{"gene":"CLOCK","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":2018,"finding":"CLOCK:BMAL1 binds synchronously to all target genes but its transcriptional output is heterogeneous. Genome-wide analysis revealed that CLOCK:BMAL1 rhythmic DNA binding promotes rhythmic nucleosome removal but is not sufficient to generate transcriptionally active enhancers (as assessed by H3K27ac signal, RNA Pol II recruitment, and eRNA expression). Instead, transcriptional activity of CLOCK:BMAL1 enhancers depends on ubiquitously expressed co-binding transcription factors at nearby sites, suggesting CLOCK:BMAL1 promotes a transcriptionally permissive chromatin landscape rather than directly activating transcription.","method":"Meta-analysis of genome-wide ChIP-seq, H3K27ac ChIP-seq, RNA Pol II ChIP-seq, eRNA expression, and ATAC-seq datasets; fasting experiments to modulate transcription factor activity","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal genome-wide methods in a single lab meta-analysis; no in vitro reconstitution or mutagenesis","pmids":["29300726"],"is_preprint":false},{"year":2022,"finding":"In glioma stem cells (GSCs), the CLOCK-BMAL1 heterodimer directly drives transcription of legumain (LGMN) and olfactomedin-like 3 (OLFML3). OLFML3 upregulates LGMN via HIF1α signaling, and LGMN promotes immunosuppressive microglial infiltration via CD162 upregulation. ChIP and functional knockdown/overexpression experiments established the CLOCK-OLFML3-HIF1α-LGMN-CD162 axis as a molecular switch controlling microglial biology in glioblastoma.","method":"ChIP assay, transcriptome profiling, scRNA-seq, TCGA dataset analysis, functional knockdown/overexpression studies, GBM mouse models with anti-PD-1 combination","journal":"Cancer immunology research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus functional loss-of-function with defined cellular phenotype in a single lab; multiple orthogonal methods but no in vitro reconstitution","pmids":["35413115"],"is_preprint":false},{"year":2016,"finding":"The circadian gene CLOCK directly activates transcription of Pdia3 (protein disulfide isomerase family A member 3, the 1,25-dihydroxyvitamin D3 receptor) by binding E-box elements in the Pdia3 promoter. Clock mutant (ClockΔ19) mice show reduced Pdia3 transcription, decreased bone density, and increased apoptosis in osteoblasts. Forced expression of PDIA3 or CLOCK rescues osteogenic defects in mutant mice, and siRNA ablation of PDIA3 blocks the compensatory effect of CLOCK overexpression.","method":"Luciferase reporter assay, ChIP assay, histology, real-time PCR, in vivo forced expression rescue experiments, siRNA knockdown","journal":"Journal of bone and mineral research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and luciferase assays confirming direct E-box binding plus in vivo rescue, single lab","pmids":["27883226"],"is_preprint":false},{"year":2017,"finding":"CLOCK-mediated transcription of Pdia3 is required to suppress endoplasmic reticulum (ER) stress and reactive oxygen species (ROS) in liver. In Clock mutant mice, Pdia3 transcription is reduced due to low E-box affinity in the promoter, leading to sustained phosphorylation of PERK and eIF2α, upregulation of UPR target genes, increased apoptosis, elevated ROS, and a liver aging/senescence phenotype. siRNA ablation of Pdia3 phenocopies Clock mutation effects on ER stress.","method":"Immunoblot, immunoprecipitation, real-time PCR, siRNA knockdown, ChIP assay (E-box promoter binding), histology in ClockΔ19 mutant mice","journal":"Aging","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (ChIP, siRNA, immunoblot) in a single lab, extends findings from the companion bone paper","pmids":["29283886"],"is_preprint":false},{"year":2019,"finding":"The CLOCK mutation (ClockΔ19) promotes osteoarthritis by reducing total lysine acetylation and specifically inhibiting acetylation of NFκB at Lys310 while promoting its phosphorylation at Ser276, leading to increased NFκB nuclear translocation and upregulation of pro-inflammatory mediators (IL-1β, IL-6, MCP-1). Wild-type CLOCK protein positively regulates NFκB at the transcriptional level by binding E-box elements. Forced in vivo expression of CLOCK inhibited NFκB activation by increasing acetylation and decreasing phosphorylation, reducing cartilage damage.","method":"ChIP assay, luciferase assay, immunoblot, immunoprecipitation, real-time PCR, histology, nanoparticle-mediated in vivo CLOCK expression, ClockΔ19 mutant mice","journal":"Osteoarthritis and cartilage","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and luciferase establish direct E-box binding; post-translational modification of NFκB shown by IP/immunoblot; single lab with multiple orthogonal methods","pmids":["30716535"],"is_preprint":false},{"year":2014,"finding":"The CLOCK:BMAL1 heterodimer directly activates the adiponectin promoter in adipocytes. siRNA knockdown of CLOCK or BMAL1 and reconstitution of the core clock in cell culture demonstrated that the CLOCK:BMAL1 complex directly regulates adiponectin expression. Additionally, CLOCK:BMAL1 controls adiponectin indirectly through circadian regulation of its transcription factor PPARγ and co-activator PGC1α in mouse white adipose tissue.","method":"siRNA knockdown, core clock reconstitution in cell culture, promoter reporter assay, real-time PCR, mouse white adipose tissue circadian expression analysis","journal":"Molecular and cellular endocrinology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, siRNA and reporter assay without ChIP or mutagenesis to confirm direct E-box binding; mechanistic follow-up is partial","pmids":["25448847"],"is_preprint":false},{"year":2006,"finding":"Clock knockout mice demonstrate that CLOCK protein is dispensable for rhythmic gene expression and circadian behavior, presumably because other proteins (potentially NPAS2) can substitute for CLOCK in driving circadian transcription. This challenges the previously established view that CLOCK is an essential, non-redundant component of the mammalian circadian oscillator.","method":"Clock knockout mouse model; analysis of rhythmic gene expression and locomotor behavior","journal":"Trends in cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout with defined behavioral and molecular phenotype; reported as a commentary on Reppert lab Clock KO data; single set of experiments","pmids":["16996737"],"is_preprint":false},{"year":2021,"finding":"In Drosophila clock neurons, the CLOCK protein (ortholog of mammalian CLOCK) localizes to discrete foci at the nuclear envelope during the circadian repression phase. CLOCK plays a role in the subnuclear positioning of core clock genes (period and timeless) close to the nuclear periphery specifically during the repression phase. Loss of Lamin B receptor disrupts CLOCK foci and per gene peripheral localization, causing circadian rhythm defects.","method":"High-resolution live imaging, DNA-FISH, genetic loss-of-function (Lamin B receptor mutants), immunofluorescence in Drosophila clock neurons","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct imaging and DNA-FISH with genetic validation in Drosophila ortholog; single lab but multiple orthogonal methods","pmids":["34234015"],"is_preprint":false}],"current_model":"CLOCK forms a heterodimer with BMAL1 that binds E-box elements to activate transcription of clock-controlled genes (including Pdia3, LGMN, and adiponectin), promotes permissive chromatin remodeling (nucleosome removal) at target enhancers without being sufficient for full transcriptional activation (which requires co-binding transcription factors), regulates NFκB activity through post-translational acetylation, and localizes to discrete nuclear envelope foci during the repression phase where it participates in subnuclear repositioning of core clock genes; CLOCK is partially redundant in vivo as Clock knockout mice remain rhythmic, likely due to compensation by NPAS2."},"narrative":{"mechanistic_narrative":"CLOCK is a transcription factor that, as a heterodimer with BMAL1, binds E-box elements to drive circadian and clock-controlled gene expression across multiple tissues [PMID:27883226, PMID:25448847]. Genome-wide, rhythmic CLOCK:BMAL1 binding promotes nucleosome removal and a transcriptionally permissive chromatin state but is not sufficient on its own to activate transcription, which additionally requires ubiquitously expressed co-binding transcription factors at nearby sites [PMID:29300726]. Through direct E-box binding, CLOCK activates specific targets including Pdia3, where CLOCK-driven Pdia3 expression maintains osteoblast viability and bone density [PMID:27883226] and suppresses ER stress and ROS in liver to limit a senescence/aging phenotype [PMID:29283886]. CLOCK also controls adiponectin expression in adipocytes both directly and via circadian regulation of PPARgamma and PGC1alpha [PMID:25448847], and in glioma stem cells drives an OLFML3-HIF1alpha-LGMN-CD162 axis promoting immunosuppressive microglial infiltration [PMID:35413115]. Beyond transcriptional activation, CLOCK positively regulates NFkappaB: loss of functional CLOCK reduces NFkappaB Lys310 acetylation and increases Ser276 phosphorylation, enhancing NFkappaB nuclear translocation and pro-inflammatory output, while restored CLOCK suppresses this and reduces tissue inflammation [PMID:30716535]. CLOCK is functionally redundant in vivo, as Clock knockout mice remain rhythmic, likely through compensation by NPAS2 [PMID:16996737], and in Drosophila clock neurons CLOCK localizes to nuclear-envelope foci during the repression phase and participates in subnuclear repositioning of core clock genes to the periphery in a Lamin B receptor-dependent manner [PMID:34234015].","teleology":[{"year":2006,"claim":"Testing whether CLOCK is an essential core oscillator component, knockout revealed it is dispensable for rhythmicity, redefining it as a redundant rather than indispensable clock factor.","evidence":"Clock knockout mouse with analysis of rhythmic gene expression and locomotor behavior","pmids":["16996737"],"confidence":"Medium","gaps":["Did not directly demonstrate NPAS2 as the compensating factor","Does not address tissue-specific or non-circadian CLOCK functions"]},{"year":2014,"claim":"To connect the clock to metabolism, CLOCK:BMAL1 was shown to regulate adiponectin both directly at its promoter and indirectly through PPARgamma/PGC1alpha, establishing a metabolic output of the heterodimer.","evidence":"siRNA knockdown, core clock reconstitution in cell culture, promoter reporter assay, and circadian expression analysis in mouse white adipose tissue","pmids":["25448847"],"confidence":"Low","gaps":["No ChIP or E-box mutagenesis to confirm direct binding to the adiponectin promoter","Relative contributions of direct vs indirect regulation not quantified"]},{"year":2016,"claim":"Identifying a non-clock target, CLOCK was shown to directly activate Pdia3 via E-box binding, linking CLOCK to osteoblast survival and bone density through in vivo rescue.","evidence":"Luciferase reporter, ChIP, histology, real-time PCR, and forced-expression rescue plus siRNA in Clock-delta19 mutant mice","pmids":["27883226"],"confidence":"Medium","gaps":["Single tissue context","Mechanism of PDIA3 protection of osteoblasts not detailed here"]},{"year":2017,"claim":"Extending the Pdia3 axis, CLOCK-driven Pdia3 was shown to suppress ER stress and ROS in liver, establishing how loss of CLOCK target output produces a senescence/aging phenotype.","evidence":"Immunoblot, immunoprecipitation, real-time PCR, siRNA, and ChIP in Clock-delta19 mutant mice liver","pmids":["29283886"],"confidence":"Medium","gaps":["Does not establish whether low E-box affinity is the sole cause of reduced Pdia3 in vivo","Causality between ER stress relief and aging phenotype is correlative"]},{"year":2018,"claim":"Addressing whether CLOCK:BMAL1 binding is sufficient for activation, genome-wide analysis showed it promotes rhythmic nucleosome removal and permissive chromatin but requires co-binding transcription factors for actual transcription.","evidence":"Meta-analysis of ChIP-seq, H3K27ac, RNA Pol II ChIP-seq, eRNA, and ATAC-seq datasets with fasting perturbation","pmids":["29300726"],"confidence":"Medium","gaps":["Identity of required co-binding factors at each enhancer not resolved","No in vitro reconstitution or mutagenesis to test sufficiency directly"]},{"year":2019,"claim":"Beyond transcriptional activation, CLOCK was shown to control NFkappaB post-translationally, with functional CLOCK promoting Lys310 acetylation and suppressing Ser276 phosphorylation to limit inflammatory signaling in cartilage.","evidence":"ChIP, luciferase, immunoblot, immunoprecipitation, histology, and nanoparticle-mediated in vivo CLOCK expression in Clock-delta19 mice","pmids":["30716535"],"confidence":"Medium","gaps":["Whether CLOCK directly modifies NFkappaB or acts via an intermediary acetyltransferase is unresolved","Single tissue (cartilage/osteoarthritis) context"]},{"year":2021,"claim":"Probing a spatial dimension of clock repression, the CLOCK ortholog was shown to form nuclear-envelope foci and reposition core clock genes to the periphery during the repression phase via Lamin B receptor.","evidence":"Live imaging, DNA-FISH, immunofluorescence, and Lamin B receptor loss-of-function in Drosophila clock neurons","pmids":["34234015"],"confidence":"Medium","gaps":["Demonstrated in Drosophila ortholog, not confirmed for mammalian CLOCK","Molecular mechanism tethering CLOCK to the nuclear envelope unknown"]},{"year":2022,"claim":"Extending CLOCK to disease, the heterodimer was shown to drive an OLFML3-HIF1alpha-LGMN-CD162 axis in glioma stem cells that promotes immunosuppressive microglial infiltration.","evidence":"ChIP, transcriptome and scRNA-seq, TCGA analysis, knockdown/overexpression, and GBM mouse models with anti-PD-1","pmids":["35413115"],"confidence":"Medium","gaps":["Whether this axis operates rhythmically or independently of circadian timing is unclear","Direct E-box binding to OLFML3 vs LGMN not fully delineated"]},{"year":null,"claim":"How CLOCK selects between permissive chromatin priming, direct target activation, and post-translational regulation of partners such as NFkappaB across tissues, and whether nuclear-envelope repositioning operates in mammals, remains open.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying mechanism for context-dependent transcriptional output","Mammalian relevance of subnuclear repositioning untested","Direct vs indirect basis of NFkappaB modification unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,1,2,3,4]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[2,3,4]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[2,4,7]},{"term_id":"GO:0005635","term_label":"nuclear envelope","supporting_discovery_ids":[7]}],"pathway":[{"term_id":"R-HSA-9909396","term_label":"Circadian clock","supporting_discovery_ids":[6,7]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,2,5]}],"complexes":["CLOCK:BMAL1"],"partners":["BMAL1","NPAS2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O15516","full_name":"Circadian locomoter output cycles protein kaput","aliases":["Class E basic helix-loop-helix protein 8","bHLHe8"],"length_aa":846,"mass_kda":95.3,"function":"Transcriptional activator which forms a core component of the circadian clock. The circadian clock, an internal time-keeping system, regulates various physiological processes through the generation of approximately 24 hour circadian rhythms in gene expression, which are translated into rhythms in metabolism and behavior. It is derived from the Latin roots 'circa' (about) and 'diem' (day) and acts as an important regulator of a wide array of physiological functions including metabolism, sleep, body temperature, blood pressure, endocrine, immune, cardiovascular, and renal function. Consists of two major components: the central clock, residing in the suprachiasmatic nucleus (SCN) of the brain, and the peripheral clocks that are present in nearly every tissue and organ system. Both the central and peripheral clocks can be reset by environmental cues, also known as Zeitgebers (German for 'timegivers'). The predominant Zeitgeber for the central clock is light, which is sensed by retina and signals directly to the SCN. The central clock entrains the peripheral clocks through neuronal and hormonal signals, body temperature and feeding-related cues, aligning all clocks with the external light/dark cycle. Circadian rhythms allow an organism to achieve temporal homeostasis with its environment at the molecular level by regulating gene expression to create a peak of protein expression once every 24 hours to control when a particular physiological process is most active with respect to the solar day. Transcription and translation of core clock components (CLOCK, NPAS2, BMAL1, BMAL2, PER1, PER2, PER3, CRY1 and CRY2) plays a critical role in rhythm generation, whereas delays imposed by post-translational modifications (PTMs) are important for determining the period (tau) of the rhythms (tau refers to the period of a rhythm and is the length, in time, of one complete cycle). A diurnal rhythm is synchronized with the day/night cycle, while the ultradian and infradian rhythms have a period shorter and longer than 24 hours, respectively. Disruptions in the circadian rhythms contribute to the pathology of cardiovascular diseases, cancer, metabolic syndromes and aging. A transcription/translation feedback loop (TTFL) forms the core of the molecular circadian clock mechanism. Transcription factors, CLOCK or NPAS2 and BMAL1 or BMAL2, form the positive limb of the feedback loop, act in the form of a heterodimer and activate the transcription of core clock genes and clock-controlled genes (involved in key metabolic processes), harboring E-box elements (5'-CACGTG-3') within their promoters. The core clock genes: PER1/2/3 and CRY1/2 which are transcriptional repressors form the negative limb of the feedback loop and interact with the CLOCK|NPAS2-BMAL1|BMAL2 heterodimer inhibiting its activity and thereby negatively regulating their own expression. This heterodimer also activates nuclear receptors NR1D1/2 and RORA/B/G, which form a second feedback loop and which activate and repress BMAL1 transcription, respectively. Regulates the circadian expression of ICAM1, VCAM1, CCL2, THPO and MPL and also acts as an enhancer of the transactivation potential of NF-kappaB. Plays an important role in the homeostatic regulation of sleep. The CLOCK-BMAL1 heterodimer regulates the circadian expression of SERPINE1/PAI1, VWF, B3, CCRN4L/NOC, NAMPT, DBP, MYOD1, PPARGC1A, PPARGC1B, SIRT1, GYS2, F7, NGFR, GNRHR, BHLHE40/DEC1, ATF4, MTA1, KLF10 and also genes implicated in glucose and lipid metabolism. Promotes rhythmic chromatin opening, regulating the DNA accessibility of other transcription factors. The CLOCK-BMAL2 heterodimer activates the transcription of SERPINE1/PAI1 and BHLHE40/DEC1. The preferred binding motif for the CLOCK-BMAL1 heterodimer is 5'-CACGTGA-3', which contains a flanking adenine nucleotide at the 3-prime end of the canonical 6-nucleotide E-box sequence (PubMed:23229515). CLOCK specifically binds to the half-site 5'-CAC-3', while BMAL1 binds to the half-site 5'-GTGA-3' (PubMed:23229515). The CLOCK-BMAL1 heterodimer also recognizes the non-canonical E-box motifs 5'-AACGTGA-3' and 5'-CATGTGA-3' (PubMed:23229515). CLOCK has an intrinsic acetyltransferase activity, which enables circadian chromatin remodeling by acetylating histones and nonhistone proteins, including its own partner BMAL1. Represses glucocorticoid receptor NR3C1/GR-induced transcriptional activity by reducing the association of NR3C1/GR to glucocorticoid response elements (GREs) via the acetylation of multiple lysine residues located in its hinge region (PubMed:21980503). The acetyltransferase activity of CLOCK is as important as its transcription activity in circadian control. Acetylates metabolic enzymes IMPDH2 and NDUFA9 in a circadian manner. Facilitated by BMAL1, rhythmically interacts and acetylates argininosuccinate synthase 1 (ASS1) leading to enzymatic inhibition of ASS1 as well as the circadian oscillation of arginine biosynthesis and subsequent ureagenesis (PubMed:28985504). Drives the circadian rhythm of blood pressure through transcriptional activation of ATP1B1 (By similarity)","subcellular_location":"Nucleus; Cytoplasm; Cytoplasm, cytosol","url":"https://www.uniprot.org/uniprotkb/O15516/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CLOCK","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CLOCK","total_profiled":1310},"omim":[{"mim_id":"620468","title":"VERTEBRAE DEVELOPMENT-ASSOCIATED GENE; VRTN","url":"https://www.omim.org/entry/620468"},{"mim_id":"620015","title":"ADVANCED SLEEP PHASE SYNDROME, FAMILIAL, 4; FASPS4","url":"https://www.omim.org/entry/620015"},{"mim_id":"619987","title":"NOTCH-REGULATED ANKYRIN REPEAT-CONTAINING PROTEIN; NRARP","url":"https://www.omim.org/entry/619987"},{"mim_id":"619771","title":"VRK SERINE/THREONINE KINASE 3; VRK3","url":"https://www.omim.org/entry/619771"},{"mim_id":"616995","title":"CLOCK-INTERACTING PACEMAKER; CIPC","url":"https://www.omim.org/entry/616995"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Vesicles","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/CLOCK"},"hgnc":{"alias_symbol":["KIAA0334","KAT13D","bHLHe8"],"prev_symbol":[]},"alphafold":{"accession":"O15516","domains":[{"cath_id":"4.10.280.10","chopping":"26-91","consensus_level":"medium","plddt":87.8292,"start":26,"end":91},{"cath_id":"3.30.450.20","chopping":"119-224_249-262","consensus_level":"medium","plddt":89.0748,"start":119,"end":262},{"cath_id":"3.30.450.20","chopping":"276-390","consensus_level":"high","plddt":96.5406,"start":276,"end":390}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O15516","model_url":"https://alphafold.ebi.ac.uk/files/AF-O15516-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O15516-F1-predicted_aligned_error_v6.png","plddt_mean":60.59},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CLOCK","jax_strain_url":"https://www.jax.org/strain/search?query=CLOCK"},"sequence":{"accession":"O15516","fasta_url":"https://rest.uniprot.org/uniprotkb/O15516.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O15516/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O15516"}},"corpus_meta":[{"pmid":"5002428","id":"PMC_5002428","title":"Clock mutants of Drosophila melanogaster.","date":"1971","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/5002428","citation_count":1586,"is_preprint":false},{"pmid":"1722017","id":"PMC_1722017","title":"Telomere loss: mitotic clock or genetic time bomb?","date":"1991","source":"Mutation research","url":"https://pubmed.ncbi.nlm.nih.gov/1722017","citation_count":1024,"is_preprint":false},{"pmid":"8395408","id":"PMC_8395408","title":"The melatonin rhythm: both a clock and a calendar.","date":"1993","source":"Experientia","url":"https://pubmed.ncbi.nlm.nih.gov/8395408","citation_count":784,"is_preprint":false},{"pmid":"24560196","id":"PMC_24560196","title":"Circadian clock proteins and immunity.","date":"2014","source":"Immunity","url":"https://pubmed.ncbi.nlm.nih.gov/24560196","citation_count":490,"is_preprint":false},{"pmid":"31557726","id":"PMC_31557726","title":"Circadian clock genes and the transcriptional architecture of the clock mechanism.","date":"2019","source":"Journal of molecular endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/31557726","citation_count":378,"is_preprint":false},{"pmid":"18971218","id":"PMC_18971218","title":"Glucocorticoids and the circadian clock.","date":"2008","source":"The Journal of endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/18971218","citation_count":361,"is_preprint":false},{"pmid":"12111534","id":"PMC_12111534","title":"Clock mechanisms in zebrafish.","date":"2002","source":"Cell and tissue research","url":"https://pubmed.ncbi.nlm.nih.gov/12111534","citation_count":209,"is_preprint":false},{"pmid":"31300477","id":"PMC_31300477","title":"Cancer and the Circadian Clock.","date":"2019","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/31300477","citation_count":187,"is_preprint":false},{"pmid":"39270656","id":"PMC_39270656","title":"Metformin decelerates aging clock in male monkeys.","date":"2024","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/39270656","citation_count":144,"is_preprint":false},{"pmid":"12622838","id":"PMC_12622838","title":"Melatonin: a clock-output, a clock-input.","date":"2003","source":"Journal of neuroendocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/12622838","citation_count":140,"is_preprint":false},{"pmid":"22390237","id":"PMC_22390237","title":"Clock genes and clock-controlled genes in the regulation of metabolic rhythms.","date":"2012","source":"Chronobiology international","url":"https://pubmed.ncbi.nlm.nih.gov/22390237","citation_count":140,"is_preprint":false},{"pmid":"26842252","id":"PMC_26842252","title":"The Circadian Clock Mutation Promotes Intestinal Dysbiosis.","date":"2016","source":"Alcoholism, clinical and experimental research","url":"https://pubmed.ncbi.nlm.nih.gov/26842252","citation_count":136,"is_preprint":false},{"pmid":"29300726","id":"PMC_29300726","title":"Regulation of circadian clock transcriptional output by CLOCK:BMAL1.","date":"2018","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/29300726","citation_count":135,"is_preprint":false},{"pmid":"12511866","id":"PMC_12511866","title":"Replicating by the clock.","date":"2003","source":"Nature reviews. 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Molecular cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/39753699","citation_count":29,"is_preprint":false},{"pmid":"26332974","id":"PMC_26332974","title":"The molecular clock as a metabolic rheostat.","date":"2015","source":"Diabetes, obesity & metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/26332974","citation_count":29,"is_preprint":false},{"pmid":"20934870","id":"PMC_20934870","title":"Simplicity and complexity in the cyanobacterial circadian clock mechanism.","date":"2010","source":"Current opinion in genetics & development","url":"https://pubmed.ncbi.nlm.nih.gov/20934870","citation_count":29,"is_preprint":false},{"pmid":"36503722","id":"PMC_36503722","title":"Circadian clock organization in the retina: From clock components to rod and cone pathways and visual function.","date":"2022","source":"Progress in retinal and eye research","url":"https://pubmed.ncbi.nlm.nih.gov/36503722","citation_count":28,"is_preprint":false},{"pmid":"14769866","id":"PMC_14769866","title":"Chicktacking pineal clock.","date":"2003","source":"Journal of biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/14769866","citation_count":27,"is_preprint":false},{"pmid":"15358206","id":"PMC_15358206","title":"Transcription, translation, degradation, and circadian clock.","date":"2004","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/15358206","citation_count":27,"is_preprint":false},{"pmid":"30687965","id":"PMC_30687965","title":"Principles of the animal molecular clock learned from Neurospora.","date":"2019","source":"The European journal of neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/30687965","citation_count":27,"is_preprint":false},{"pmid":"30589961","id":"PMC_30589961","title":"Development of the mammalian circadian clock.","date":"2019","source":"The European journal of neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/30589961","citation_count":26,"is_preprint":false},{"pmid":"33370580","id":"PMC_33370580","title":"Translating around the clock: Multi-level regulation of post-transcriptional processes by the circadian clock.","date":"2020","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/33370580","citation_count":26,"is_preprint":false},{"pmid":"16687294","id":"PMC_16687294","title":"A network of (autonomic) clock outputs.","date":"2006","source":"Chronobiology international","url":"https://pubmed.ncbi.nlm.nih.gov/16687294","citation_count":26,"is_preprint":false},{"pmid":"35972269","id":"PMC_35972269","title":"Immunity, Infection, and the Zebrafish Clock.","date":"2022","source":"Infection and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/35972269","citation_count":25,"is_preprint":false},{"pmid":"31379749","id":"PMC_31379749","title":"Oxysterols and Gastrointestinal Cancers Around the Clock.","date":"2019","source":"Frontiers in endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/31379749","citation_count":25,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":38077,"output_tokens":2888,"usd":0.078775,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9813,"output_tokens":3196,"usd":0.064482,"stage2_stop_reason":"end_turn"},"total_usd":0.143257,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking through the abstracts, I need to identify papers that describe direct mechanistic experiments about the CLOCK protein (the mammalian/vertebrate circadian clock gene CLOCK, also known as KIAA0334, KAT13D, bHLHe8).\n\nLet me classify each paper:\n- Most papers are general reviews about circadian biology, epigenetic clocks, molecular evolution clocks, segmentation clocks, or other \"clock\" concepts unrelated to the CLOCK gene specifically\n- Papers about CLOCK the gene with direct mechanistic experiments: 13, 18, 72, 73, 74, 78, 80, 87\n\nLet me analyze these carefully:\n\n- PMID 29300726 (paper 13): Meta-analysis of genome-wide datasets, mechanistic insight about CLOCK:BMAL1 transcriptional output\n- PMID 35413115 (paper 18): CLOCK-BMAL1 drives LGMN expression, ChIP/functional studies\n- PMID 27883226 (paper 72): CLOCK activates Pdia3 via E-box, ChIP/luciferase assays\n- PMID 29283886 (paper 80): CLOCK-mediated Pdia3 expression, ER stress\n- PMID 30716535 (paper 87): CLOCK regulates NFκB acetylation\n- PMID 25448847 (paper 73): CLOCK:BMAL1 regulates adiponectin\n- PMID 16996737 (paper 74): Clock knockout mice - CLOCK dispensable\n- PMID 34234015 (paper 78): Drosophila CLOCK protein spatial organization (ortholog)\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2018,\n      \"finding\": \"CLOCK:BMAL1 binds synchronously to all target genes but its transcriptional output is heterogeneous. Genome-wide analysis revealed that CLOCK:BMAL1 rhythmic DNA binding promotes rhythmic nucleosome removal but is not sufficient to generate transcriptionally active enhancers (as assessed by H3K27ac signal, RNA Pol II recruitment, and eRNA expression). Instead, transcriptional activity of CLOCK:BMAL1 enhancers depends on ubiquitously expressed co-binding transcription factors at nearby sites, suggesting CLOCK:BMAL1 promotes a transcriptionally permissive chromatin landscape rather than directly activating transcription.\",\n      \"method\": \"Meta-analysis of genome-wide ChIP-seq, H3K27ac ChIP-seq, RNA Pol II ChIP-seq, eRNA expression, and ATAC-seq datasets; fasting experiments to modulate transcription factor activity\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal genome-wide methods in a single lab meta-analysis; no in vitro reconstitution or mutagenesis\",\n      \"pmids\": [\"29300726\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In glioma stem cells (GSCs), the CLOCK-BMAL1 heterodimer directly drives transcription of legumain (LGMN) and olfactomedin-like 3 (OLFML3). OLFML3 upregulates LGMN via HIF1α signaling, and LGMN promotes immunosuppressive microglial infiltration via CD162 upregulation. ChIP and functional knockdown/overexpression experiments established the CLOCK-OLFML3-HIF1α-LGMN-CD162 axis as a molecular switch controlling microglial biology in glioblastoma.\",\n      \"method\": \"ChIP assay, transcriptome profiling, scRNA-seq, TCGA dataset analysis, functional knockdown/overexpression studies, GBM mouse models with anti-PD-1 combination\",\n      \"journal\": \"Cancer immunology research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus functional loss-of-function with defined cellular phenotype in a single lab; multiple orthogonal methods but no in vitro reconstitution\",\n      \"pmids\": [\"35413115\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"The circadian gene CLOCK directly activates transcription of Pdia3 (protein disulfide isomerase family A member 3, the 1,25-dihydroxyvitamin D3 receptor) by binding E-box elements in the Pdia3 promoter. Clock mutant (ClockΔ19) mice show reduced Pdia3 transcription, decreased bone density, and increased apoptosis in osteoblasts. Forced expression of PDIA3 or CLOCK rescues osteogenic defects in mutant mice, and siRNA ablation of PDIA3 blocks the compensatory effect of CLOCK overexpression.\",\n      \"method\": \"Luciferase reporter assay, ChIP assay, histology, real-time PCR, in vivo forced expression rescue experiments, siRNA knockdown\",\n      \"journal\": \"Journal of bone and mineral research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and luciferase assays confirming direct E-box binding plus in vivo rescue, single lab\",\n      \"pmids\": [\"27883226\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CLOCK-mediated transcription of Pdia3 is required to suppress endoplasmic reticulum (ER) stress and reactive oxygen species (ROS) in liver. In Clock mutant mice, Pdia3 transcription is reduced due to low E-box affinity in the promoter, leading to sustained phosphorylation of PERK and eIF2α, upregulation of UPR target genes, increased apoptosis, elevated ROS, and a liver aging/senescence phenotype. siRNA ablation of Pdia3 phenocopies Clock mutation effects on ER stress.\",\n      \"method\": \"Immunoblot, immunoprecipitation, real-time PCR, siRNA knockdown, ChIP assay (E-box promoter binding), histology in ClockΔ19 mutant mice\",\n      \"journal\": \"Aging\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (ChIP, siRNA, immunoblot) in a single lab, extends findings from the companion bone paper\",\n      \"pmids\": [\"29283886\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"The CLOCK mutation (ClockΔ19) promotes osteoarthritis by reducing total lysine acetylation and specifically inhibiting acetylation of NFκB at Lys310 while promoting its phosphorylation at Ser276, leading to increased NFκB nuclear translocation and upregulation of pro-inflammatory mediators (IL-1β, IL-6, MCP-1). Wild-type CLOCK protein positively regulates NFκB at the transcriptional level by binding E-box elements. Forced in vivo expression of CLOCK inhibited NFκB activation by increasing acetylation and decreasing phosphorylation, reducing cartilage damage.\",\n      \"method\": \"ChIP assay, luciferase assay, immunoblot, immunoprecipitation, real-time PCR, histology, nanoparticle-mediated in vivo CLOCK expression, ClockΔ19 mutant mice\",\n      \"journal\": \"Osteoarthritis and cartilage\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and luciferase establish direct E-box binding; post-translational modification of NFκB shown by IP/immunoblot; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"30716535\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"The CLOCK:BMAL1 heterodimer directly activates the adiponectin promoter in adipocytes. siRNA knockdown of CLOCK or BMAL1 and reconstitution of the core clock in cell culture demonstrated that the CLOCK:BMAL1 complex directly regulates adiponectin expression. Additionally, CLOCK:BMAL1 controls adiponectin indirectly through circadian regulation of its transcription factor PPARγ and co-activator PGC1α in mouse white adipose tissue.\",\n      \"method\": \"siRNA knockdown, core clock reconstitution in cell culture, promoter reporter assay, real-time PCR, mouse white adipose tissue circadian expression analysis\",\n      \"journal\": \"Molecular and cellular endocrinology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, siRNA and reporter assay without ChIP or mutagenesis to confirm direct E-box binding; mechanistic follow-up is partial\",\n      \"pmids\": [\"25448847\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Clock knockout mice demonstrate that CLOCK protein is dispensable for rhythmic gene expression and circadian behavior, presumably because other proteins (potentially NPAS2) can substitute for CLOCK in driving circadian transcription. This challenges the previously established view that CLOCK is an essential, non-redundant component of the mammalian circadian oscillator.\",\n      \"method\": \"Clock knockout mouse model; analysis of rhythmic gene expression and locomotor behavior\",\n      \"journal\": \"Trends in cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout with defined behavioral and molecular phenotype; reported as a commentary on Reppert lab Clock KO data; single set of experiments\",\n      \"pmids\": [\"16996737\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In Drosophila clock neurons, the CLOCK protein (ortholog of mammalian CLOCK) localizes to discrete foci at the nuclear envelope during the circadian repression phase. CLOCK plays a role in the subnuclear positioning of core clock genes (period and timeless) close to the nuclear periphery specifically during the repression phase. Loss of Lamin B receptor disrupts CLOCK foci and per gene peripheral localization, causing circadian rhythm defects.\",\n      \"method\": \"High-resolution live imaging, DNA-FISH, genetic loss-of-function (Lamin B receptor mutants), immunofluorescence in Drosophila clock neurons\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct imaging and DNA-FISH with genetic validation in Drosophila ortholog; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"34234015\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CLOCK forms a heterodimer with BMAL1 that binds E-box elements to activate transcription of clock-controlled genes (including Pdia3, LGMN, and adiponectin), promotes permissive chromatin remodeling (nucleosome removal) at target enhancers without being sufficient for full transcriptional activation (which requires co-binding transcription factors), regulates NFκB activity through post-translational acetylation, and localizes to discrete nuclear envelope foci during the repression phase where it participates in subnuclear repositioning of core clock genes; CLOCK is partially redundant in vivo as Clock knockout mice remain rhythmic, likely due to compensation by NPAS2.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CLOCK is a transcription factor that, as a heterodimer with BMAL1, binds E-box elements to drive circadian and clock-controlled gene expression across multiple tissues [#2, #5]. Genome-wide, rhythmic CLOCK:BMAL1 binding promotes nucleosome removal and a transcriptionally permissive chromatin state but is not sufficient on its own to activate transcription, which additionally requires ubiquitously expressed co-binding transcription factors at nearby sites [#0]. Through direct E-box binding, CLOCK activates specific targets including Pdia3, where CLOCK-driven Pdia3 expression maintains osteoblast viability and bone density [#2] and suppresses ER stress and ROS in liver to limit a senescence/aging phenotype [#3]. CLOCK also controls adiponectin expression in adipocytes both directly and via circadian regulation of PPARgamma and PGC1alpha [#5], and in glioma stem cells drives an OLFML3-HIF1alpha-LGMN-CD162 axis promoting immunosuppressive microglial infiltration [#1]. Beyond transcriptional activation, CLOCK positively regulates NFkappaB: loss of functional CLOCK reduces NFkappaB Lys310 acetylation and increases Ser276 phosphorylation, enhancing NFkappaB nuclear translocation and pro-inflammatory output, while restored CLOCK suppresses this and reduces tissue inflammation [#4]. CLOCK is functionally redundant in vivo, as Clock knockout mice remain rhythmic, likely through compensation by NPAS2 [#6], and in Drosophila clock neurons CLOCK localizes to nuclear-envelope foci during the repression phase and participates in subnuclear repositioning of core clock genes to the periphery in a Lamin B receptor-dependent manner [#7].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Testing whether CLOCK is an essential core oscillator component, knockout revealed it is dispensable for rhythmicity, redefining it as a redundant rather than indispensable clock factor.\",\n      \"evidence\": \"Clock knockout mouse with analysis of rhythmic gene expression and locomotor behavior\",\n      \"pmids\": [\"16996737\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not directly demonstrate NPAS2 as the compensating factor\", \"Does not address tissue-specific or non-circadian CLOCK functions\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"To connect the clock to metabolism, CLOCK:BMAL1 was shown to regulate adiponectin both directly at its promoter and indirectly through PPARgamma/PGC1alpha, establishing a metabolic output of the heterodimer.\",\n      \"evidence\": \"siRNA knockdown, core clock reconstitution in cell culture, promoter reporter assay, and circadian expression analysis in mouse white adipose tissue\",\n      \"pmids\": [\"25448847\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No ChIP or E-box mutagenesis to confirm direct binding to the adiponectin promoter\", \"Relative contributions of direct vs indirect regulation not quantified\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identifying a non-clock target, CLOCK was shown to directly activate Pdia3 via E-box binding, linking CLOCK to osteoblast survival and bone density through in vivo rescue.\",\n      \"evidence\": \"Luciferase reporter, ChIP, histology, real-time PCR, and forced-expression rescue plus siRNA in Clock-delta19 mutant mice\",\n      \"pmids\": [\"27883226\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single tissue context\", \"Mechanism of PDIA3 protection of osteoblasts not detailed here\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Extending the Pdia3 axis, CLOCK-driven Pdia3 was shown to suppress ER stress and ROS in liver, establishing how loss of CLOCK target output produces a senescence/aging phenotype.\",\n      \"evidence\": \"Immunoblot, immunoprecipitation, real-time PCR, siRNA, and ChIP in Clock-delta19 mutant mice liver\",\n      \"pmids\": [\"29283886\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not establish whether low E-box affinity is the sole cause of reduced Pdia3 in vivo\", \"Causality between ER stress relief and aging phenotype is correlative\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Addressing whether CLOCK:BMAL1 binding is sufficient for activation, genome-wide analysis showed it promotes rhythmic nucleosome removal and permissive chromatin but requires co-binding transcription factors for actual transcription.\",\n      \"evidence\": \"Meta-analysis of ChIP-seq, H3K27ac, RNA Pol II ChIP-seq, eRNA, and ATAC-seq datasets with fasting perturbation\",\n      \"pmids\": [\"29300726\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Identity of required co-binding factors at each enhancer not resolved\", \"No in vitro reconstitution or mutagenesis to test sufficiency directly\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Beyond transcriptional activation, CLOCK was shown to control NFkappaB post-translationally, with functional CLOCK promoting Lys310 acetylation and suppressing Ser276 phosphorylation to limit inflammatory signaling in cartilage.\",\n      \"evidence\": \"ChIP, luciferase, immunoblot, immunoprecipitation, histology, and nanoparticle-mediated in vivo CLOCK expression in Clock-delta19 mice\",\n      \"pmids\": [\"30716535\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether CLOCK directly modifies NFkappaB or acts via an intermediary acetyltransferase is unresolved\", \"Single tissue (cartilage/osteoarthritis) context\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Probing a spatial dimension of clock repression, the CLOCK ortholog was shown to form nuclear-envelope foci and reposition core clock genes to the periphery during the repression phase via Lamin B receptor.\",\n      \"evidence\": \"Live imaging, DNA-FISH, immunofluorescence, and Lamin B receptor loss-of-function in Drosophila clock neurons\",\n      \"pmids\": [\"34234015\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Demonstrated in Drosophila ortholog, not confirmed for mammalian CLOCK\", \"Molecular mechanism tethering CLOCK to the nuclear envelope unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Extending CLOCK to disease, the heterodimer was shown to drive an OLFML3-HIF1alpha-LGMN-CD162 axis in glioma stem cells that promotes immunosuppressive microglial infiltration.\",\n      \"evidence\": \"ChIP, transcriptome and scRNA-seq, TCGA analysis, knockdown/overexpression, and GBM mouse models with anti-PD-1\",\n      \"pmids\": [\"35413115\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether this axis operates rhythmically or independently of circadian timing is unclear\", \"Direct E-box binding to OLFML3 vs LGMN not fully delineated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CLOCK selects between permissive chromatin priming, direct target activation, and post-translational regulation of partners such as NFkappaB across tissues, and whether nuclear-envelope repositioning operates in mammals, remains open.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying mechanism for context-dependent transcriptional output\", \"Mammalian relevance of subnuclear repositioning untested\", \"Direct vs indirect basis of NFkappaB modification unresolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 1, 2, 3, 4]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [2, 3, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [2, 4, 7]},\n      {\"term_id\": \"GO:0005635\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9909396\", \"supporting_discovery_ids\": [6, 7]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 2, 5]}\n    ],\n    \"complexes\": [\"CLOCK:BMAL1\"],\n    \"partners\": [\"BMAL1\", \"NPAS2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}