BHLHE40 (DEC1/STRA13/SHARP2) is a class E basic helix-loop-helix-Orange transcription factor of the HES-related family that acts predominantly as a sequence-specific transcriptional repressor in the nucleus. It binds class B CACGTG E-boxes as a homodimer or as a heterodimer with its paralog BHLHE41/DEC2, and represses RNA polymerase II target genes by competing with activators such as CLOCK-BMAL1 and by HDAC1-dependent and -independent mechanisms. It is a clock-controlled gene and an auxiliary component of the circadian clock: it represses PER1, DBP, BHLHE41 and its own promoter, and tunes the phase and robustness of E-box-driven clock gene expression. It also acts as a corepressor of RXR and RXR heterodimers through an LXXLL motif, and interacts with p53. BHLHE40 is strongly induced by hypoxia (a direct HIF-1 target) and by retinoic acid, serum deprivation, DNA damage and immune activation. In immune cells it controls cytokine programmes, promoting GM-CSF and repressing IL-10 in T cells and myeloid cells. In tissue-resident macrophages it supports self-renewal and proliferation by repressing c-Maf/MafB. Its activity and stability are modulated by SUMOylation and ubiquitin-proteasome turnover.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000122 negative regulation of transcription by RNA polymerase II | IBA GO_REF:0000033 | ACCEPT | Summary: IBA: BHLHE40 inherits repression of RNA polymerase II transcription from the HES/HEY/DEC bHLH-Orange repressor clade. Reason: Repression of Pol II target promoters (PER1, DEC2/BHLHE41, DBP, its own promoter, NR0B2, ATP1B1) through CACGTG E-boxes is the best-documented activity of BHLHE40, and the PAINT node placement across the bHLH-Orange repressor family is consistent with the experimental data on the human protein itself. Supporting Evidence: file:human/BHLHE40/BHLHE40-uniprot.txt Transcriptional repressor involved in the regulation of the circadian rhythm by negatively regulating the activity of the clock genes and clock-controlled genes PMID:15193144 In the absence of Clock/Bmal1, both DEC1 and DEC2 markedly repressed the mPer1 promoter reporter; however, DNA-binding mutants showed no repressive activity |
| GO:0000122 negative regulation of transcription by RNA polymerase II | IDA PMID:12397359 Dec1 and Dec2 are regulators of the mammalian molecular cloc... | ACCEPT | Summary: Honma et al. 2002 showed DEC1 represses CLOCK/BMAL1-driven Per1 promoter activity. Reason: Direct reporter-based evidence that DEC1 represses a Pol II-transcribed clock gene promoter; core function. Supporting Evidence: PMID:12397359 repressed Clock/Bmal1-induced transactivation of the mouse Per1 promoter through direct protein-protein interactions with Bmal1 and/or competition for E-box elements |
| GO:0000122 negative regulation of transcription by RNA polymerase II | IDA PMID:12624110 DEC1 negatively regulates the expression of DEC2 through bin... | ACCEPT | Summary: Li et al. 2003 showed DEC1 represses the DEC2 promoter through a proximal E-box, dependent on DNA binding. Reason: Repression of the BHLHE41 promoter requires DEC1 DNA binding and an intact E-box; direct evidence for repression of Pol II transcription. Supporting Evidence: PMID:12624110 The repression was observed with wild type DEC1 but not its DNA binding-defective mutants PMID:12624110 Our findings assign for DEC1 the first target gene that is regulated through direct DNA binding |
| GO:0000122 negative regulation of transcription by RNA polymerase II | IDA PMID:14672706 A novel autofeedback loop of Dec1 transcription involved in ... | ACCEPT | Summary: Kawamoto et al. 2004 showed DEC1 represses CLOCK/BMAL-induced Dec1 promoter activity (autofeedback loop). Reason: Repression through CACGTG E-boxes of its own Pol II promoter; core function. Supporting Evidence: PMID:14672706 DEC1 and DEC2 as well as PERs and CRYs suppressed the induced expression. Three CACGTG E-boxes are responsible for both the activation and the suppression of Dec1 transcription |
| GO:0000122 negative regulation of transcription by RNA polymerase II | IDA PMID:15193144 DNA binding, but not interaction with Bmal1, is responsible ... | ACCEPT | Summary: Li et al. 2004 showed DEC1 represses the mPer1 promoter in a DNA-binding-dependent manner. Reason: Mutational evidence that DNA binding, not BMAL1 interaction, is required for repression of the Per1 promoter; core function. Supporting Evidence: PMID:15193144 In the absence of Clock/Bmal1, both DEC1 and DEC2 markedly repressed the mPer1 promoter reporter; however, DNA-binding mutants showed no repressive activity PMID:15193144 providing direct evidence that DNA binding, rather than Bmal1 interactions, is responsible for the repression on the mPer1 promoter |
| GO:0000122 negative regulation of transcription by RNA polymerase II | IDA PMID:18411297 DEC1 modulates the circadian phase of clock gene expression. | ACCEPT | Summary: Nakashima et al. 2008 showed DEC1 binds and transrepresses CACGTG E-boxes of clock genes in ChIP, EMSA and reporter assays. Reason: Direct evidence of repression of E-box-containing Pol II clock genes; core function. Supporting Evidence: PMID:18411297 DEC1 showed strong binding and transrepression on the E box, but not on the E' box, in chromatin immunoprecipitation, electrophoretic mobility shift, and luciferase reporter assays PMID:18411297 Overexpression of Dec1 delayed the phase of clock genes such as Dec1, Dec2, Per1, and Dbp that contain E boxes in their regulatory regions |
| GO:0000785 chromatin | ISA GO_REF:0000113 | ACCEPT | Summary: TFClass-based ISA assignment of chromatin location for a sequence-specific DNA-binding transcription factor. Reason: BHLHE40 occupies E-box elements of target promoters in chromatin, shown by ChIP for SHP/NR0B2, ATP1B1 and clock genes, so chromatin is a correct location for its repressor activity. Supporting Evidence: PMID:28797635 Site-directed mutagenesis, electrophoretic mobility shift assay and chromatin immunoprecipitation established that the repression was achieved through the E-box in the proximal promoter PMID:30012868 we found that DEC1 and CLOCK bound to E-boxes in the ATP1B1 promoter PMID:18411297 DEC1 showed strong binding and transrepression on the E box, but not on the E' box, in chromatin immunoprecipitation, electrophoretic mobility shift, and luciferase reporter assays |
| GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding | IBA GO_REF:0000033 | ACCEPT | Summary: IBA annotation for RNA polymerase II cis-regulatory region sequence-specific DNA binding. Reason: BHLHE40 binds CACGTG E-boxes in the proximal promoters of Pol II genes (DEC2, PER1, NR0B2, ATP1B1). E-box binding (GO:0070888), accepted elsewhere, is a descendant, but this term still states the cis-regulatory, Pol II context and is consistent with that evidence. Supporting Evidence: PMID:12624110 Our findings assign for DEC1 the first target gene that is regulated through direct DNA binding PMID:28797635 Site-directed mutagenesis, electrophoretic mobility shift assay and chromatin immunoprecipitation established that the repression was achieved through the E-box in the proximal promoter |
| GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding | IEA GO_REF:0000107 | ACCEPT | Summary: IEA (Ensembl Compara from mouse) annotation for RNA polymerase II cis-regulatory region sequence-specific DNA binding. Reason: BHLHE40 binds CACGTG E-boxes in the proximal promoters of Pol II genes (DEC2, PER1, NR0B2, ATP1B1). E-box binding (GO:0070888), accepted elsewhere, is a descendant, but this term still states the cis-regulatory, Pol II context and is consistent with that evidence. Supporting Evidence: PMID:12624110 Our findings assign for DEC1 the first target gene that is regulated through direct DNA binding PMID:28797635 Site-directed mutagenesis, electrophoretic mobility shift assay and chromatin immunoprecipitation established that the repression was achieved through the E-box in the proximal promoter |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | IBA GO_REF:0000033 | ACCEPT | Summary: IBA annotation for RNA polymerase II-specific DNA-binding transcription factor activity. Reason: BHLHE40 is a sequence-specific E-box-binding transcription factor acting on Pol II promoters. Most direct targets are repressed (GO:0001227 is accepted), but ChIP-seq studies in mouse immune cells also report direct positive effects on some loci (e.g. GM-CSF, cell-cycle genes), so the general DbTF term is retained alongside the repressor term rather than replaced. Supporting Evidence: file:human/BHLHE40/BHLHE40-uniprot.txt Transcriptional repressor involved in the regulation of the circadian rhythm by negatively regulating the activity of the clock genes and clock-controlled genes PMID:15193144 In the absence of Clock/Bmal1, both DEC1 and DEC2 markedly repressed the mPer1 promoter reporter; however, DNA-binding mutants showed no repressive activity |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | IDA PMID:12397359 Dec1 and Dec2 are regulators of the mammalian molecular cloc... | ACCEPT | Summary: IDA (Honma et al. 2002) annotation for RNA polymerase II-specific DNA-binding transcription factor activity. Reason: BHLHE40 is a sequence-specific E-box-binding transcription factor acting on Pol II promoters. Most direct targets are repressed (GO:0001227 is accepted), but ChIP-seq studies in mouse immune cells also report direct positive effects on some loci (e.g. GM-CSF, cell-cycle genes), so the general DbTF term is retained alongside the repressor term rather than replaced. Supporting Evidence: PMID:12397359 repressed Clock/Bmal1-induced transactivation of the mouse Per1 promoter through direct protein-protein interactions with Bmal1 and/or competition for E-box elements |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | IEA GO_REF:0000107 | ACCEPT | Summary: IEA (Ensembl Compara) annotation for RNA polymerase II-specific DNA-binding transcription factor activity. Reason: BHLHE40 is a sequence-specific E-box-binding transcription factor acting on Pol II promoters. Most direct targets are repressed (GO:0001227 is accepted), but ChIP-seq studies in mouse immune cells also report direct positive effects on some loci (e.g. GM-CSF, cell-cycle genes), so the general DbTF term is retained alongside the repressor term rather than replaced. Supporting Evidence: file:human/BHLHE40/BHLHE40-uniprot.txt Transcriptional repressor involved in the regulation of the circadian rhythm by negatively regulating the activity of the clock genes and clock-controlled genes PMID:15193144 In the absence of Clock/Bmal1, both DEC1 and DEC2 markedly repressed the mPer1 promoter reporter; however, DNA-binding mutants showed no repressive activity |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | ISA GO_REF:0000113 | ACCEPT | Summary: ISA (TFClass) annotation for RNA polymerase II-specific DNA-binding transcription factor activity. Reason: BHLHE40 is a sequence-specific E-box-binding transcription factor acting on Pol II promoters. Most direct targets are repressed (GO:0001227 is accepted), but ChIP-seq studies in mouse immune cells also report direct positive effects on some loci (e.g. GM-CSF, cell-cycle genes), so the general DbTF term is retained alongside the repressor term rather than replaced. Supporting Evidence: file:human/BHLHE40/BHLHE40-uniprot.txt Transcriptional repressor involved in the regulation of the circadian rhythm by negatively regulating the activity of the clock genes and clock-controlled genes PMID:15193144 In the absence of Clock/Bmal1, both DEC1 and DEC2 markedly repressed the mPer1 promoter reporter; however, DNA-binding mutants showed no repressive activity |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | ISS GO_REF:0000024 | ACCEPT | Summary: ISS (from mouse O35185) annotation for RNA polymerase II-specific DNA-binding transcription factor activity. Reason: BHLHE40 is a sequence-specific E-box-binding transcription factor acting on Pol II promoters. Most direct targets are repressed (GO:0001227 is accepted), but ChIP-seq studies in mouse immune cells also report direct positive effects on some loci (e.g. GM-CSF, cell-cycle genes), so the general DbTF term is retained alongside the repressor term rather than replaced. Supporting Evidence: file:human/BHLHE40/BHLHE40-uniprot.txt Transcriptional repressor involved in the regulation of the circadian rhythm by negatively regulating the activity of the clock genes and clock-controlled genes PMID:15193144 In the absence of Clock/Bmal1, both DEC1 and DEC2 markedly repressed the mPer1 promoter reporter; however, DNA-binding mutants showed no repressive activity |
| GO:0001227 DNA-binding transcription repressor activity, RNA polymerase II-specific | IDA PMID:12397359 Dec1 and Dec2 are regulators of the mammalian molecular cloc... | ACCEPT | Summary: Honma et al. 2002: DEC1 represses CLOCK/BMAL1-activated Per1 promoter, partly by competing for E-boxes. Reason: DNA-binding repressor activity at Pol II E-box promoters is the core molecular function. Supporting Evidence: PMID:12397359 repressed Clock/Bmal1-induced transactivation of the mouse Per1 promoter through direct protein-protein interactions with Bmal1 and/or competition for E-box elements |
| GO:0001227 DNA-binding transcription repressor activity, RNA polymerase II-specific | IDA PMID:12624110 DEC1 negatively regulates the expression of DEC2 through bin... | ACCEPT | Summary: Li et al. 2003: DEC1 represses DEC2 promoter through a proximal E-box; DNA-binding mutants inactive. Reason: Direct mutational evidence for a DNA-binding-dependent repressor activity on a Pol II promoter. Supporting Evidence: PMID:12624110 The repression was observed with wild type DEC1 but not its DNA binding-defective mutants PMID:12624110 Our findings assign for DEC1 the first target gene that is regulated through direct DNA binding |
| GO:0001227 DNA-binding transcription repressor activity, RNA polymerase II-specific | IDA PMID:15193144 DNA binding, but not interaction with Bmal1, is responsible ... | ACCEPT | Summary: Li et al. 2004: DEC1 represses mPer1 dependent on DNA binding. Reason: Shows the repressor activity requires E-box binding. Supporting Evidence: PMID:15193144 In the absence of Clock/Bmal1, both DEC1 and DEC2 markedly repressed the mPer1 promoter reporter; however, DNA-binding mutants showed no repressive activity PMID:15193144 providing direct evidence that DNA binding, rather than Bmal1 interactions, is responsible for the repression on the mPer1 promoter |
| GO:0001227 DNA-binding transcription repressor activity, RNA polymerase II-specific | IDA PMID:18411297 DEC1 modulates the circadian phase of clock gene expression. | ACCEPT | Summary: Nakashima et al. 2008: DEC1 binds and transrepresses E-boxes (ChIP, EMSA, reporter). Reason: Binding plus repression at the same element; core function. Supporting Evidence: PMID:18411297 DEC1 showed strong binding and transrepression on the E box, but not on the E' box, in chromatin immunoprecipitation, electrophoretic mobility shift, and luciferase reporter assays |
| GO:0001227 DNA-binding transcription repressor activity, RNA polymerase II-specific | IDA PMID:19786558 The basic helix-loop-helix proteins differentiated embryo ch... | ACCEPT | Summary: Cho et al. 2009: DEC1 represses RXR/LXR target gene induction and associates with an LXR target promoter. Reason: The main mechanism in this paper is corepression of RXR through an LXXLL motif, which is better captured by transcription corepressor activity (added as NEW). The curator, who had the full text, also recorded promoter association, and the DNA-binding repressor activity is in any case well established by other papers, so the row is kept. Supporting Evidence: PMID:19786558 DEC1 and DEC2 repressed the induction of LXR target genes, associated with the promoter of an LXR target gene, and dissociated from the promoter with ligand treatment PMID:15193144 providing direct evidence that DNA binding, rather than Bmal1 interactions, is responsible for the repression on the mPer1 promoter |
| GO:0001227 DNA-binding transcription repressor activity, RNA polymerase II-specific | IEA GO_REF:0000107 | ACCEPT | Summary: IEA (Ensembl Compara) transfer of DNA-binding transcription repressor activity from mouse. Reason: Consistent with extensive human experimental evidence. Supporting Evidence: file:human/BHLHE40/BHLHE40-uniprot.txt Represses the activity of the circadian transcriptional activator: CLOCK-BMAL1|BMAL2 heterodimer by competing for the binding to E-box elements (5'-CACGTG-3') found within the promoters of its target genes |
| GO:0003677 DNA binding | IEA GO_REF:0000120 | TOO GENERAL | Summary: Combined IEA for DNA binding. Reason: True, but uninformative beside the accepted E-box binding (GO:0070888) and RNA polymerase II cis-regulatory region sequence-specific DNA binding terms, which entail it. Supporting Evidence: PMID:12297495 Stra13 binds with high affinity to CACGTG class B E-box elements as a homodimer |
| GO:0003700 DNA-binding transcription factor activity | NAS PMID:9240428 Molecular characterization of the novel basic helix-loop-hel... | TOO GENERAL | Summary: NAS from the original cloning paper (Shen et al. 1997) for DNA-binding transcription factor activity. Reason: The cloning paper only predicts a bHLH transcription factor from sequence. The claim is true but is entailed by the accepted RNA polymerase II-specific DNA-binding transcription factor and repressor activity terms. Supporting Evidence: PMID:9240428 a novel human cDNA for a basic helix-loop-helix (bHLH) protein (named DEC1) |
| GO:0005515 protein binding | IPI PMID:11278694 Regulation of STRA13 by the von Hippel-Lindau tumor suppress... | REMOVE | Summary: Ivanova et al. 2001: yeast two-hybrid and cell-based interaction of STRA13 with UBC9 (UBE2I). Reason: The interaction concerns the turnover of BHLHE40 itself (UBC9-promoted ubiquitination and proteasomal degradation), i.e. BHLHE40 as a substrate rather than a function it performs. No more informative MF term is warranted, and bare protein binding is uninformative. Supporting Evidence: PMID:11278694 The yeast two-hybrid screening revealed interaction of the STRA13 protein with the human ubiquitin-conjugating enzyme (UBC9) protein PMID:11278694 Co-expression of STRA13 and UBC9 led to an increase of the pSTRA13 ubiquitination and subsequent degradation |
| GO:0005515 protein binding | IPI PMID:12397359 Dec1 and Dec2 are regulators of the mammalian molecular cloc... | MODIFY | Summary: Honma et al. 2002: DEC1 interaction with BMAL1 (bHLH-PAS transcription factor). Reason: The partner is the bHLH transcription factor BMAL1, so bHLH transcription factor binding (GO:0043425), already present in GOA from the same paper, is the informative term. Proposed replacements: bHLH transcription factor binding Supporting Evidence: PMID:12397359 repressed Clock/Bmal1-induced transactivation of the mouse Per1 promoter through direct protein-protein interactions with Bmal1 and/or competition for E-box elements |
| GO:0005515 protein binding | IPI PMID:17347673 Stra13 is induced by genotoxic stress and regulates ionizing... | MODIFY | Summary: Physical interaction of DEC1/Stra13 with p53. Reason: The interaction with TP53 is shown by GST pull-down and co-immunoprecipitation and modulates p53 activity (stabilization by Stra13; attenuation of p53 transactivation of MIC-1 by DEC1), so p53 binding (GO:0002039) is the informative term. Peripheral to the core clock/E-box repressor function. Proposed replacements: p53 binding Supporting Evidence: PMID:17347673 Stra13 regulates p53 levels in a mouse double mutant 2 (Mdm2)-dependent manner by physically interacting with p53 |
| GO:0005515 protein binding | IPI PMID:19786558 The basic helix-loop-helix proteins differentiated embryo ch... | MODIFY | Summary: Direct interaction of DEC1 with RXRalpha. Reason: DEC1 binds RXRalpha through an LXXLL motif and represses RXR-dependent transactivation; nuclear retinoid X receptor binding (GO:0046965) captures this. Proposed replacements: nuclear retinoid X receptor binding Supporting Evidence: PMID:19786558 DEC1 and DEC2 interacted directly with RXRalpha, and ligand addition enhanced their association PMID:19786558 an LXXLL motif in DEC1 and DEC2 is necessary for RXRalpha repression |
| GO:0005515 protein binding | IPI PMID:22458338 Host-pathogen interactome mapping for HTLV-1 and -2 retrovir... | REMOVE | Summary: Host-pathogen interactome screen reporting interaction with an HTLV protein. Reason: Uninformative bare protein binding with a viral protein from a large-scale screen; no functional consequence for BHLHE40 shown. |
| GO:0005515 protein binding | IPI PMID:22723347 Differentiated embryo-chondrocyte expressed gene 1 regulates... | MODIFY | Summary: Physical interaction of DEC1/Stra13 with p53. Reason: The interaction with TP53 is shown by GST pull-down and co-immunoprecipitation and modulates p53 activity (stabilization by Stra13; attenuation of p53 transactivation of MIC-1 by DEC1), so p53 binding (GO:0002039) is the informative term. Peripheral to the core clock/E-box repressor function. Proposed replacements: p53 binding Supporting Evidence: PMID:22723347 DEC1 and p53 physically interact on the MIC-1 promoter via the basic helix-loop-helix domain in DEC1 and the tetramerization domain in p53 |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: High-throughput binary interaction screen (yeast two-hybrid) reporting an interaction with UniProtKB:A1A580. Reason: Bare protein binding from a proteome-scale interaction screen is uninformative under the protein-binding policy; no specific functional consequence for BHLHE40 is shown. Removal does not mean the interaction is false. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: High-throughput binary interaction screen (yeast two-hybrid) reporting an interaction with UniProtKB:B7ZLI8. Reason: Bare protein binding from a proteome-scale interaction screen is uninformative under the protein-binding policy; no specific functional consequence for BHLHE40 is shown. Removal does not mean the interaction is false. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: High-throughput binary interaction screen (yeast two-hybrid) reporting an interaction with UniProtKB:C9JG97. Reason: Bare protein binding from a proteome-scale interaction screen is uninformative under the protein-binding policy; no specific functional consequence for BHLHE40 is shown. Removal does not mean the interaction is false. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: High-throughput binary interaction screen (yeast two-hybrid) reporting an interaction with UniProtKB:O60248. Reason: Bare protein binding from a proteome-scale interaction screen is uninformative under the protein-binding policy; no specific functional consequence for BHLHE40 is shown. Removal does not mean the interaction is false. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: High-throughput binary interaction screen (yeast two-hybrid) reporting an interaction with UniProtKB:O75553. Reason: Bare protein binding from a proteome-scale interaction screen is uninformative under the protein-binding policy; no specific functional consequence for BHLHE40 is shown. Removal does not mean the interaction is false. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: High-throughput binary interaction screen (yeast two-hybrid) reporting an interaction with UniProtKB:O75909. Reason: Bare protein binding from a proteome-scale interaction screen is uninformative under the protein-binding policy; no specific functional consequence for BHLHE40 is shown. Removal does not mean the interaction is false. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: High-throughput binary interaction screen (yeast two-hybrid) reporting an interaction with UniProtKB:O94955. Reason: Bare protein binding from a proteome-scale interaction screen is uninformative under the protein-binding policy; no specific functional consequence for BHLHE40 is shown. Removal does not mean the interaction is false. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: High-throughput binary interaction screen (yeast two-hybrid) reporting an interaction with UniProtKB:P10606. Reason: Bare protein binding from a proteome-scale interaction screen is uninformative under the protein-binding policy; no specific functional consequence for BHLHE40 is shown. Removal does not mean the interaction is false. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: High-throughput binary interaction screen (yeast two-hybrid) reporting an interaction with UniProtKB:P18545. Reason: Bare protein binding from a proteome-scale interaction screen is uninformative under the protein-binding policy; no specific functional consequence for BHLHE40 is shown. Removal does not mean the interaction is false. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: High-throughput binary interaction screen (yeast two-hybrid) reporting an interaction with UniProtKB:Q08117. Reason: Bare protein binding from a proteome-scale interaction screen is uninformative under the protein-binding policy; no specific functional consequence for BHLHE40 is shown. Removal does not mean the interaction is false. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: High-throughput binary interaction screen (yeast two-hybrid) reporting an interaction with UniProtKB:Q08426. Reason: Bare protein binding from a proteome-scale interaction screen is uninformative under the protein-binding policy; no specific functional consequence for BHLHE40 is shown. Removal does not mean the interaction is false. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: High-throughput binary interaction screen (yeast two-hybrid) reporting an interaction with UniProtKB:Q08AM6. Reason: Bare protein binding from a proteome-scale interaction screen is uninformative under the protein-binding policy; no specific functional consequence for BHLHE40 is shown. Removal does not mean the interaction is false. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: High-throughput binary interaction screen (yeast two-hybrid) reporting an interaction with UniProtKB:Q13131. Reason: Bare protein binding from a proteome-scale interaction screen is uninformative under the protein-binding policy; no specific functional consequence for BHLHE40 is shown. Removal does not mean the interaction is false. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: High-throughput binary interaction screen (yeast two-hybrid) reporting an interaction with UniProtKB:Q14106. Reason: Bare protein binding from a proteome-scale interaction screen is uninformative under the protein-binding policy; no specific functional consequence for BHLHE40 is shown. Removal does not mean the interaction is false. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: High-throughput binary interaction screen (yeast two-hybrid) reporting an interaction with UniProtKB:Q16613. Reason: Bare protein binding from a proteome-scale interaction screen is uninformative under the protein-binding policy; no specific functional consequence for BHLHE40 is shown. Removal does not mean the interaction is false. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: High-throughput binary interaction screen (yeast two-hybrid) reporting an interaction with UniProtKB:Q5W5X9. Reason: Bare protein binding from a proteome-scale interaction screen is uninformative under the protein-binding policy; no specific functional consequence for BHLHE40 is shown. Removal does not mean the interaction is false. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: High-throughput binary interaction screen (yeast two-hybrid) reporting an interaction with UniProtKB:Q6NVV7. Reason: Bare protein binding from a proteome-scale interaction screen is uninformative under the protein-binding policy; no specific functional consequence for BHLHE40 is shown. Removal does not mean the interaction is false. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: High-throughput binary interaction screen (yeast two-hybrid) reporting an interaction with UniProtKB:Q71RC2-6. Reason: Bare protein binding from a proteome-scale interaction screen is uninformative under the protein-binding policy; no specific functional consequence for BHLHE40 is shown. Removal does not mean the interaction is false. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: High-throughput binary interaction screen (yeast two-hybrid) reporting an interaction with UniProtKB:Q86U06. Reason: Bare protein binding from a proteome-scale interaction screen is uninformative under the protein-binding policy; no specific functional consequence for BHLHE40 is shown. Removal does not mean the interaction is false. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: High-throughput binary interaction screen (yeast two-hybrid) reporting an interaction with UniProtKB:Q86U06-2. Reason: Bare protein binding from a proteome-scale interaction screen is uninformative under the protein-binding policy; no specific functional consequence for BHLHE40 is shown. Removal does not mean the interaction is false. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: High-throughput binary interaction screen (yeast two-hybrid) reporting an interaction with UniProtKB:Q8NB12. Reason: Bare protein binding from a proteome-scale interaction screen is uninformative under the protein-binding policy; no specific functional consequence for BHLHE40 is shown. Removal does not mean the interaction is false. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: High-throughput binary interaction screen (yeast two-hybrid) reporting an interaction with UniProtKB:Q8NEA9. Reason: Bare protein binding from a proteome-scale interaction screen is uninformative under the protein-binding policy; no specific functional consequence for BHLHE40 is shown. Removal does not mean the interaction is false. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: High-throughput binary interaction screen (yeast two-hybrid) reporting an interaction with UniProtKB:Q93062. Reason: Bare protein binding from a proteome-scale interaction screen is uninformative under the protein-binding policy; no specific functional consequence for BHLHE40 is shown. Removal does not mean the interaction is false. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: High-throughput binary interaction screen (yeast two-hybrid) reporting an interaction with UniProtKB:Q96CS7. Reason: Bare protein binding from a proteome-scale interaction screen is uninformative under the protein-binding policy; no specific functional consequence for BHLHE40 is shown. Removal does not mean the interaction is false. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: High-throughput binary interaction screen (yeast two-hybrid) reporting an interaction with UniProtKB:Q9BVI4. Reason: Bare protein binding from a proteome-scale interaction screen is uninformative under the protein-binding policy; no specific functional consequence for BHLHE40 is shown. Removal does not mean the interaction is false. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: High-throughput binary interaction screen (yeast two-hybrid) reporting an interaction with UniProtKB:Q9GZZ1. Reason: Bare protein binding from a proteome-scale interaction screen is uninformative under the protein-binding policy; no specific functional consequence for BHLHE40 is shown. Removal does not mean the interaction is false. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: High-throughput binary interaction screen (yeast two-hybrid) reporting an interaction with UniProtKB:Q9H4E5. Reason: Bare protein binding from a proteome-scale interaction screen is uninformative under the protein-binding policy; no specific functional consequence for BHLHE40 is shown. Removal does not mean the interaction is false. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: High-throughput binary interaction screen (yeast two-hybrid) reporting an interaction with UniProtKB:Q9NX01. Reason: Bare protein binding from a proteome-scale interaction screen is uninformative under the protein-binding policy; no specific functional consequence for BHLHE40 is shown. Removal does not mean the interaction is false. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: High-throughput binary interaction screen (yeast two-hybrid) reporting an interaction with UniProtKB:Q9Y5V3. Reason: Bare protein binding from a proteome-scale interaction screen is uninformative under the protein-binding policy; no specific functional consequence for BHLHE40 is shown. Removal does not mean the interaction is false. |
| GO:0005515 protein binding | IPI PMID:25910212 Widespread macromolecular interaction perturbations in human... | REMOVE | Summary: High-throughput binary interaction screen (yeast two-hybrid) reporting an interaction with UniProtKB:Q16613. Reason: Bare protein binding from a proteome-scale interaction screen is uninformative under the protein-binding policy; no specific functional consequence for BHLHE40 is shown. Removal does not mean the interaction is false. |
| GO:0005515 protein binding | IPI PMID:29234281 Interleukin-6 Induces DEC1, Promotes DEC1 Interaction with R... | MODIFY | Summary: Direct interaction of DEC1 with RXRalpha. Reason: DEC1 binds RXRalpha through an LXXLL motif and represses RXR-dependent transactivation; nuclear retinoid X receptor binding (GO:0046965) captures this. Proposed replacements: nuclear retinoid X receptor binding Supporting Evidence: PMID:29234281 DEC1 was found to interact with RXRΞ± and IL-6 enhanced the interaction PMID:19786558 an LXXLL motif in DEC1 and DEC2 is necessary for RXRalpha repression |
| GO:0005515 protein binding | IPI PMID:29892012 An interactome perturbation framework prioritizes damaging m... | REMOVE | Summary: High-throughput binary interaction screen (yeast two-hybrid) reporting an interaction with UniProtKB:Q8NB12. Reason: Bare protein binding from a proteome-scale interaction screen is uninformative under the protein-binding policy; no specific functional consequence for BHLHE40 is shown. Removal does not mean the interaction is false. |
| GO:0005515 protein binding | IPI PMID:31515488 Extensive disruption of protein interactions by genetic vari... | REMOVE | Summary: High-throughput binary interaction screen (yeast two-hybrid) reporting an interaction with UniProtKB:O94955. Reason: Bare protein binding from a proteome-scale interaction screen is uninformative under the protein-binding policy; no specific functional consequence for BHLHE40 is shown. Removal does not mean the interaction is false. |
| GO:0005515 protein binding | IPI PMID:31515488 Extensive disruption of protein interactions by genetic vari... | REMOVE | Summary: High-throughput binary interaction screen (yeast two-hybrid) reporting an interaction with UniProtKB:P10606. Reason: Bare protein binding from a proteome-scale interaction screen is uninformative under the protein-binding policy; no specific functional consequence for BHLHE40 is shown. Removal does not mean the interaction is false. |
| GO:0005515 protein binding | IPI PMID:31515488 Extensive disruption of protein interactions by genetic vari... | REMOVE | Summary: High-throughput binary interaction screen (yeast two-hybrid) reporting an interaction with UniProtKB:Q8NB12. Reason: Bare protein binding from a proteome-scale interaction screen is uninformative under the protein-binding policy; no specific functional consequence for BHLHE40 is shown. Removal does not mean the interaction is false. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: High-throughput binary interaction screen (yeast two-hybrid) reporting an interaction with UniProtKB:B7ZLI8. Reason: Bare protein binding from a proteome-scale interaction screen is uninformative under the protein-binding policy; no specific functional consequence for BHLHE40 is shown. Removal does not mean the interaction is false. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: High-throughput binary interaction screen (yeast two-hybrid) reporting an interaction with UniProtKB:O43189. Reason: Bare protein binding from a proteome-scale interaction screen is uninformative under the protein-binding policy; no specific functional consequence for BHLHE40 is shown. Removal does not mean the interaction is false. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: High-throughput binary interaction screen (yeast two-hybrid) reporting an interaction with UniProtKB:O94955. Reason: Bare protein binding from a proteome-scale interaction screen is uninformative under the protein-binding policy; no specific functional consequence for BHLHE40 is shown. Removal does not mean the interaction is false. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: High-throughput binary interaction screen (yeast two-hybrid) reporting an interaction with UniProtKB:O94964-4. Reason: Bare protein binding from a proteome-scale interaction screen is uninformative under the protein-binding policy; no specific functional consequence for BHLHE40 is shown. Removal does not mean the interaction is false. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: High-throughput binary interaction screen (yeast two-hybrid) reporting an interaction with UniProtKB:O95231. Reason: Bare protein binding from a proteome-scale interaction screen is uninformative under the protein-binding policy; no specific functional consequence for BHLHE40 is shown. Removal does not mean the interaction is false. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: High-throughput binary interaction screen (yeast two-hybrid) reporting an interaction with UniProtKB:P19544-6. Reason: Bare protein binding from a proteome-scale interaction screen is uninformative under the protein-binding policy; no specific functional consequence for BHLHE40 is shown. Removal does not mean the interaction is false. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: High-throughput binary interaction screen (yeast two-hybrid) reporting an interaction with UniProtKB:P54253. Reason: Bare protein binding from a proteome-scale interaction screen is uninformative under the protein-binding policy; no specific functional consequence for BHLHE40 is shown. Removal does not mean the interaction is false. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: High-throughput binary interaction screen (yeast two-hybrid) reporting an interaction with UniProtKB:P78424. Reason: Bare protein binding from a proteome-scale interaction screen is uninformative under the protein-binding policy; no specific functional consequence for BHLHE40 is shown. Removal does not mean the interaction is false. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: High-throughput binary interaction screen (yeast two-hybrid) reporting an interaction with UniProtKB:P86480. Reason: Bare protein binding from a proteome-scale interaction screen is uninformative under the protein-binding policy; no specific functional consequence for BHLHE40 is shown. Removal does not mean the interaction is false. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: High-throughput binary interaction screen (yeast two-hybrid) reporting an interaction with UniProtKB:Q01974. Reason: Bare protein binding from a proteome-scale interaction screen is uninformative under the protein-binding policy; no specific functional consequence for BHLHE40 is shown. Removal does not mean the interaction is false. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: High-throughput binary interaction screen (yeast two-hybrid) reporting an interaction with UniProtKB:Q03060-25. Reason: Bare protein binding from a proteome-scale interaction screen is uninformative under the protein-binding policy; no specific functional consequence for BHLHE40 is shown. Removal does not mean the interaction is false. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: High-throughput binary interaction screen (yeast two-hybrid) reporting an interaction with UniProtKB:Q08117-2. Reason: Bare protein binding from a proteome-scale interaction screen is uninformative under the protein-binding policy; no specific functional consequence for BHLHE40 is shown. Removal does not mean the interaction is false. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: High-throughput binary interaction screen (yeast two-hybrid) reporting an interaction with UniProtKB:Q08AM6. Reason: Bare protein binding from a proteome-scale interaction screen is uninformative under the protein-binding policy; no specific functional consequence for BHLHE40 is shown. Removal does not mean the interaction is false. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: High-throughput binary interaction screen (yeast two-hybrid) reporting an interaction with UniProtKB:Q13895. Reason: Bare protein binding from a proteome-scale interaction screen is uninformative under the protein-binding policy; no specific functional consequence for BHLHE40 is shown. Removal does not mean the interaction is false. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: High-throughput binary interaction screen (yeast two-hybrid) reporting an interaction with UniProtKB:Q14847-2. Reason: Bare protein binding from a proteome-scale interaction screen is uninformative under the protein-binding policy; no specific functional consequence for BHLHE40 is shown. Removal does not mean the interaction is false. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: High-throughput binary interaction screen (yeast two-hybrid) reporting an interaction with UniProtKB:Q15038. Reason: Bare protein binding from a proteome-scale interaction screen is uninformative under the protein-binding policy; no specific functional consequence for BHLHE40 is shown. Removal does not mean the interaction is false. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: High-throughput binary interaction screen (yeast two-hybrid) reporting an interaction with UniProtKB:Q15911-2. Reason: Bare protein binding from a proteome-scale interaction screen is uninformative under the protein-binding policy; no specific functional consequence for BHLHE40 is shown. Removal does not mean the interaction is false. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: High-throughput binary interaction screen (yeast two-hybrid) reporting an interaction with UniProtKB:Q3LI64. Reason: Bare protein binding from a proteome-scale interaction screen is uninformative under the protein-binding policy; no specific functional consequence for BHLHE40 is shown. Removal does not mean the interaction is false. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: High-throughput binary interaction screen (yeast two-hybrid) reporting an interaction with UniProtKB:Q3LI66. Reason: Bare protein binding from a proteome-scale interaction screen is uninformative under the protein-binding policy; no specific functional consequence for BHLHE40 is shown. Removal does not mean the interaction is false. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: High-throughput binary interaction screen (yeast two-hybrid) reporting an interaction with UniProtKB:Q3LI72. Reason: Bare protein binding from a proteome-scale interaction screen is uninformative under the protein-binding policy; no specific functional consequence for BHLHE40 is shown. Removal does not mean the interaction is false. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: High-throughput binary interaction screen (yeast two-hybrid) reporting an interaction with UniProtKB:Q3SYF9. Reason: Bare protein binding from a proteome-scale interaction screen is uninformative under the protein-binding policy; no specific functional consequence for BHLHE40 is shown. Removal does not mean the interaction is false. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: High-throughput binary interaction screen (yeast two-hybrid) reporting an interaction with UniProtKB:Q6ZRY4. Reason: Bare protein binding from a proteome-scale interaction screen is uninformative under the protein-binding policy; no specific functional consequence for BHLHE40 is shown. Removal does not mean the interaction is false. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: High-throughput binary interaction screen (yeast two-hybrid) reporting an interaction with UniProtKB:Q70EL1-9. Reason: Bare protein binding from a proteome-scale interaction screen is uninformative under the protein-binding policy; no specific functional consequence for BHLHE40 is shown. Removal does not mean the interaction is false. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: High-throughput binary interaction screen (yeast two-hybrid) reporting an interaction with UniProtKB:Q86UY5. Reason: Bare protein binding from a proteome-scale interaction screen is uninformative under the protein-binding policy; no specific functional consequence for BHLHE40 is shown. Removal does not mean the interaction is false. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: High-throughput binary interaction screen (yeast two-hybrid) reporting an interaction with UniProtKB:Q86YR5-3. Reason: Bare protein binding from a proteome-scale interaction screen is uninformative under the protein-binding policy; no specific functional consequence for BHLHE40 is shown. Removal does not mean the interaction is false. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: High-throughput binary interaction screen (yeast two-hybrid) reporting an interaction with UniProtKB:Q8IUB9. Reason: Bare protein binding from a proteome-scale interaction screen is uninformative under the protein-binding policy; no specific functional consequence for BHLHE40 is shown. Removal does not mean the interaction is false. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: High-throughput binary interaction screen (yeast two-hybrid) reporting an interaction with UniProtKB:Q8IUC2. Reason: Bare protein binding from a proteome-scale interaction screen is uninformative under the protein-binding policy; no specific functional consequence for BHLHE40 is shown. Removal does not mean the interaction is false. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: High-throughput binary interaction screen (yeast two-hybrid) reporting an interaction with UniProtKB:Q8IUG1. Reason: Bare protein binding from a proteome-scale interaction screen is uninformative under the protein-binding policy; no specific functional consequence for BHLHE40 is shown. Removal does not mean the interaction is false. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: High-throughput binary interaction screen (yeast two-hybrid) reporting an interaction with UniProtKB:Q8NB12. Reason: Bare protein binding from a proteome-scale interaction screen is uninformative under the protein-binding policy; no specific functional consequence for BHLHE40 is shown. Removal does not mean the interaction is false. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: High-throughput binary interaction screen (yeast two-hybrid) reporting an interaction with UniProtKB:Q8TAP4-4. Reason: Bare protein binding from a proteome-scale interaction screen is uninformative under the protein-binding policy; no specific functional consequence for BHLHE40 is shown. Removal does not mean the interaction is false. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: High-throughput binary interaction screen (yeast two-hybrid) reporting an interaction with UniProtKB:Q8WU79. Reason: Bare protein binding from a proteome-scale interaction screen is uninformative under the protein-binding policy; no specific functional consequence for BHLHE40 is shown. Removal does not mean the interaction is false. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: High-throughput binary interaction screen (yeast two-hybrid) reporting an interaction with UniProtKB:Q92997. Reason: Bare protein binding from a proteome-scale interaction screen is uninformative under the protein-binding policy; no specific functional consequence for BHLHE40 is shown. Removal does not mean the interaction is false. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: High-throughput binary interaction screen (yeast two-hybrid) reporting an interaction with UniProtKB:Q96A09. Reason: Bare protein binding from a proteome-scale interaction screen is uninformative under the protein-binding policy; no specific functional consequence for BHLHE40 is shown. Removal does not mean the interaction is false. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: High-throughput binary interaction screen (yeast two-hybrid) reporting an interaction with UniProtKB:Q96EZ8. Reason: Bare protein binding from a proteome-scale interaction screen is uninformative under the protein-binding policy; no specific functional consequence for BHLHE40 is shown. Removal does not mean the interaction is false. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: High-throughput binary interaction screen (yeast two-hybrid) reporting an interaction with UniProtKB:Q96G42. Reason: Bare protein binding from a proteome-scale interaction screen is uninformative under the protein-binding policy; no specific functional consequence for BHLHE40 is shown. Removal does not mean the interaction is false. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: High-throughput binary interaction screen (yeast two-hybrid) reporting an interaction with UniProtKB:Q99471. Reason: Bare protein binding from a proteome-scale interaction screen is uninformative under the protein-binding policy; no specific functional consequence for BHLHE40 is shown. Removal does not mean the interaction is false. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: High-throughput binary interaction screen (yeast two-hybrid) reporting an interaction with UniProtKB:Q9GZZ1. Reason: Bare protein binding from a proteome-scale interaction screen is uninformative under the protein-binding policy; no specific functional consequence for BHLHE40 is shown. Removal does not mean the interaction is false. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: High-throughput binary interaction screen (yeast two-hybrid) reporting an interaction with UniProtKB:Q9HC98-4. Reason: Bare protein binding from a proteome-scale interaction screen is uninformative under the protein-binding policy; no specific functional consequence for BHLHE40 is shown. Removal does not mean the interaction is false. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: High-throughput binary interaction screen (yeast two-hybrid) reporting an interaction with UniProtKB:Q9NWB1-5. Reason: Bare protein binding from a proteome-scale interaction screen is uninformative under the protein-binding policy; no specific functional consequence for BHLHE40 is shown. Removal does not mean the interaction is false. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: High-throughput binary interaction screen (yeast two-hybrid) reporting an interaction with UniProtKB:Q9Y4B4. Reason: Bare protein binding from a proteome-scale interaction screen is uninformative under the protein-binding policy; no specific functional consequence for BHLHE40 is shown. Removal does not mean the interaction is false. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: High-throughput binary interaction screen (yeast two-hybrid) reporting an interaction with UniProtKB:Q9Y5V3. Reason: Bare protein binding from a proteome-scale interaction screen is uninformative under the protein-binding policy; no specific functional consequence for BHLHE40 is shown. Removal does not mean the interaction is false. |
| GO:0005634 nucleus | EXP PMID:11278694 Regulation of STRA13 by the von Hippel-Lindau tumor suppress... | ACCEPT | Summary: Ivanova et al. 2001: STRA13 protein detected in the nucleus. Reason: BHLHE40 is predominantly nuclear, consistent with its role as a DNA-binding repressor. Supporting Evidence: file:human/BHLHE40/BHLHE40-uniprot.txt Note=Predominantly localized in the nucleus (PubMed:11278694) |
| GO:0005634 nucleus | EXP PMID:21829689 SUMOylation of DEC1 protein regulates its transcriptional ac... | ACCEPT | Summary: Hong et al. 2011: nuclear and cytoplasmic fractionation/immunostaining of DEC1. Reason: Predominantly nuclear localization; core location of function. Supporting Evidence: PMID:21829689 DEC1 is predominantly localized in the nucleus, but can also be found in the cytoplasm |
| GO:0005634 nucleus | IBA GO_REF:0000033 | ACCEPT | Summary: IBA nucleus for the bHLH-Orange repressor family. Reason: Consistent with experimental data on BHLHE40 itself. Supporting Evidence: PMID:21829689 DEC1 is predominantly localized in the nucleus, but can also be found in the cytoplasm |
| GO:0005634 nucleus | IDA PMID:12624110 DEC1 negatively regulates the expression of DEC2 through bin... | ACCEPT | Summary: Li et al. 2003: nuclear localization of DEC1 (IDA). Reason: Consistent with E-box binding and repression of the DEC2 promoter. Supporting Evidence: PMID:12624110 Our findings assign for DEC1 the first target gene that is regulated through direct DNA binding PMID:21829689 DEC1 is predominantly localized in the nucleus, but can also be found in the cytoplasm |
| GO:0005634 nucleus | IDA PMID:28797635 Circadian rhythmicity: A functional connection between diffe... | ACCEPT | Summary: Marczak and Yan 2017: nuclear DEC1 in ChIP/EMSA analysis of the SHP promoter. Reason: Nuclear localization consistent with promoter occupancy. Supporting Evidence: PMID:28797635 Site-directed mutagenesis, electrophoretic mobility shift assay and chromatin immunoprecipitation established that the repression was achieved through the E-box in the proximal promoter PMID:21829689 DEC1 is predominantly localized in the nucleus, but can also be found in the cytoplasm |
| GO:0005634 nucleus | IEA GO_REF:0000120 | ACCEPT | Summary: Combined IEA nucleus. Reason: Consistent with experimental evidence. Supporting Evidence: PMID:21829689 DEC1 is predominantly localized in the nucleus, but can also be found in the cytoplasm |
| GO:0005634 nucleus | NAS PMID:9240428 Molecular characterization of the novel basic helix-loop-hel... | ACCEPT | Summary: NAS nucleus from the cloning paper. Reason: Correct and well supported by later experimental data. Supporting Evidence: PMID:21829689 DEC1 is predominantly localized in the nucleus, but can also be found in the cytoplasm |
| GO:0005737 cytoplasm | EXP PMID:21829689 SUMOylation of DEC1 protein regulates its transcriptional ac... | KEEP AS NON CORE | Summary: Hong et al. 2011: a minor fraction of DEC1 is detected in the cytoplasm. Reason: A minor cytoplasmic pool exists (increased by loss of SUMOylation), but the function is nuclear. Supporting Evidence: PMID:21829689 DEC1 is predominantly localized in the nucleus, but can also be found in the cytoplasm |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: IEA cytoplasm from the UniProt subcellular location vocabulary. Reason: Reflects the minor cytoplasmic pool documented experimentally; not where the function acts. Supporting Evidence: PMID:21829689 DEC1 is predominantly localized in the nucleus, but can also be found in the cytoplasm |
| GO:0006355 regulation of DNA-templated transcription | IEA GO_REF:0000002 | TOO GENERAL | Summary: InterPro (Orange domain) IEA for regulation of DNA-templated transcription. Reason: True but entailed by the accepted negative regulation of transcription by RNA polymerase II (GO:0000122). Supporting Evidence: file:human/BHLHE40/BHLHE40-uniprot.txt Transcriptional repressor involved in the regulation of the circadian rhythm by negatively regulating the activity of the clock genes and clock-controlled genes |
| GO:0006355 regulation of DNA-templated transcription | NAS PMID:9240428 Molecular characterization of the novel basic helix-loop-hel... | TOO GENERAL | Summary: NAS from the cloning paper for regulation of DNA-templated transcription. Reason: True but entailed by the accepted, more specific GO:0000122. Supporting Evidence: file:human/BHLHE40/BHLHE40-uniprot.txt Transcriptional repressor involved in the regulation of the circadian rhythm by negatively regulating the activity of the clock genes and clock-controlled genes |
| GO:0007623 circadian rhythm | IDA PMID:28797635 Circadian rhythmicity: A functional connection between diffe... | ACCEPT | Summary: Marczak and Yan 2017: DEC1 participates in the negative limb of SHP circadian oscillation. Reason: BHLHE40 is a component of an auxiliary clock feedback loop; circadian rhythm is broader than the accepted circadian regulation of gene expression but remains informative. Supporting Evidence: PMID:28797635 DEC1 participates in the negative loop of SHP oscillating expression |
| GO:0007623 circadian rhythm | IEA GO_REF:0000107 | ACCEPT | Summary: IEA (Ensembl Compara) circadian rhythm. Reason: Supported by human and mouse clock studies. Supporting Evidence: PMID:12397359 Dec1 and Dec2 are regulators of the mammalian molecular clock, and form a fifth clock-gene family PMID:18411297 Dec1-/- mice showed behavioral rhythms with slightly but significantly longer circadian periods under conditions of constant darkness and faster reentrainment to a 6-h phase-advanced shift of a light-dark cycle |
| GO:0009952 anterior/posterior pattern specification | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: IBA anterior/posterior pattern specification propagated from the HES subfamily node (PTN000105428), seeded by segmentation-clock genes such as Hes7/her genes. Reason: Anterior/posterior patterning is a HES/HER segmentation-clock function. There is no experimental evidence that BHLHE40 (DEC subfamily, no WRPW motif) acts in somitogenesis or axial patterning, and Stra13/Bhlhe40-null mice are viable and are studied mainly for adult immune and clock phenotypes. The deep node placement probably over-propagates this function to the divergent DEC branch. Propagation Review Root cause: PROPAGATION BAD Failure modes: FUNCTIONAL DIVERGENCE Sources checked: PANTHER:PTN000105428 SUPPORTS SOURCE BUT NOT TARGET HES-related ancestral node whose patterning evidence comes from HES/HER segmentation-clock members (e.g. zebrafish her genes, mouse Hes7). The DEC branch (BHLHE40/BHLHE41) lacks the WRPW motif and has no somitogenesis or axial-patterning evidence, so the function likely did not persist on that branch. Supporting Evidence: PMID:11668339 aging Stra13-/- mice develop autoimmune disease PMID:10737769 Stra13 expression is transcriptionally repressed and maintained at a low level in cells through a negative autoregulatory mechanism that is brought about by its interaction with the corepressor histone deacetylase (HDAC1) |
| GO:0016604 nuclear body | IDA GO_REF:0000052 | KEEP AS NON CORE | Summary: HPA immunofluorescence (GO_REF:0000052) places BHLHE40 in nuclear bodies. Reason: Plausible sub-nuclear staining from an antibody-based atlas. Hong et al. also describe SUMOylation-dependent nucleolar distribution, but no functional significance of nuclear bodies has been shown. Supporting Evidence: PMID:21829689 DEC1 is predominantly localized in the nucleus, but can also be found in the cytoplasm |
| GO:0019904 protein domain specific binding | IPI PMID:15560782 Functional analysis of the basic helix-loop-helix transcript... | MODIFY | Summary: Sato et al. 2004: interaction of DEC1 with BMAL1 depends on the N-terminal basic/bHLH region. Reason: Protein domain specific binding is vague. The partner is the bHLH-PAS factor BMAL1, so bHLH transcription factor binding (GO:0043425) is the informative MF. Proposed replacements: bHLH transcription factor binding Supporting Evidence: PMID:15560782 N-terminal region, which includes the basic helix-loop-helix domain, was essential for both the suppressive activity and the interaction with BMAL1 |
| GO:0032922 circadian regulation of gene expression | IBA GO_REF:0000033 | ACCEPT | Summary: IBA circadian regulation of gene expression (DEC subfamily node, seeded by BHLHE40/BHLHE41 data). Reason: Core biological role: BHLHE40 represses CLOCK/BMAL1-driven E-box clock genes and clock-controlled genes. Supporting Evidence: file:human/BHLHE40/BHLHE40-uniprot.txt Transcriptional repressor involved in the regulation of the circadian rhythm by negatively regulating the activity of the clock genes and clock-controlled genes PMID:18411297 Overexpression of Dec1 delayed the phase of clock genes such as Dec1, Dec2, Per1, and Dbp that contain E boxes in their regulatory regions |
| GO:0032922 circadian regulation of gene expression | IDA PMID:18411297 DEC1 modulates the circadian phase of clock gene expression. | ACCEPT | Summary: Nakashima et al. 2008: DEC1 overexpression delays and deficiency advances the phase of E-box clock genes. Reason: Direct evidence for circadian regulation of gene expression; core. Supporting Evidence: PMID:18411297 Overexpression of Dec1 delayed the phase of clock genes such as Dec1, Dec2, Per1, and Dbp that contain E boxes in their regulatory regions PMID:18411297 DEC1 showed strong binding and transrepression on the E box, but not on the E' box, in chromatin immunoprecipitation, electrophoretic mobility shift, and luciferase reporter assays |
| GO:0032922 circadian regulation of gene expression | IEA GO_REF:0000107 | ACCEPT | Summary: IEA (Ensembl Compara) circadian regulation of gene expression. Reason: Consistent with experimental evidence. Supporting Evidence: PMID:18411297 Overexpression of Dec1 delayed the phase of clock genes such as Dec1, Dec2, Per1, and Dbp that contain E boxes in their regulatory regions |
| GO:0042752 regulation of circadian rhythm | IEA GO_REF:0000107 | ACCEPT | Summary: IEA (Ensembl Compara) regulation of circadian rhythm. Reason: Dec1-/- mice show altered circadian period and re-entrainment. Supporting Evidence: PMID:18411297 Dec1-/- mice showed behavioral rhythms with slightly but significantly longer circadian periods under conditions of constant darkness and faster reentrainment to a 6-h phase-advanced shift of a light-dark cycle |
| GO:0042752 regulation of circadian rhythm | ISS GO_REF:0000024 | ACCEPT | Summary: ISS from mouse regulation of circadian rhythm. Reason: Supported by the mouse knockout phenotype and blood-pressure rhythm data. Supporting Evidence: PMID:18411297 Dec1-/- mice showed behavioral rhythms with slightly but significantly longer circadian periods under conditions of constant darkness and faster reentrainment to a 6-h phase-advanced shift of a light-dark cycle PMID:30012868 CLOCK:BMAL1 heterodimer enhanced transcription from the ATP1B1 promoter, whereas DEC1 suppressed this transactivation |
| GO:0042803 protein homodimerization activity | IDA PMID:15560782 Functional analysis of the basic helix-loop-helix transcript... | ACCEPT | Summary: Sato et al. 2004: DEC1 homodimer formation (dominant-negative behaviour of basic-region deletion). Reason: BHLHE40 binds E-boxes as a homodimer; homodimerization through the HLH region is part of its DNA-binding repressor mechanism. Supporting Evidence: PMID:15560782 the basic region-deleted DEC1 acted in a dominant-negative manner for DEC1 activity, indicating that the basic region was not required for homodimer formation of DEC1 PMID:12297495 Stra13 binds with high affinity to CACGTG class B E-box elements as a homodimer |
| GO:0043153 entrainment of circadian clock by photoperiod | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA (Ensembl Compara) entrainment of circadian clock by photoperiod. Reason: Dec1 is light-inducible in the SCN and Dec1-/- mice re-entrain faster after a phase advance, so a role in entrainment is supported in mouse but peripheral to the core repressor function. Supporting Evidence: PMID:12397359 A brief light pulse induced Dec1 but not Dec2 expression in the suprachiasmic nucleus in a phase-dependent manner PMID:18411297 Dec1-/- mice showed behavioral rhythms with slightly but significantly longer circadian periods under conditions of constant darkness and faster reentrainment to a 6-h phase-advanced shift of a light-dark cycle |
| GO:0043153 entrainment of circadian clock by photoperiod | ISS PMID:18411297 DEC1 modulates the circadian phase of clock gene expression. | KEEP AS NON CORE | Summary: ISS from mouse (Nakashima et al. 2008) for entrainment of circadian clock by photoperiod. Reason: Faster re-entrainment of Dec1-/- mice to a shifted light-dark cycle. Supporting Evidence: PMID:18411297 Dec1-/- mice showed behavioral rhythms with slightly but significantly longer circadian periods under conditions of constant darkness and faster reentrainment to a 6-h phase-advanced shift of a light-dark cycle |
| GO:0043425 bHLH transcription factor binding | IPI PMID:12397359 Dec1 and Dec2 are regulators of the mammalian molecular cloc... | KEEP AS NON CORE | Summary: Honma et al. 2002: DEC1 interacts with BMAL1. Reason: The BMAL1 interaction is real but was later shown not to be required for repression of Per1, which depends on E-box binding; kept as non-core. Supporting Evidence: PMID:12397359 repressed Clock/Bmal1-induced transactivation of the mouse Per1 promoter through direct protein-protein interactions with Bmal1 and/or competition for E-box elements PMID:15193144 providing direct evidence that DNA binding, rather than Bmal1 interactions, is responsible for the repression on the mPer1 promoter |
| GO:0043425 bHLH transcription factor binding | IPI PMID:15193144 DNA binding, but not interaction with Bmal1, is responsible ... | KEEP AS NON CORE | Summary: Li et al. 2004: DEC1 forms heterodimers with DEC2 (BHLHE41). Reason: Co-immunoprecipitation shows DEC1-DEC2 heterodimers are preferred over DEC1-BMAL1 complexes. Binding to the bHLH factors BHLHE41 and BMAL1 is real, but the repressor activity depends mainly on BHLHE40's own E-box binding, so the binding term is kept as non-core. Heterodimerization is captured as an accepted MF elsewhere. Supporting Evidence: PMID:15193144 DEC proteins prefer to form DEC1βDEC2 heterodimers (presumably homodimers as well) instead of forming Bmal1βDEC1 complexes |
| GO:0043425 bHLH transcription factor binding | IPI PMID:15193144 DNA binding, but not interaction with Bmal1, is responsible ... | KEEP AS NON CORE | Summary: Li et al. 2004: DEC1 interaction with BMAL1 tested by co-immunoprecipitation. Reason: This paper shows DEC1 preferentially forms DEC1-DEC2 complexes over BMAL1 complexes and that the BMAL1 interaction is dispensable for Per1 repression. Supporting Evidence: PMID:15193144 DEC proteins prefer to form DEC1βDEC2 heterodimers (presumably homodimers as well) instead of forming Bmal1βDEC1 complexes PMID:15193144 providing direct evidence that DNA binding, rather than Bmal1 interactions, is responsible for the repression on the mPer1 promoter |
| GO:0043426 MRF binding | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA (Ensembl Compara) MRF binding transferred from mouse Bhlhe40. Reason: The mouse source annotation (Fujimoto et al. 2007) rests on Dec proteins repressing MyoD-activated transcription through class A E-boxes. The abstract describes the MyoD heterodimer for Dec2; the curator had the full text. Plausible but peripheral to BHLHE40's core role. Supporting Evidence: PMID:17487425 Dec proteins repressed a MyoD-activated promoter activity of muscle creatine kinase gene through class A E-box in an HDAC1-independent manner |
| GO:0043426 MRF binding | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS from mouse for MRF binding. Reason: As for the IEA row: plausible MyoD interaction/antagonism, non-core. Supporting Evidence: PMID:17487425 Dec proteins repressed a MyoD-activated promoter activity of muscle creatine kinase gene through class A E-box in an HDAC1-independent manner |
| GO:0045892 negative regulation of DNA-templated transcription | IDA PMID:12397359 Dec1 and Dec2 are regulators of the mammalian molecular cloc... | MODIFY | Summary: Experimental evidence that DEC1 represses transcription of a target gene. Reason: Correct but general: the repressed targets (Per1, ATP1B1, SHP/NR0B2) are RNA polymerase II-transcribed genes repressed via promoter E-boxes, so the more specific negative regulation of transcription by RNA polymerase II (GO:0000122), already accepted for the gene, is appropriate. Proposed replacements: negative regulation of transcription by RNA polymerase II Supporting Evidence: PMID:12397359 repressed Clock/Bmal1-induced transactivation of the mouse Per1 promoter through direct protein-protein interactions with Bmal1 and/or competition for E-box elements |
| GO:0045892 negative regulation of DNA-templated transcription | IDA PMID:30012868 Dec1 and CLOCK Regulate Na(+)/K(+)-ATPase Ξ²1 Subunit Express... | MODIFY | Summary: Experimental evidence that DEC1 represses transcription of a target gene. Reason: Correct but general: the repressed targets (Per1, ATP1B1, SHP/NR0B2) are RNA polymerase II-transcribed genes repressed via promoter E-boxes, so the more specific negative regulation of transcription by RNA polymerase II (GO:0000122), already accepted for the gene, is appropriate. Proposed replacements: negative regulation of transcription by RNA polymerase II Supporting Evidence: PMID:30012868 CLOCK:BMAL1 heterodimer enhanced transcription from the ATP1B1 promoter, whereas DEC1 suppressed this transactivation |
| GO:0045892 negative regulation of DNA-templated transcription | IMP PMID:28797635 Circadian rhythmicity: A functional connection between diffe... | MODIFY | Summary: Experimental evidence that DEC1 represses transcription of a target gene. Reason: Correct but general: the repressed targets (Per1, ATP1B1, SHP/NR0B2) are RNA polymerase II-transcribed genes repressed via promoter E-boxes, so the more specific negative regulation of transcription by RNA polymerase II (GO:0000122), already accepted for the gene, is appropriate. Proposed replacements: negative regulation of transcription by RNA polymerase II Supporting Evidence: PMID:28797635 Site-directed mutagenesis, electrophoretic mobility shift assay and chromatin immunoprecipitation established that the repression was achieved through the E-box in the proximal promoter |
| GO:0046982 protein heterodimerization activity | IPI PMID:12397359 Dec1 and Dec2 are regulators of the mammalian molecular cloc... | ACCEPT | Summary: Honma et al. 2002: DEC1-BMAL1 interaction recorded as heterodimerization. Reason: Heterodimerization activity of BHLHE40 is well supported, chiefly with its paralog BHLHE41 (see the other rows). The BMAL1 interaction reported here is dispensable for Per1 repression, but it does not undermine the general heterodimerization claim. Supporting Evidence: PMID:12397359 repressed Clock/Bmal1-induced transactivation of the mouse Per1 promoter through direct protein-protein interactions with Bmal1 and/or competition for E-box elements PMID:15193144 providing direct evidence that DNA binding, rather than Bmal1 interactions, is responsible for the repression on the mPer1 promoter |
| GO:0046982 protein heterodimerization activity | IPI PMID:15193144 DNA binding, but not interaction with Bmal1, is responsible ... | ACCEPT | Summary: Li et al. 2004: DEC1-DEC2 heterodimers by co-immunoprecipitation. Reason: Heterodimerization with BHLHE41 is a well-supported feature of the DEC repressors. Supporting Evidence: PMID:15193144 DEC proteins prefer to form DEC1βDEC2 heterodimers (presumably homodimers as well) instead of forming Bmal1βDEC1 complexes |
| GO:0046982 protein heterodimerization activity | IPI PMID:15193144 DNA binding, but not interaction with Bmal1, is responsible ... | ACCEPT | Summary: Li et al. 2004: DEC1-BMAL1 complex recorded as heterodimerization. Reason: Same paper demonstrates DEC1-DEC2 heterodimers by co-immunoprecipitation; DEC1-BMAL1 complexes form less readily. Heterodimerization activity is accepted on the strength of the BHLHE41 data. Supporting Evidence: PMID:15193144 DEC proteins prefer to form DEC1βDEC2 heterodimers (presumably homodimers as well) instead of forming Bmal1βDEC1 complexes |
| GO:0046982 protein heterodimerization activity | IPI PMID:15560782 Functional analysis of the basic helix-loop-helix transcript... | ACCEPT | Summary: Sato et al. 2004: DEC1-DEC2 (mouse Bhlhe41, Q99PV5) heterodimer by pull-down. Reason: Heterodimerization with BHLHE41 confirmed independently. Supporting Evidence: PMID:15560782 The heterodimer formation of DEC1 and DEC2 was confirmed by pull-down assay |
| GO:0046983 protein dimerization activity | IEA GO_REF:0000002 | TOO GENERAL | Summary: InterPro (bHLH domain) IEA protein dimerization activity. Reason: Entailed by the accepted protein homodimerization and heterodimerization activity terms. Supporting Evidence: file:human/BHLHE40/BHLHE40-uniprot.txt Pfam; PF00010; HLH; 1. |
| GO:0050767 regulation of neurogenesis | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: IBA regulation of neurogenesis from the HES subfamily node (PTN000105428). Reason: Overexpression of mouse Stra13 drives neuronal differentiation of P19 cells, so some support exists, but in vivo evidence for a neurogenic role of BHLHE40 is lacking; non-core. Supporting Evidence: PMID:9284045 overexpression of Stra13 in P19 cells results in neuronal differentiation in monolayer culture |
| GO:0061629 RNA polymerase II-specific DNA-binding transcription factor binding | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA (Ensembl Compara) RNA polymerase II-specific DNA-binding transcription factor binding, from mouse. Reason: BHLHE40 binds other DNA-binding transcription factors (BHLHE41, BMAL1, RXRA, TP53, MyoD-type bHLH factors). True, but peripheral to its own DNA-binding repressor activity. Supporting Evidence: PMID:15193144 DEC proteins prefer to form DEC1βDEC2 heterodimers (presumably homodimers as well) instead of forming Bmal1βDEC1 complexes PMID:19786558 DEC1 and DEC2 interacted directly with RXRalpha, and ligand addition enhanced their association |
| GO:0061629 RNA polymerase II-specific DNA-binding transcription factor binding | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS from mouse for RNA polymerase II-specific DNA-binding transcription factor binding. Reason: As for the IEA row. Supporting Evidence: PMID:17487425 Dec proteins repressed a MyoD-activated promoter activity of muscle creatine kinase gene through class A E-box in an HDAC1-independent manner PMID:19786558 DEC1 and DEC2 interacted directly with RXRalpha, and ligand addition enhanced their association |
| GO:0070888 E-box binding | IDA PMID:12397359 Dec1 and Dec2 are regulators of the mammalian molecular cloc... | ACCEPT | Summary: Evidence that BHLHE40 binds CACGTG E-box elements. Reason: E-box (class B CACGTG) binding is the core DNA-binding specificity of BHLHE40, required for its repressor activity. Supporting Evidence: PMID:12397359 repressed Clock/Bmal1-induced transactivation of the mouse Per1 promoter through direct protein-protein interactions with Bmal1 and/or competition for E-box elements |
| GO:0070888 E-box binding | IDA PMID:12624110 DEC1 negatively regulates the expression of DEC2 through bin... | ACCEPT | Summary: Evidence that BHLHE40 binds CACGTG E-box elements. Reason: E-box (class B CACGTG) binding is the core DNA-binding specificity of BHLHE40, required for its repressor activity. Supporting Evidence: PMID:12624110 Our findings assign for DEC1 the first target gene that is regulated through direct DNA binding |
| GO:0070888 E-box binding | IDA PMID:14672706 A novel autofeedback loop of Dec1 transcription involved in ... | ACCEPT | Summary: Evidence that BHLHE40 binds CACGTG E-box elements. Reason: E-box (class B CACGTG) binding is the core DNA-binding specificity of BHLHE40, required for its repressor activity. Supporting Evidence: PMID:14672706 DEC1 and DEC2 as well as PERs and CRYs suppressed the induced expression. Three CACGTG E-boxes are responsible for both the activation and the suppression of Dec1 transcription |
| GO:0070888 E-box binding | IDA PMID:15193144 DNA binding, but not interaction with Bmal1, is responsible ... | ACCEPT | Summary: Evidence that BHLHE40 binds CACGTG E-box elements. Reason: E-box (class B CACGTG) binding is the core DNA-binding specificity of BHLHE40, required for its repressor activity. Supporting Evidence: PMID:15193144 In the absence of Clock/Bmal1, both DEC1 and DEC2 markedly repressed the mPer1 promoter reporter; however, DNA-binding mutants showed no repressive activity |
| GO:0070888 E-box binding | IDA PMID:15560782 Functional analysis of the basic helix-loop-helix transcript... | ACCEPT | Summary: Evidence that BHLHE40 binds CACGTG E-box elements. Reason: E-box (class B CACGTG) binding is the core DNA-binding specificity of BHLHE40, required for its repressor activity. Supporting Evidence: PMID:15560782 Arg65 in the basic region, which is conserved among group B basic helix-loop-helix proteins, was responsible for the suppression, for the interaction with BMAL1 and for its binding to CACGTG E-boxes |
| GO:0070888 E-box binding | IDA PMID:18411297 DEC1 modulates the circadian phase of clock gene expression. | ACCEPT | Summary: Evidence that BHLHE40 binds CACGTG E-box elements. Reason: E-box (class B CACGTG) binding is the core DNA-binding specificity of BHLHE40, required for its repressor activity. Supporting Evidence: PMID:18411297 DEC1 showed strong binding and transrepression on the E box, but not on the E' box, in chromatin immunoprecipitation, electrophoretic mobility shift, and luciferase reporter assays |
| GO:0070888 E-box binding | IDA PMID:28797635 Circadian rhythmicity: A functional connection between diffe... | ACCEPT | Summary: Evidence that BHLHE40 binds CACGTG E-box elements. Reason: E-box (class B CACGTG) binding is the core DNA-binding specificity of BHLHE40, required for its repressor activity. Supporting Evidence: PMID:28797635 Site-directed mutagenesis, electrophoretic mobility shift assay and chromatin immunoprecipitation established that the repression was achieved through the E-box in the proximal promoter |
| GO:0070888 E-box binding | IEA GO_REF:0000120 | ACCEPT | Summary: Evidence that BHLHE40 binds CACGTG E-box elements. Reason: E-box (class B CACGTG) binding is the core DNA-binding specificity of BHLHE40, required for its repressor activity. Supporting Evidence: file:human/BHLHE40/BHLHE40-uniprot.txt Represses the activity of the circadian transcriptional activator: CLOCK-BMAL1|BMAL2 heterodimer by competing for the binding to E-box elements (5'-CACGTG-3') found within the promoters of its target genes PMID:12297495 Stra13 binds with high affinity to CACGTG class B E-box elements as a homodimer |
| GO:1990837 sequence-specific double-stranded DNA binding | IDA PMID:28473536 Impact of cytosine methylation on DNA binding specificities ... | TOO GENERAL | Summary: Yin et al. 2017 methylation-sensitive HT-SELEX includes BHLHE40 among TFs with defined binding specificities. Reason: True, but entailed by the accepted E-box binding (GO:0070888); the cached paper text does not discuss BHLHE40 individually (data in supplementary tables). Supporting Evidence: PMID:12297495 Stra13 binds with high affinity to CACGTG class B E-box elements as a homodimer |
| GO:0003714 transcription corepressor activity | IDA PMID:19786558 The basic helix-loop-helix proteins differentiated embryo ch... | NEW | Summary: DEC1 binds RXRalpha through an LXXLL motif and represses ligand-dependent RXR and RXR-heterodimer transactivation. Reason: Corepression of nuclear receptors that DEC1 does not itself bind to DNA for is a distinct activity from its E-box DNA-binding repressor function, documented with knockdown, interaction and motif mutagenesis. No corepressor term is present in GOA. Supporting Evidence: PMID:19786558 Transfection assays showed that DEC1 and DEC2 repressed ligand-dependent transactivation by RXR PMID:19786558 DEC1 and DEC2 interacted directly with RXRalpha, and ligand addition enhanced their association PMID:19786558 an LXXLL motif in DEC1 and DEC2 is necessary for RXRalpha repression file:human/BHLHE40/BHLHE40-uniprot.txt Acts as a corepressor of RXR and the RXR-LXR heterodimers and represses the ligand-induced RXRA and NR1H3/LXRA transactivation activity |
| GO:0032693 negative regulation of interleukin-10 production | ISS PMID:29773644 Bhlhe40 is an essential repressor of IL-10 during Mycobacter... | NEW | Summary: Mouse Bhlhe40 directly binds the Il10 locus and represses Il10 expression in T cells and myeloid cells. Reason: Bhlhe40 itself does the regulatory work here: it binds a conserved +6 kb Il10 element (ChIP-seq) and Il10 is derepressed in Bhlhe40-/- T cells and CD11c+ cells, with Il10 deletion reversing the phenotype. Transferred to human by orthology; non-core immune role. Supporting Evidence: PMID:29773644 is required to repress Il10 expression during Mtb infection PMID:29773644 our ChIP-seq experiment identified a Bhlhe40 binding site at +6 kb relative to the transcriptional start site of Il10 PMID:24699451 it positively regulates the production of GM-CSF and negatively regulates the production of IL-10 PMID:24699451 Chromatin immunoprecipitation-sequencing (ChIP-Seq) reveals binding of Bhlhe40 to the Il3/Csf2 and Il10 loci |
| GO:0120041 positive regulation of macrophage proliferation | ISS PMID:31061528 Bhlhe40 mediates tissue-specific control of macrophage proli... | NEW | Summary: Mouse Bhlhe40 is required cell-intrinsically for self-renewal of large peritoneal macrophages and for efferocytosis-induced macrophage proliferation, acting by repressing Maf. Reason: Bhlhe40 binds the Maf promoter and represses this anti-proliferative transcription factor, which permits macrophage cell cycling, so it acts as a direct transcriptional regulator of macrophage proliferation. Shown in two independent settings (IL-4/helminth-driven LPM expansion; Myc-Bhlhe40-c-Maf after apoptotic-cell uptake). Transferred by orthology; non-core, tissue-specific role. Supporting Evidence: PMID:31061528 Bhlhe40 was required in a cell-intrinsic manner for the self-renewal and maintenance of large peritoneal macrophages (LPMs) PMID:31061528 Our data suggest that Bhlhe40 is a transcriptional repressor of Maf in LPMs PMID:34784501 Bhlhe40 then represses the cell-cycling-inhibitor c-Maf to drive proliferation PMID:34784501 silencing Bhlhe40 completely prevented the increase in EdU incorporation in AC+ macrophages |
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Download this section (compressed HTML)Q: Is the IBA to anterior/posterior pattern specification (HES subfamily node PTN000105428) appropriately propagated to the divergent DEC branch (BHLHE40/BHLHE41), which lacks the WRPW motif and has no segmentation phenotype?
Q: Does human BHLHE40 directly activate any target genes (e.g. CSF2/GM-CSF, cell-cycle genes), or are reported positive effects indirect consequences of repressing other repressors?
Q: Should hypoxia induction of BHLHE40 (a direct HIF-1 target) and its role in hypoxic inhibition of adipogenesis via PPARG repression be represented as process annotations, or are these expression responses better left to GO-CAM?
Q: Which BHLHE40 functions depend on its BHLHE41 paralog (redundancy in alveolar macrophages, clock), and should annotations note this redundancy?
Experiment: Genome-wide ChIP-seq/CUT&RUN of endogenous BHLHE40 in human macrophages and T cells, combined with acute degron depletion and nascent transcription (PRO-seq), to separate direct repressed and activated targets.
Hypothesis: Direct BHLHE40 targets are predominantly repressed through CACGTG E-boxes; activated genes are mostly indirect.
Type: genome-wide occupancy with acute depletion
Experiment: Test whether the LXXLL motif mutant (L78A/L79A) of human BHLHE40 retains E-box repression but loses RXR corepression in hepatocytes, and assess effects on hepatic lipid gene rhythms.
Hypothesis: E-box DNA-binding repression and RXR corepression are separable activities of BHLHE40.
Type: structure-function mutagenesis
Experiment: Assess human monocyte-derived and tissue macrophages with BHLHE40 knockout for IL-10 production and proliferation after IL-4 or apoptotic-cell exposure.
Hypothesis: The mouse Bhlhe40-Il10 and Bhlhe40-Maf regulatory axes are conserved in human macrophages.
Type: loss-of-function in primary human cells
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