
2020 BHLHE41 suppresses MCF-7 cell invasion via MAPK/JNK pathway. Journal of cellular and molecular medicine 15 32073238
2006 Molecular analysis of Dec1 and Dec2 in the peripheral circadian clock of zebrafish photosensitive cells. Biochemical and biophysical research communications 15 17097613
2022 Dec2 inhibits macrophage pyroptosis to promote periodontal homeostasis. Journal of periodontal & implant science 14 35187871
2017 DEC2 Blocks the Effect of the ARNTL2/NPAS2 Dimer on the Expression of PER3 and DBP. Journal of circadian rhythms 14 30210560
2009 Sharp-1 modulates the cellular response to DNA damage. FEBS letters 14 20006609
2018 Correlation between DEC1/DEC2 and epithelial‑mesenchymal transition in human prostate cancer PC‑3 cells. Molecular medicine reports 13 30106153
2021 CHRONO and DEC1/DEC2 compensate for lack of CRY1/CRY2 in expression of coherent circadian rhythm but not in generation of circadian oscillation in the neonatal mouse SCN. Scientific reports 12 34584158
2016 Rhythmic expression of DEC2 protein in vitro and in vivo. Biomedical reports 12 27284410
2024 Cancer-associated fibroblasts-derived CXCL1 activates DEC2-mediated dormancy in oral squamous cell carcinoma. Heliyon 11 39469703
2022 Postnatal regulation of B-1a cell development and survival by the CIC-PER2-BHLHE41 axis. Cell reports 11 35172136
2012 Tissue-specific interaction of Per1/2 and Dec2 in the regulation of fibroblast circadian rhythms. Journal of biological rhythms 11 23223373
2023 Hypoxia induced cell dormancy of salivary adenoid cystic carcinoma through miR-922/DEC2 axis. Translational oncology 10 38141378
2022 Identification of novel B-1 transitional progenitors by B-1 lymphocyte fate-mapping transgenic mouse model Bhlhe41 dTomato-Cre. Frontiers in immunology 10 36189231
2019 Mutual suppression between BHLHE40/BHLHE41 and the MIR301B-MIR130B cluster is involved in epithelial-to-mesenchymal transition of endometrial cancer cells. Oncotarget 10 31384392
2018 Contribution of the clock gene DEC2 to VEGF mRNA upregulation by modulation of HIF1α protein levels in hypoxic MIO-M1 cells, a human cell line of retinal glial (Müller) cells. Japanese journal of ophthalmology 10 30250985
2010 Basic-helix-loop-helix transcription factor DEC2 constitutes negative feedback loop in IFN-β-mediated inflammatory responses in human mesangial cells. Immunology letters 10 21129405
2024 BHLHE41, a transcriptional repressor involved in physiological processes and tumor development. Cellular oncology (Dordrecht, Netherlands) 9 39254779
2019 Single cell RNA-sequencing identified Dec2 as a suppressive factor for spermatogonial differentiation by inhibiting Sohlh1 expression. Scientific reports 9 30988352
2017 DEC2 expression antagonizes cisplatin‑induced apoptosis in human esophageal squamous cell carcinoma. Molecular medicine reports 9 28498447
2016 DEC2 is a negative regulator for the proliferation and differentiation of chondrocyte lineage-committed mesenchymal stem cells. International journal of molecular medicine 9 27430159
2015 DEC2-E4BP4 Heterodimer Represses the Transcriptional Enhancer Activity of the EE Element in the Per2 Promoter. Frontiers in neurology 9 26257703
2011 Significant dissociation of expression patterns of the basic helix-loop-helix transcription factors Dec1 and Dec2 in rat kidney. The Journal of experimental biology 9 21430201
2023 Knockdown of DEC2 expression inhibits the proliferation of mesangial cells through suppressed glycolysis and p38 MAPK/Erk pathway in lupus nephritis. Molecular medicine (Cambridge, Mass.) 8 37488524
2023 Approach to Functions of BHLHE41/DEC2 in Non-Small Lung Cancer Development. International journal of molecular sciences 8 37511489
2014 The basic helix-loop-helix (bHLH) transcription factor DEC2 negatively regulates Twist1 through an E-box element. Biochemical and biophysical research communications 8 25446074
2006 Common polymorphisms in D12S1034 flanking genes RASSF8 and BHLHB3 are not associated with lung adenocarcinoma risk. Lung cancer (Amsterdam, Netherlands) 8 17194498
2003 Cloning and characterization of canine SHARP1 and its evaluation as a positional candidate for canine early retinal degeneration (erd). Gene 8 12909371
2018 Expression of DEC2 enhances chemosensitivity by inhibiting STAT5A in gastric cancer. Journal of cellular biochemistry 7 30485509
2016 Roles of SHARP1 in thyroid cancer. Molecular medicine reports 7 27121679
2016 Bone muscle crosstalk targets muscle regeneration pathway regulated by core circadian transcriptional repressors DEC1 and DEC2. BoneKEy reports 7 27867498
2014 Insulin stimulates the expression of the SHARP-1 gene via multiple signaling pathways. Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme 7 24446161
2020 DEC2 Serves as Potential Tumor Suppressor in Breast Carcinoma. Disease markers 6 33101542
2018 Loss of the basic helix-loop-helix transcription factor Bhlhe41 induces cell death and impairs neurite outgrowth in Neuro2a cells. Molecular and cellular biochemistry 6 29926321
2020 Dec2 attenuates autophagy in inflamed periodontal tissues. Immunity, inflammation and disease 5 33270996

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