{"gene":"RFX7","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":2018,"finding":"Rfx7 deletion in mice leads to decreased NK cell maintenance and immunity in vivo; Rfx7-/- NK cells show increased size, granularity, proliferation, and energetic state, and genetic reduction of mTOR activity mitigated those defects, placing Rfx7 upstream of mTOR in a metabolic regulatory pathway. IL-15 rescue of Rfx7-deficient NK cells occurs through the JAK pathway.","method":"Genetic knockout mouse model, genomic/transcriptomic approaches, epistasis with mTOR reduction, in vivo NK cell assays","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic KO with defined cellular and metabolic phenotype, genetic epistasis with mTOR, replicated across multiple assays in one rigorous study","pmids":["29967452"],"is_preprint":false},{"year":2014,"finding":"RFX7 in Xenopus laevis is required for ciliogenesis in the neural tube; knockdown of RFX7 causes defects in cilia formation and neural tube closure. RFX7 controls cilia formation by regulating expression of RFX4 (a known ciliogenesis regulator). Foxj1 (master regulator of motile cilia) suppresses RFX4 but not RFX7, placing RFX7 upstream of RFX4 in a ciliogenesis cascade.","method":"Morpholino knockdown in Xenopus, epistasis with Foxj1 overexpression, gene expression analysis","journal":"Mechanisms of development","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined phenotype and genetic epistasis in Xenopus ortholog, single lab","pmids":["24530844"],"is_preprint":false},{"year":2021,"finding":"p53 activates DDIT4 indirectly through RFX7; RFX7 is required for p53-mediated inhibition of mTORC1, and DDIT4 (downstream of RFX7) is required for p53-mediated inhibition of mTORC2-dependent AKT activation. Under physiological nutrient conditions, basal p53 and RFX7 activity critically restrict mTORC1 activity, establishing a p53-RFX7-DDIT4 axis in metabolic control.","method":"Loss-of-function (RFX7 and DDIT4 knockdown/knockout), mTOR activity assays, physiological cell culture media, genetic epistasis","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean loss-of-function with defined molecular phenotype (mTORC1/2, AKT), multiple cell systems, epistasis established within a single rigorous study","pmids":["34907345"],"is_preprint":false},{"year":2021,"finding":"RFX7 directly binds DNA and controls the transcription of multiple established tumor suppressors including PDCD4, PIK3IP1, MXD4, and PNRC1 across cell types. RFX7 is activated downstream of p53 and stress signals and sensitizes cells to Doxorubicin by promoting apoptosis.","method":"ChIP-seq (cistrome mapping), transcriptome analysis in three cell systems, integration of DNA binding landscape with regulated transcriptome, cell viability assays","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP-seq cistrome plus transcriptome in three independent cell systems with functional apoptosis readout; multiple orthogonal methods","pmids":["34197623"],"is_preprint":false},{"year":2023,"finding":"Multi-omics integration (transcriptome, cistrome, proteome) in RFX7 knockout cells identifies novel RFX7 target genes linked to tumor suppression and neurological processes, and confirms RFX7 as a mechanistic link enabling p53-responsive activation of these genes.","method":"CRISPR knockout, transcriptomics, ChIP-seq, proteomics (multi-omics integration)","journal":"Cell death discovery","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean KO with multiple orthogonal omics methods in single lab, directly extends prior findings","pmids":["36864036"],"is_preprint":false},{"year":2023,"finding":"During HCMV infection, the viral kinase pUL97 upregulates SOCS3 expression in neural progenitor cells (NPCs) via the transcription factor RFX7. Proteomic analysis identified RFX7 as a pUL97-interacting host protein. pUL97 increases RFX7 phosphorylation, and both pUL97 kinase activity and RFX7 are required for SOCS3 upregulation, as shown by depletion of either pUL97 or RFX7 preventing HCMV-induced SOCS3 upregulation.","method":"Proteomics (pUL97-interacting proteins), promoter-luciferase assay, RFX7 depletion, phosphorylation analysis, viral protein screening","journal":"PLoS pathogens","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proteomics identification of interaction, functional validation by depletion and luciferase assay, phosphorylation evidence; single lab","pmids":["36753521"],"is_preprint":false},{"year":2019,"finding":"Crystal structures of a RFX7 fragment bound to the ANKRA2 ankyrin domain and to the RFXANK ankyrin domain reveal that both ANKRA2 and RFXANK recognize the PXLPXL motif of RFX7 and its flanking sequences via extensive hydrophobic interactions. Structural comparison explains the different RFX7 binding affinities of ANKRA2 and RFXANK.","method":"X-ray crystallography (two structures), structural analysis","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structures with defined binding interface and mechanistic explanation of differential affinity; single lab but structural evidence is direct","pmids":["31864703"],"is_preprint":false},{"year":2024,"finding":"RFX7 regulates PDCD4 through direct interaction with its X-box promoter motif (reporter gene assay). Mass spectrometry identified RFX5, RFXAP, RFXANK, and ANKRA2 as proteins that bind to DNA together with RFX7 at the PDCD4 promoter. ANKRA2 is a bona fide direct p53 target gene and functions as a critical cofactor of RFX7 for tumor suppressor gene regulation, while RFXANK regulates a largely distinct gene set.","method":"Reporter gene assay, mass spectrometry (co-DNA-binding proteomics), transcriptome analysis in two cell systems, siRNA knockdown","journal":"Cell death discovery","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct DNA binding assay, MS-based complex identification, transcriptome in two systems, multiple orthogonal methods; single lab","pmids":["39181888"],"is_preprint":false},{"year":2026,"finding":"DYRK1B expression is induced by p53 via RFX7 in response to cytostatic drugs. DYRK1B physically interacts with RFX7 and counteracts RFX7 activation by p53, establishing a negative feedback loop. The inhibitory effect of DYRK1B on RFX7-dependent gene expression requires DYRK1B catalytic activity and can be blocked by DYRK1 inhibitors.","method":"Co-immunoprecipitation (physical interaction), pharmacological inhibition, catalytic-dead mutant analysis, gene expression assays in multiple cancer cell lines","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal physical interaction, kinase-dead mutant, pharmacological validation; single lab with multiple cell lines","pmids":["41888523"],"is_preprint":false},{"year":2026,"finding":"In glioblastoma, RFX7 promoter hypermethylation reduces RFX7 expression. Restoration of RFX7 enhances PIK3IP1 expression, suppresses PI3K/AKT activation, and inhibits malignant progression. Loss of PIK3IP1 increases lactate production and histone H4K12 lactylation, upregulates PD-L1 and CSF1, and enhances tumor immunosuppressive features, defining an RFX7-PIK3IP1-PI3K/AKT axis linking metabolic and immune regulation.","method":"ChIP-seq, transcriptomic profiling, metabolic analysis, gene perturbation experiments (KO/overexpression), epigenetic (methylation) analysis","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gene perturbation with defined molecular phenotype and multiple orthogonal methods; single lab, single study","pmids":["42206447"],"is_preprint":false},{"year":2021,"finding":"RFX7 binds to the ABCA1 promoter and increases ABCA1 expression in macrophages, promoting cholesterol efflux. miR-140-5p downregulates RFX7, and PCA3 lncRNA sponges miR-140-5p to upregulate RFX7 and thereby ABCA1.","method":"Chromatin immunoprecipitation assay (RFX7 binding to ABCA1 promoter), dual-luciferase reporter assay, Western blot, qPCR","journal":"Biochimica et biophysica acta. Molecular and cell biology of lipids","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP assay directly shows RFX7 binding to ABCA1 promoter, supported by reporter assay; single lab","pmids":["33578049"],"is_preprint":false},{"year":2024,"finding":"In pig granulosa cells, RFX7 is transcriptionally activated by p53 and acts as a transcriptional activator of the lncRNA NORSF by binding its promoter. A G-A variant at -478 nt of the NORSF promoter reduces RFX7 binding activity, decreasing NORSF transcription and weakening inhibition of CYP19A1, thereby affecting estradiol synthesis via the p53/RFX7/NORSF/CYP19A1 pathway.","method":"Promoter-luciferase assay, chromatin immunoprecipitation, site-directed mutagenesis of RFX7 binding site, gene expression analysis","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — ChIP and luciferase assay support direct binding, but study is in porcine cells and single lab","pmids":["39155648"],"is_preprint":false}],"current_model":"RFX7 is a transcription factor that binds X-box DNA motifs (directly and in complex with ANKRA2, RFXAP, RFXANK) to activate tumor suppressor genes (PDCD4, PIK3IP1, MXD4, PNRC1, DDIT4, ABCA1, SOCS3) downstream of p53 and cellular stress signals; it restricts mTORC1/AKT activity and cell metabolism, is required for NK cell homeostasis and ciliogenesis, is structurally recognized by ANKRA2 and RFXANK via its PXLPXL motif, is post-translationally regulated by DYRK1B-mediated phosphorylation (negative feedback) and by HCMV pUL97 kinase (positive phosphorylation), and its epigenetic silencing in cancer de-represses PI3K/AKT signaling and promotes immunosuppression."},"narrative":{"mechanistic_narrative":"RFX7 is an X-box-binding transcription factor that operates as a downstream effector of p53 to enforce a tumor-suppressive transcriptional program controlling cell metabolism, growth, and immune function [PMID:34907345, PMID:34197623]. Activated by p53 and cellular stress, RFX7 directly binds the promoters of established tumor suppressors including PDCD4, PIK3IP1, MXD4, and PNRC1, and sensitizes cells to apoptosis [PMID:34197623, PMID:36864036]. A central output of this program is restraint of growth signaling: RFX7 is required for p53-mediated induction of DDIT4 to inhibit mTORC1 and mTORC2-dependent AKT activation [PMID:34907345], and it activates PIK3IP1 to suppress PI3K/AKT signaling, a circuit silenced by RFX7 promoter hypermethylation in glioblastoma where its loss drives metabolic reprogramming and immunosuppression [PMID:42206447]. Consistent with its role upstream of mTOR, RFX7 is required in vivo for NK cell homeostasis, with its loss producing enlarged, hyperproliferative, hypermetabolic NK cells rescued by reducing mTOR activity [PMID:29967452]. RFX7 acts within a multiprotein DNA-binding complex: mass spectrometry at target promoters identified RFX5, RFXAP, RFXANK, and ANKRA2 as co-binding partners, with ANKRA2—itself a p53 target—serving as a critical cofactor for tumor suppressor gene regulation while RFXANK governs a largely distinct gene set [PMID:39181888]. Both ANKRA2 and RFXANK ankyrin domains recognize RFX7 through its PXLPXL motif via hydrophobic contacts [PMID:31864703]. RFX7 activity is tuned by phosphorylation, being inhibited through a DYRK1B-mediated negative feedback loop [PMID:41888523] and stimulated by the HCMV kinase pUL97 to drive SOCS3 expression during infection [PMID:36753521]. Beyond this core axis, RFX7 also regulates ciliogenesis via RFX4 [PMID:24530844] and contributes to lipid and steroidogenic transcription [PMID:33578049, PMID:39155648].","teleology":[{"year":2014,"claim":"Established the first developmental loss-of-function role for RFX7, placing it atop a transcriptional cascade controlling cilia formation.","evidence":"Morpholino knockdown in Xenopus with Foxj1 epistasis and expression analysis","pmids":["24530844"],"confidence":"Medium","gaps":["Mechanism of RFX4 regulation by RFX7 not resolved at the DNA-binding level","Conservation of the ciliogenesis role in mammals untested","No biochemical demonstration of direct promoter occupancy"]},{"year":2018,"claim":"Defined RFX7 as a physiological regulator of immune cell metabolism by genetically placing it upstream of mTOR in NK cell homeostasis.","evidence":"Rfx7 knockout mouse with in vivo NK assays and genetic epistasis to mTOR reduction","pmids":["29967452"],"confidence":"High","gaps":["Direct transcriptional targets linking RFX7 to mTOR not identified in this study","IL-15/JAK rescue mechanism not connected to specific RFX7 target genes","Whether the metabolic role generalizes beyond NK cells unaddressed"]},{"year":2021,"claim":"Mapped the RFX7 cistrome and showed it directly activates multiple tumor suppressors downstream of p53 and stress, defining its core gene-regulatory identity.","evidence":"ChIP-seq plus transcriptome in three cell systems with apoptosis viability readout","pmids":["34197623"],"confidence":"High","gaps":["Cofactor requirements for target selection not yet defined","Signal that converts p53 activation into RFX7 activation unknown"]},{"year":2021,"claim":"Connected RFX7's tumor-suppressive transcription to metabolic control by establishing the p53-RFX7-DDIT4 axis that restrains mTORC1 and AKT.","evidence":"RFX7/DDIT4 loss-of-function, mTOR activity assays under physiological media, genetic epistasis","pmids":["34907345"],"confidence":"High","gaps":["How basal p53/RFX7 activity is maintained under unstressed conditions unclear","Whether DDIT4 is the sole metabolic effector of RFX7 not established"]},{"year":2021,"claim":"Extended the RFX7 regulon to lipid metabolism, showing direct activation of ABCA1 and an upstream lncRNA/miRNA regulatory layer.","evidence":"ChIP and dual-luciferase reporter assays in macrophages with miR-140-5p/PCA3 perturbation","pmids":["33578049"],"confidence":"Medium","gaps":["Single-lab finding without cistrome-wide validation","Relationship to the p53-driven program not examined"]},{"year":2019,"claim":"Provided the structural basis for RFX7 cofactor recognition, defining the PXLPXL motif as the docking site for ANKRA2 and RFXANK ankyrin domains.","evidence":"Two X-ray crystal structures of RFX7 fragment bound to ANKRA2 and RFXANK ankyrin domains","pmids":["31864703"],"confidence":"High","gaps":["Functional consequence of differential affinity not tested in cells in this study","Full-length complex architecture on DNA not resolved"]},{"year":2023,"claim":"Integrated multi-omics in RFX7 knockout cells to confirm RFX7 as the mechanistic link enabling p53-responsive activation and to broaden its target set.","evidence":"CRISPR knockout with transcriptomics, ChIP-seq, and proteomics integration","pmids":["36864036"],"confidence":"High","gaps":["Functional validation of novel neurological-process targets pending","Direct vs indirect targets not fully partitioned"]},{"year":2023,"claim":"Revealed RFX7 as a host substrate hijacked during HCMV infection, with viral kinase pUL97 phosphorylating it to drive SOCS3 expression.","evidence":"Proteomic interaction mapping, RFX7/pUL97 depletion, promoter-luciferase, phosphorylation analysis in NPCs","pmids":["36753521"],"confidence":"Medium","gaps":["Specific RFX7 residues phosphorylated by pUL97 not mapped","Whether phosphorylation alters DNA binding or cofactor assembly unknown","Single-lab study"]},{"year":2024,"claim":"Resolved the functional composition of the RFX7 DNA-binding complex and identified ANKRA2 as a p53-target cofactor distinct in function from RFXANK.","evidence":"Reporter assay, co-DNA-binding mass spectrometry at PDCD4 promoter, transcriptome in two systems with siRNA","pmids":["39181888"],"confidence":"High","gaps":["Stoichiometry and assembly order of the RFX5/RFXAP/RFXANK/ANKRA2 complex unresolved","Determinants directing ANKRA2- vs RFXANK-dependent target choice not defined"]},{"year":2024,"claim":"Demonstrated a conserved p53/RFX7-driven steroidogenic regulatory pathway and a functional promoter variant affecting RFX7 binding.","evidence":"Promoter-luciferase, ChIP, site-directed mutagenesis in porcine granulosa cells","pmids":["39155648"],"confidence":"Medium","gaps":["Demonstrated only in porcine cells","Human relevance of the NORSF/CYP19A1 axis untested"]},{"year":2026,"claim":"Defined post-translational down-tuning of RFX7 via a DYRK1B-mediated negative feedback loop closing the p53-RFX7 circuit.","evidence":"Co-IP, kinase-dead mutant, DYRK1 inhibitor rescue, gene expression in multiple cancer lines","pmids":["41888523"],"confidence":"Medium","gaps":["RFX7 phosphosites targeted by DYRK1B not mapped","Mechanism by which phosphorylation suppresses RFX7 activity unknown","Single-lab study"]},{"year":2026,"claim":"Linked RFX7 epigenetic silencing to cancer metabolic-immune reprogramming through the RFX7-PIK3IP1-PI3K/AKT axis in glioblastoma.","evidence":"ChIP-seq, transcriptomics, metabolic analysis, gene perturbation and methylation analysis","pmids":["42206447"],"confidence":"Medium","gaps":["Causal contribution of RFX7 methylation in patient outcomes not established","Generalizability beyond glioblastoma untested","Single study"]},{"year":null,"claim":"How upstream signals and phosphorylation events are integrated to set RFX7 activity, and how the multiprotein complex selects among its diverse target programs, remain open.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No mapped phosphosite-to-activity relationships for DYRK1B or pUL97","Rules governing ANKRA2- vs RFXANK-dependent target selection undefined","Mechanism converting p53 activation into RFX7 transcriptional activity unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[3,7,10,11]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[2,3,7]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[3,7]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[3,7]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,9]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,9]}],"complexes":["RFX7-ANKRA2-RFX5-RFXAP-RFXANK DNA-binding complex"],"partners":["ANKRA2","RFXANK","RFX5","RFXAP","DYRK1B","P53","DDIT4","PIK3IP1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q2KHR2","full_name":"DNA-binding protein RFX7","aliases":["Regulatory factor X 7","Regulatory factor X domain-containing protein 2"],"length_aa":1460,"mass_kda":157.4,"function":"Transcription factor (PubMed:29967452). Acts as a transcriptional activator by binding to promoter regions of target genes, such as PDCD4, PIK3IP1, MXD4, PNRC1, and RFX5 (PubMed:29967452, PubMed:34197623). Plays a role in natural killer (NK) cell maintenance and immunity (PubMed:29967452). May play a role in the process of ciliogenesis in the neural tube and neural tube closure (By similarity)","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q2KHR2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/RFX7","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":77,"dependency_fraction":0.03896103896103896},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/RFX7","total_profiled":1310},"omim":[{"mim_id":"620330","title":"INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 71, WITH BEHAVIORAL ABNORMALITIES; MRD71","url":"https://www.omim.org/entry/620330"},{"mim_id":"612660","title":"REGULATORY FACTOR X, 7; RFX7","url":"https://www.omim.org/entry/612660"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Nuclear membrane","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/RFX7"},"hgnc":{"alias_symbol":["FLJ12994"],"prev_symbol":["RFXDC2"]},"alphafold":{"accession":"Q2KHR2","domains":[{"cath_id":"1.10.10.10","chopping":"2-88","consensus_level":"medium","plddt":92.093,"start":2,"end":88},{"cath_id":"-","chopping":"119-169","consensus_level":"medium","plddt":91.3825,"start":119,"end":169}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q2KHR2","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q2KHR2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q2KHR2-F1-predicted_aligned_error_v6.png","plddt_mean":43.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RFX7","jax_strain_url":"https://www.jax.org/strain/search?query=RFX7"},"sequence":{"accession":"Q2KHR2","fasta_url":"https://rest.uniprot.org/uniprotkb/Q2KHR2.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q2KHR2/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q2KHR2"}},"corpus_meta":[{"pmid":"29967452","id":"PMC_29967452","title":"The transcription factor Rfx7 limits metabolism of NK cells and promotes their maintenance and immunity.","date":"2018","source":"Nature immunology","url":"https://pubmed.ncbi.nlm.nih.gov/29967452","citation_count":44,"is_preprint":false},{"pmid":"24530844","id":"PMC_24530844","title":"RFX7 is required for the formation of cilia in the neural tube.","date":"2014","source":"Mechanisms of development","url":"https://pubmed.ncbi.nlm.nih.gov/24530844","citation_count":39,"is_preprint":false},{"pmid":"34907345","id":"PMC_34907345","title":"p53-mediated AKT and mTOR inhibition requires RFX7 and DDIT4 and depends on nutrient abundance.","date":"2021","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/34907345","citation_count":30,"is_preprint":false},{"pmid":"34197623","id":"PMC_34197623","title":"Transcription factor RFX7 governs a tumor suppressor network in response to p53 and stress.","date":"2021","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/34197623","citation_count":28,"is_preprint":false},{"pmid":"33578049","id":"PMC_33578049","title":"Long non-coding RNA PCA3 inhibits lipid accumulation and atherosclerosis through the miR-140-5p/RFX7/ABCA1 axis.","date":"2021","source":"Biochimica et biophysica acta. Molecular and cell biology of lipids","url":"https://pubmed.ncbi.nlm.nih.gov/33578049","citation_count":24,"is_preprint":false},{"pmid":"36864036","id":"PMC_36864036","title":"Multi-omics analysis identifies RFX7 targets involved in tumor suppression and neuronal processes.","date":"2023","source":"Cell death discovery","url":"https://pubmed.ncbi.nlm.nih.gov/36864036","citation_count":9,"is_preprint":false},{"pmid":"35831154","id":"PMC_35831154","title":"Hsa_circ_0030042 Ameliorates Oxidized Low-Density Lipoprotein-Induced Endothelial Cell Injury via the MiR-616-3p/RFX7 Axis.","date":"2022","source":"International heart journal","url":"https://pubmed.ncbi.nlm.nih.gov/35831154","citation_count":8,"is_preprint":false},{"pmid":"36753521","id":"PMC_36753521","title":"Human cytomegalovirus pUL97 upregulates SOCS3 expression via transcription factor RFX7 in neural progenitor cells.","date":"2023","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/36753521","citation_count":7,"is_preprint":false},{"pmid":"39181888","id":"PMC_39181888","title":"p53 target ANKRA2 cooperates with RFX7 to regulate tumor suppressor genes.","date":"2024","source":"Cell death discovery","url":"https://pubmed.ncbi.nlm.nih.gov/39181888","citation_count":7,"is_preprint":false},{"pmid":"36334883","id":"PMC_36334883","title":"Phenotype expansion and neurological manifestations of neurobehavioural disease caused by a variant in RFX7.","date":"2022","source":"European journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/36334883","citation_count":6,"is_preprint":false},{"pmid":"31864703","id":"PMC_31864703","title":"Structural basis for the recognition of RFX7 by ANKRA2 and RFXANK.","date":"2019","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/31864703","citation_count":5,"is_preprint":false},{"pmid":"39155648","id":"PMC_39155648","title":"A variant in long noncoding RNA NORSF affects granulosa cells response to transcription factor RFX7.","date":"2024","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/39155648","citation_count":1,"is_preprint":false},{"pmid":"39007708","id":"PMC_39007708","title":"Expanding the clinical phenotype and variant spectrum associated with RFX7.","date":"2024","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/39007708","citation_count":0,"is_preprint":false},{"pmid":"41888523","id":"PMC_41888523","title":"The protein kinase DYRK1B is a p53 target gene and functions as a negative feedback regulator of the transcription factor RFX7.","date":"2026","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/41888523","citation_count":0,"is_preprint":false},{"pmid":"42206447","id":"PMC_42206447","title":"Epigenetic Silencing of RFX7 Defines a Transcriptional Axis Linking Lactate Metabolism to Immune Checkpoint Therapy in Glioblastoma.","date":"2026","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/42206447","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.10.03.680219","title":"Pan-cancer analysis of patient-specific gene regulatory landscapes identifies recurrent PD-1 pathway dysregulation linked to outcome","date":"2025-10-06","source":"bioRxiv","url":"https://doi.org/10.1101/2025.10.03.680219","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.09.24.614849","title":"Rfx3 controls outer hair cell differentiation, maintenance, and hair bundle formation by regulating the expression of  <i>Insm1, Ikzf2</i>  , and  <i>Triobp</i>  genes","date":"2024-09-26","source":"bioRxiv","url":"https://doi.org/10.1101/2024.09.24.614849","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":9681,"output_tokens":3342,"usd":0.039586,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10745,"output_tokens":3971,"usd":0.0765,"stage2_stop_reason":"end_turn"},"total_usd":0.116086,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2018,\n      \"finding\": \"Rfx7 deletion in mice leads to decreased NK cell maintenance and immunity in vivo; Rfx7-/- NK cells show increased size, granularity, proliferation, and energetic state, and genetic reduction of mTOR activity mitigated those defects, placing Rfx7 upstream of mTOR in a metabolic regulatory pathway. IL-15 rescue of Rfx7-deficient NK cells occurs through the JAK pathway.\",\n      \"method\": \"Genetic knockout mouse model, genomic/transcriptomic approaches, epistasis with mTOR reduction, in vivo NK cell assays\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic KO with defined cellular and metabolic phenotype, genetic epistasis with mTOR, replicated across multiple assays in one rigorous study\",\n      \"pmids\": [\"29967452\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"RFX7 in Xenopus laevis is required for ciliogenesis in the neural tube; knockdown of RFX7 causes defects in cilia formation and neural tube closure. RFX7 controls cilia formation by regulating expression of RFX4 (a known ciliogenesis regulator). Foxj1 (master regulator of motile cilia) suppresses RFX4 but not RFX7, placing RFX7 upstream of RFX4 in a ciliogenesis cascade.\",\n      \"method\": \"Morpholino knockdown in Xenopus, epistasis with Foxj1 overexpression, gene expression analysis\",\n      \"journal\": \"Mechanisms of development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined phenotype and genetic epistasis in Xenopus ortholog, single lab\",\n      \"pmids\": [\"24530844\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"p53 activates DDIT4 indirectly through RFX7; RFX7 is required for p53-mediated inhibition of mTORC1, and DDIT4 (downstream of RFX7) is required for p53-mediated inhibition of mTORC2-dependent AKT activation. Under physiological nutrient conditions, basal p53 and RFX7 activity critically restrict mTORC1 activity, establishing a p53-RFX7-DDIT4 axis in metabolic control.\",\n      \"method\": \"Loss-of-function (RFX7 and DDIT4 knockdown/knockout), mTOR activity assays, physiological cell culture media, genetic epistasis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean loss-of-function with defined molecular phenotype (mTORC1/2, AKT), multiple cell systems, epistasis established within a single rigorous study\",\n      \"pmids\": [\"34907345\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"RFX7 directly binds DNA and controls the transcription of multiple established tumor suppressors including PDCD4, PIK3IP1, MXD4, and PNRC1 across cell types. RFX7 is activated downstream of p53 and stress signals and sensitizes cells to Doxorubicin by promoting apoptosis.\",\n      \"method\": \"ChIP-seq (cistrome mapping), transcriptome analysis in three cell systems, integration of DNA binding landscape with regulated transcriptome, cell viability assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP-seq cistrome plus transcriptome in three independent cell systems with functional apoptosis readout; multiple orthogonal methods\",\n      \"pmids\": [\"34197623\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Multi-omics integration (transcriptome, cistrome, proteome) in RFX7 knockout cells identifies novel RFX7 target genes linked to tumor suppression and neurological processes, and confirms RFX7 as a mechanistic link enabling p53-responsive activation of these genes.\",\n      \"method\": \"CRISPR knockout, transcriptomics, ChIP-seq, proteomics (multi-omics integration)\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO with multiple orthogonal omics methods in single lab, directly extends prior findings\",\n      \"pmids\": [\"36864036\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"During HCMV infection, the viral kinase pUL97 upregulates SOCS3 expression in neural progenitor cells (NPCs) via the transcription factor RFX7. Proteomic analysis identified RFX7 as a pUL97-interacting host protein. pUL97 increases RFX7 phosphorylation, and both pUL97 kinase activity and RFX7 are required for SOCS3 upregulation, as shown by depletion of either pUL97 or RFX7 preventing HCMV-induced SOCS3 upregulation.\",\n      \"method\": \"Proteomics (pUL97-interacting proteins), promoter-luciferase assay, RFX7 depletion, phosphorylation analysis, viral protein screening\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proteomics identification of interaction, functional validation by depletion and luciferase assay, phosphorylation evidence; single lab\",\n      \"pmids\": [\"36753521\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Crystal structures of a RFX7 fragment bound to the ANKRA2 ankyrin domain and to the RFXANK ankyrin domain reveal that both ANKRA2 and RFXANK recognize the PXLPXL motif of RFX7 and its flanking sequences via extensive hydrophobic interactions. Structural comparison explains the different RFX7 binding affinities of ANKRA2 and RFXANK.\",\n      \"method\": \"X-ray crystallography (two structures), structural analysis\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structures with defined binding interface and mechanistic explanation of differential affinity; single lab but structural evidence is direct\",\n      \"pmids\": [\"31864703\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"RFX7 regulates PDCD4 through direct interaction with its X-box promoter motif (reporter gene assay). Mass spectrometry identified RFX5, RFXAP, RFXANK, and ANKRA2 as proteins that bind to DNA together with RFX7 at the PDCD4 promoter. ANKRA2 is a bona fide direct p53 target gene and functions as a critical cofactor of RFX7 for tumor suppressor gene regulation, while RFXANK regulates a largely distinct gene set.\",\n      \"method\": \"Reporter gene assay, mass spectrometry (co-DNA-binding proteomics), transcriptome analysis in two cell systems, siRNA knockdown\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct DNA binding assay, MS-based complex identification, transcriptome in two systems, multiple orthogonal methods; single lab\",\n      \"pmids\": [\"39181888\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"DYRK1B expression is induced by p53 via RFX7 in response to cytostatic drugs. DYRK1B physically interacts with RFX7 and counteracts RFX7 activation by p53, establishing a negative feedback loop. The inhibitory effect of DYRK1B on RFX7-dependent gene expression requires DYRK1B catalytic activity and can be blocked by DYRK1 inhibitors.\",\n      \"method\": \"Co-immunoprecipitation (physical interaction), pharmacological inhibition, catalytic-dead mutant analysis, gene expression assays in multiple cancer cell lines\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal physical interaction, kinase-dead mutant, pharmacological validation; single lab with multiple cell lines\",\n      \"pmids\": [\"41888523\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"In glioblastoma, RFX7 promoter hypermethylation reduces RFX7 expression. Restoration of RFX7 enhances PIK3IP1 expression, suppresses PI3K/AKT activation, and inhibits malignant progression. Loss of PIK3IP1 increases lactate production and histone H4K12 lactylation, upregulates PD-L1 and CSF1, and enhances tumor immunosuppressive features, defining an RFX7-PIK3IP1-PI3K/AKT axis linking metabolic and immune regulation.\",\n      \"method\": \"ChIP-seq, transcriptomic profiling, metabolic analysis, gene perturbation experiments (KO/overexpression), epigenetic (methylation) analysis\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gene perturbation with defined molecular phenotype and multiple orthogonal methods; single lab, single study\",\n      \"pmids\": [\"42206447\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"RFX7 binds to the ABCA1 promoter and increases ABCA1 expression in macrophages, promoting cholesterol efflux. miR-140-5p downregulates RFX7, and PCA3 lncRNA sponges miR-140-5p to upregulate RFX7 and thereby ABCA1.\",\n      \"method\": \"Chromatin immunoprecipitation assay (RFX7 binding to ABCA1 promoter), dual-luciferase reporter assay, Western blot, qPCR\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular and cell biology of lipids\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP assay directly shows RFX7 binding to ABCA1 promoter, supported by reporter assay; single lab\",\n      \"pmids\": [\"33578049\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In pig granulosa cells, RFX7 is transcriptionally activated by p53 and acts as a transcriptional activator of the lncRNA NORSF by binding its promoter. A G-A variant at -478 nt of the NORSF promoter reduces RFX7 binding activity, decreasing NORSF transcription and weakening inhibition of CYP19A1, thereby affecting estradiol synthesis via the p53/RFX7/NORSF/CYP19A1 pathway.\",\n      \"method\": \"Promoter-luciferase assay, chromatin immunoprecipitation, site-directed mutagenesis of RFX7 binding site, gene expression analysis\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — ChIP and luciferase assay support direct binding, but study is in porcine cells and single lab\",\n      \"pmids\": [\"39155648\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RFX7 is a transcription factor that binds X-box DNA motifs (directly and in complex with ANKRA2, RFXAP, RFXANK) to activate tumor suppressor genes (PDCD4, PIK3IP1, MXD4, PNRC1, DDIT4, ABCA1, SOCS3) downstream of p53 and cellular stress signals; it restricts mTORC1/AKT activity and cell metabolism, is required for NK cell homeostasis and ciliogenesis, is structurally recognized by ANKRA2 and RFXANK via its PXLPXL motif, is post-translationally regulated by DYRK1B-mediated phosphorylation (negative feedback) and by HCMV pUL97 kinase (positive phosphorylation), and its epigenetic silencing in cancer de-represses PI3K/AKT signaling and promotes immunosuppression.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"RFX7 is an X-box-binding transcription factor that operates as a downstream effector of p53 to enforce a tumor-suppressive transcriptional program controlling cell metabolism, growth, and immune function [#2, #3]. Activated by p53 and cellular stress, RFX7 directly binds the promoters of established tumor suppressors including PDCD4, PIK3IP1, MXD4, and PNRC1, and sensitizes cells to apoptosis [#3, #4]. A central output of this program is restraint of growth signaling: RFX7 is required for p53-mediated induction of DDIT4 to inhibit mTORC1 and mTORC2-dependent AKT activation [#2], and it activates PIK3IP1 to suppress PI3K/AKT signaling, a circuit silenced by RFX7 promoter hypermethylation in glioblastoma where its loss drives metabolic reprogramming and immunosuppression [#9]. Consistent with its role upstream of mTOR, RFX7 is required in vivo for NK cell homeostasis, with its loss producing enlarged, hyperproliferative, hypermetabolic NK cells rescued by reducing mTOR activity [#0]. RFX7 acts within a multiprotein DNA-binding complex: mass spectrometry at target promoters identified RFX5, RFXAP, RFXANK, and ANKRA2 as co-binding partners, with ANKRA2—itself a p53 target—serving as a critical cofactor for tumor suppressor gene regulation while RFXANK governs a largely distinct gene set [#7]. Both ANKRA2 and RFXANK ankyrin domains recognize RFX7 through its PXLPXL motif via hydrophobic contacts [#6]. RFX7 activity is tuned by phosphorylation, being inhibited through a DYRK1B-mediated negative feedback loop [#8] and stimulated by the HCMV kinase pUL97 to drive SOCS3 expression during infection [#5]. Beyond this core axis, RFX7 also regulates ciliogenesis via RFX4 [#1] and contributes to lipid and steroidogenic transcription [#10, #11].\",\n  \"teleology\": [\n    {\n      \"year\": 2014,\n      \"claim\": \"Established the first developmental loss-of-function role for RFX7, placing it atop a transcriptional cascade controlling cilia formation.\",\n      \"evidence\": \"Morpholino knockdown in Xenopus with Foxj1 epistasis and expression analysis\",\n      \"pmids\": [\"24530844\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of RFX4 regulation by RFX7 not resolved at the DNA-binding level\", \"Conservation of the ciliogenesis role in mammals untested\", \"No biochemical demonstration of direct promoter occupancy\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined RFX7 as a physiological regulator of immune cell metabolism by genetically placing it upstream of mTOR in NK cell homeostasis.\",\n      \"evidence\": \"Rfx7 knockout mouse with in vivo NK assays and genetic epistasis to mTOR reduction\",\n      \"pmids\": [\"29967452\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct transcriptional targets linking RFX7 to mTOR not identified in this study\", \"IL-15/JAK rescue mechanism not connected to specific RFX7 target genes\", \"Whether the metabolic role generalizes beyond NK cells unaddressed\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Mapped the RFX7 cistrome and showed it directly activates multiple tumor suppressors downstream of p53 and stress, defining its core gene-regulatory identity.\",\n      \"evidence\": \"ChIP-seq plus transcriptome in three cell systems with apoptosis viability readout\",\n      \"pmids\": [\"34197623\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cofactor requirements for target selection not yet defined\", \"Signal that converts p53 activation into RFX7 activation unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Connected RFX7's tumor-suppressive transcription to metabolic control by establishing the p53-RFX7-DDIT4 axis that restrains mTORC1 and AKT.\",\n      \"evidence\": \"RFX7/DDIT4 loss-of-function, mTOR activity assays under physiological media, genetic epistasis\",\n      \"pmids\": [\"34907345\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How basal p53/RFX7 activity is maintained under unstressed conditions unclear\", \"Whether DDIT4 is the sole metabolic effector of RFX7 not established\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Extended the RFX7 regulon to lipid metabolism, showing direct activation of ABCA1 and an upstream lncRNA/miRNA regulatory layer.\",\n      \"evidence\": \"ChIP and dual-luciferase reporter assays in macrophages with miR-140-5p/PCA3 perturbation\",\n      \"pmids\": [\"33578049\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab finding without cistrome-wide validation\", \"Relationship to the p53-driven program not examined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Provided the structural basis for RFX7 cofactor recognition, defining the PXLPXL motif as the docking site for ANKRA2 and RFXANK ankyrin domains.\",\n      \"evidence\": \"Two X-ray crystal structures of RFX7 fragment bound to ANKRA2 and RFXANK ankyrin domains\",\n      \"pmids\": [\"31864703\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of differential affinity not tested in cells in this study\", \"Full-length complex architecture on DNA not resolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Integrated multi-omics in RFX7 knockout cells to confirm RFX7 as the mechanistic link enabling p53-responsive activation and to broaden its target set.\",\n      \"evidence\": \"CRISPR knockout with transcriptomics, ChIP-seq, and proteomics integration\",\n      \"pmids\": [\"36864036\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional validation of novel neurological-process targets pending\", \"Direct vs indirect targets not fully partitioned\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Revealed RFX7 as a host substrate hijacked during HCMV infection, with viral kinase pUL97 phosphorylating it to drive SOCS3 expression.\",\n      \"evidence\": \"Proteomic interaction mapping, RFX7/pUL97 depletion, promoter-luciferase, phosphorylation analysis in NPCs\",\n      \"pmids\": [\"36753521\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific RFX7 residues phosphorylated by pUL97 not mapped\", \"Whether phosphorylation alters DNA binding or cofactor assembly unknown\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Resolved the functional composition of the RFX7 DNA-binding complex and identified ANKRA2 as a p53-target cofactor distinct in function from RFXANK.\",\n      \"evidence\": \"Reporter assay, co-DNA-binding mass spectrometry at PDCD4 promoter, transcriptome in two systems with siRNA\",\n      \"pmids\": [\"39181888\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and assembly order of the RFX5/RFXAP/RFXANK/ANKRA2 complex unresolved\", \"Determinants directing ANKRA2- vs RFXANK-dependent target choice not defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrated a conserved p53/RFX7-driven steroidogenic regulatory pathway and a functional promoter variant affecting RFX7 binding.\",\n      \"evidence\": \"Promoter-luciferase, ChIP, site-directed mutagenesis in porcine granulosa cells\",\n      \"pmids\": [\"39155648\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Demonstrated only in porcine cells\", \"Human relevance of the NORSF/CYP19A1 axis untested\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Defined post-translational down-tuning of RFX7 via a DYRK1B-mediated negative feedback loop closing the p53-RFX7 circuit.\",\n      \"evidence\": \"Co-IP, kinase-dead mutant, DYRK1 inhibitor rescue, gene expression in multiple cancer lines\",\n      \"pmids\": [\"41888523\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"RFX7 phosphosites targeted by DYRK1B not mapped\", \"Mechanism by which phosphorylation suppresses RFX7 activity unknown\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Linked RFX7 epigenetic silencing to cancer metabolic-immune reprogramming through the RFX7-PIK3IP1-PI3K/AKT axis in glioblastoma.\",\n      \"evidence\": \"ChIP-seq, transcriptomics, metabolic analysis, gene perturbation and methylation analysis\",\n      \"pmids\": [\"42206447\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal contribution of RFX7 methylation in patient outcomes not established\", \"Generalizability beyond glioblastoma untested\", \"Single study\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How upstream signals and phosphorylation events are integrated to set RFX7 activity, and how the multiprotein complex selects among its diverse target programs, remain open.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No mapped phosphosite-to-activity relationships for DYRK1B or pUL97\", \"Rules governing ANKRA2- vs RFXANK-dependent target selection undefined\", \"Mechanism converting p53 activation into RFX7 transcriptional activity unresolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [3, 7, 10, 11]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [2, 3, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [3, 7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [3, 7]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 9]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 9]}\n    ],\n    \"complexes\": [\"RFX7-ANKRA2-RFX5-RFXAP-RFXANK DNA-binding complex\"],\n    \"partners\": [\"ANKRA2\", \"RFXANK\", \"RFX5\", \"RFXAP\", \"DYRK1B\", \"p53\", \"DDIT4\", \"PIK3IP1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}