{"gene":"ATF7","run_date":"2026-06-09T22:02:44","timeline":{"discoveries":[{"year":1994,"finding":"ATF7 (ATFa) proteins heterodimerize with c-Jun, Jun-B, and Jun-D (but not effectively with c-Fos for DNA binding), and ATFa/c-Jun heterodimers bind ATF, CRE, and AP1 sites; coexpression of c-Jun stimulates ATFa-dependent reporter activity. A C-terminal element negatively interferes with ATFa intrinsic activation. These interactions were confirmed by reciprocal co-immunoprecipitation and EMSA with in vitro synthesized proteins, and ATFa/c-Jun complexes were detected in HeLa cell extracts.","method":"Reciprocal co-immunoprecipitation, EMSA (electrophoretic band-shift assay), in vitro transcription/translation, transient transfection reporter assays","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP plus EMSA plus in vivo cell extracts, replicated in subsequent studies","pmids":["8290251"],"is_preprint":false},{"year":1994,"finding":"ATF-a0, a splice variant of ATF7 (ATFa) lacking the P/S/T-rich transactivation domain, has no transactivating function on the E-selectin NF-ELAM1/deltaA element and acts as a dominant inhibitor when heterodimerized with full-length ATFa, completely blocking its transactivating activity. Both ATFa forms bind the p50 subunit of NF-κB as shown by affinity chromatography.","method":"Transient transfection reporter assays, RT-PCR, Northern blot, affinity chromatography","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional reporter assays plus affinity chromatography for NF-κB p50 binding, single lab","pmids":["8288576"],"is_preprint":false},{"year":1995,"finding":"ATFa interacts with c-Jun and c-Fos in vivo; complexes containing ATFa and either c-Jun or c-Fos were specifically retained on glutathione-agarose beads from crude extracts of transfected cells expressing GST-ATFa fusions. The leucine zipper domain of ATFa is essential for this interaction.","method":"GST pulldown from mammalian cell extracts, immunoblot, domain deletion analysis","journal":"BioTechniques","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — GST pulldown from mammalian cells with domain mapping, single lab with multiple orthogonal confirmations","pmids":["7702840"],"is_preprint":false},{"year":1995,"finding":"The retinoblastoma gene product (pRb) differentially modulates ATFa and ATF2: co-expression of pRb strongly inhibits ATFa transcriptional activity on the TGF-β2 promoter CRE element, while it has additive or greater stimulatory effects with ATF2, revealing a functional distinction between these two related factors.","method":"Transient transfection reporter assays in CHO cells, in vitro DNA binding (CRE element)","journal":"Archives of biochemistry and biophysics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single method (reporter assay), no direct binding confirmed","pmids":["7786026"],"is_preprint":false},{"year":1996,"finding":"ATF7 (ATFa) is associated in vivo with JNK/SAP kinase activity (identified as 54/55 kDa JNK2) as revealed by co-immunoprecipitation from whole cell extracts. Two independent regions mediate kinase binding: the major site is within N-terminal residues 1–82 (containing the metal-chelating element); a weaker site is in the basic region preceding the leucine zipper.","method":"Co-immunoprecipitation from whole cell extracts, in vitro binding assays, in vivo kinase assays, immunological characterization","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus in vitro binding plus domain mapping, single lab with multiple orthogonal methods","pmids":["8649858"],"is_preprint":false},{"year":1996,"finding":"The ATFa gene maps to chromosome 12 (band 12q13); ATFa isoforms are generated by alternative splice donor site usage; ATFa protein accumulates in the nucleus of transfected cells and the nuclear localization signal was mapped to the region adjacent to the leucine zipper domain. A minimal promoter of ~200 bp retains near-full transcriptional activity.","method":"Chromosomal mapping, expression analysis, nuclear localization by transfection/immunofluorescence, DNase I footprinting, Northern blot","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization by transfection/imaging plus chromosomal mapping and domain mapping, single lab","pmids":["8939888"],"is_preprint":false},{"year":1999,"finding":"The N-terminal activation domain of ATF7 (ATFa) requires specific threonine residues (Thr51 and Thr53) in addition to the metal-binding domain for transcriptional activation. Although the N-terminal domain stably binds JNK2, ATFa is not itself a JNK2 substrate in vivo; instead, the N-terminal domain serves as a JNK2-docking site, allowing ATFa-associated partners such as JunD to be phosphorylated by the bound kinase.","method":"Site-directed mutagenesis of Thr51/Thr53, in vivo phosphorylation assays, transient transfection reporter assays, co-immunoprecipitation","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — mutagenesis plus in vivo kinase assays plus reporter assays, single lab with multiple orthogonal methods","pmids":["10376527"],"is_preprint":false},{"year":2000,"finding":"A novel protein mAM (mouse ATFa-associated Modulator, 1306 residues) was identified by yeast two-hybrid screening using the N-terminal half of ATF7 as bait. mAM colocalizes and interacts with ATFa in mammalian cells, contains a bipartite NLS, possesses ATPase activity, and downregulates transcriptional activity in an ATPase-independent manner by interacting with components of the basal transcription machinery (TFIIE, TFIIH, and RNA Pol II itself).","method":"Yeast two-hybrid, co-immunoprecipitation, co-localization, ATPase assay, transient transfection reporter assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid plus co-IP plus co-localization plus functional assays, single lab","pmids":["10777215"],"is_preprint":false},{"year":2001,"finding":"ATF-7 physically interacts with the PRL-1 protein-tyrosine phosphatase; the interaction was initially identified by yeast two-hybrid and confirmed biochemically. The interaction maps to ATF-7's bZIP region and PRL-1's phosphatase domain. PRL-1 is able to dephosphorylate ATF-7 in vitro. ATF-7 homodimers bind CRE elements specifically.","method":"Yeast two-hybrid, co-immunoprecipitation, in vitro dephosphorylation assay, EMSA (CRE binding)","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid plus in vitro biochemical confirmation plus domain mapping, single lab","pmids":["11278933"],"is_preprint":false},{"year":2005,"finding":"ATF7 interacts directly with TAF12 (hsTAF12, a subunit of TFIID), and this interaction potentiates ATF7-induced transcriptional activation. Overexpression of hsTAF12 stimulates ATF7-dependent transcription; ChIP confirms ATF7-TAF12 co-occupancy at an ATF7-responsive promoter in vivo. TAF12-mediated activation is competitively inhibited by TAF4. Both TAF12 isoforms (TAF12-1 and -2) interact with the ATF7 activation region through their histone-fold domain, but only TAF12-1 mediates activation through its N-terminal region.","method":"Co-immunoprecipitation, chromatin immunoprecipitation (ChIP), transient transfection reporter assays, domain deletion analysis","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP plus ChIP at endogenous promoter plus functional reporter assays plus domain mapping in a single study","pmids":["15735663"],"is_preprint":false},{"year":2007,"finding":"ATF7 is sumoylated in vitro (using RanBP2 as E3 SUMO ligase) and in vivo at a consensus IKEE motif within its N-terminal activation domain. Sumoylation delays ATF7 nuclear entry and inhibits its transcriptional activity by (i) impairing its association with TAF12 and (ii) blocking binding to specific sequences within target promoters.","method":"In vitro sumoylation assay, in vivo sumoylation (immunoprecipitation), nuclear localization tracking, co-immunoprecipitation, reporter assays, site-directed mutagenesis","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro reconstitution plus in vivo validation plus multiple orthogonal functional assays (localization, TAF12 interaction, promoter binding) in one study","pmids":["17264123"],"is_preprint":false},{"year":2008,"finding":"p38β2 MAPK phosphorylates ATF7 at Thr51 in a sequential two-step mechanism: an unknown kinase first phosphorylates Thr53, which then permits p38β2 to phosphorylate Thr51. EGF treatment triggers this cascade. Phosphorylation at Thr51/53 and sumoylation of ATF7 are mutually exclusive modifications; phosphorylation increases ATF7 transcriptional activity via enhanced TAF12 association, while excluding sumoylation.","method":"In vitro kinase assays, site-directed mutagenesis (phospho-mimetic/phospho-deficient mutants), co-immunoprecipitation, reporter assays","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro kinase reconstitution plus mutagenesis plus functional assays establishing mutually exclusive PTM mechanism in one study","pmids":["18950637"],"is_preprint":false},{"year":2009,"finding":"ATF7 silences transcription of the serotonin receptor 5B gene (Htr5b) by directly binding its 5'-regulatory region and mediating histone H3-K9 trimethylation via interaction with the ESET histone methyltransferase. Upon social isolation stress, ATF7 is phosphorylated via p38 and released from the Htr5b promoter, upregulating Htr5b. Atf7-deficient mice exhibit abnormal behavior and increased Htr5b mRNA in the dorsal raphe nucleus.","method":"ChIP, co-immunoprecipitation (ATF7-ESET interaction), Atf7 knockout mouse phenotype, quantitative RT-PCR","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP showing direct promoter binding plus co-IP of ATF7-ESET complex plus in vivo KO with specific molecular phenotype, multiple orthogonal methods","pmids":["19893493"],"is_preprint":false},{"year":2010,"finding":"C. elegans ATF-7, an ortholog of mammalian ATF2/ATF7, functions as a repressor of PMK-1 p38 MAPK-regulated innate immunity genes in the basal state and switches to an activator upon direct phosphorylation by PMK-1. Loss-of-function mutations in atf-7 restore basal expression of PMK-1-regulated genes in pmk-1 null mutants (genetic epistasis), but pathogen-induced gene induction by P. aeruginosa PA14 is abrogated in atf-7 loss-of-function animals.","method":"Genetic epistasis (loss-of-function and gain-of-function allele analysis), biochemical characterization of ATF-7/PMK-1 interaction, gene expression analysis","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis plus biochemical interaction plus expression analysis, replicated across multiple alleles in single study","pmids":["20369020"],"is_preprint":false},{"year":2011,"finding":"A cytoplasmic alternatively spliced isoform of ATF7, named ATF7-4, inhibits both ATF7 and ATF2 transcriptional activity by blocking the first phosphorylation event on Thr53/Thr71 residues. ATF7-4 sequesters the Thr53-phosphorylating kinase in the cytoplasm. Upon stimulus-induced phosphorylation, ATF7-4 is poly-ubiquitinated and degraded, releasing the kinase and enabling ATF7/ATF2 activation.","method":"Alternative splicing characterization, co-immunoprecipitation, subcellular fractionation, phosphorylation assays (phospho-specific antibodies), ubiquitination assays, reporter assays","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (Co-IP, fractionation, ubiquitination, reporter) in single lab","pmids":["21858082"],"is_preprint":false},{"year":2013,"finding":"ATF7 physically interacts with TAF12 in osteoclast (OCL) precursors (confirmed by reciprocal co-immunoprecipitation). ATF7 contributes to 1,25-(OH)2D3-induced CYP24A1 (24-hydroxylase) gene expression; knockdown of ATF7 in MVNP-expressing OCL precursors decreases CYP24A1 induction by 1,25-(OH)2D3 and reduces TAF12 binding to the CYP24A1 promoter (by ChIP).","method":"Reciprocal co-immunoprecipitation, chromatin immunoprecipitation (ChIP), siRNA knockdown, reporter/gene expression assays","journal":"Journal of bone and mineral research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP plus ChIP plus functional knockdown, single lab","pmids":["23426901"],"is_preprint":false},{"year":2014,"finding":"Cdk1-cyclin B1 phosphorylates ATF7 at Thr51/Thr53 from early prophase to anaphase during mitosis (in the absence of stress). Knockdown of ATF7 decreases cell proliferation rate and M-phase cell number. Expression of a mitotically non-phosphorylatable ATF7 mutant inhibits G2/M progression despite endogenous ATF7 presence. Mitotic phosphorylation of ATF7 promotes activation of Aurora kinases.","method":"In vitro kinase assay (Cdk1-cyclin B1), phospho-specific antibodies, siRNA knockdown, cell cycle analysis (FACS), phospho-deficient/phospho-mimetic mutant expression","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — in vitro kinase assay plus mutagenesis plus cell cycle phenotype, single lab","pmids":["25545367"],"is_preprint":false},{"year":2015,"finding":"ATF7 mediates innate immunological memory in macrophages by suppressing innate immunity genes through recruitment of the histone H3K9 dimethyltransferase G9a to chromatin. LPS treatment induces p38-mediated phosphorylation of ATF7, causing its release from chromatin and a decrease in repressive H3K9me2 marks; the partially open chromatin structure and increased basal expression of target genes are maintained long-term.","method":"ChIP (ATF7 chromatin binding and H3K9me2 levels), co-immunoprecipitation (ATF7-G9a interaction), ATF7 knockout/knockdown, p38 inhibitor treatment, LPS stimulation experiments","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP plus Co-IP plus genetic KO plus pharmacological inhibition with orthogonal readouts, published in high-impact journal with extensive validation","pmids":["26322480"],"is_preprint":false},{"year":2015,"finding":"ATF7 phosphorylation on residue Thr112 occurs exclusively during mitosis and is CDK1/cyclin B-dependent. ATF7 is excluded from condensed chromatin during mitosis. Thr112 phosphorylation protects ATF7 from proteasomal degradation (demonstrated using a transduced neutralizing intrabody), but does not affect displacement from condensed chromatin. ATF7 silencing by CRISPR/Cas9 decreases cyclin D1 protein levels, suggesting ATF7 re-localizes to chromatin after telophase to drive cyclin D1 expression.","method":"Phospho-specific antibodies, CDK1 inhibitor treatment, transduced neutralizing monoclonal antibody (intrabody), phospho-mimetic/phospho-deficient mutants, CRISPR/Cas9 knockdown, immunofluorescence","journal":"Cell cycle","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — intrabody plus mutagenesis plus CRISPR plus cell biology, multiple orthogonal approaches in single lab","pmids":["26101806"],"is_preprint":false},{"year":2018,"finding":"ATF7 and telomerase are localized on telomeres via interactions with the Ku complex. In response to TNF-α, ATF7 is phosphorylated by p38, leading to the release of ATF7 and telomerase from telomeres and resulting in telomere shortening. ATF7-deficient mice show telomere shortening consistent with this mechanism.","method":"ChIP (ATF7 and telomerase at telomeres), co-immunoprecipitation (ATF7-Ku complex), p38 inhibitor treatment, ATF7 KO mouse model, telomere length measurement","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP demonstrating telomere localization plus Co-IP of Ku complex plus in vivo KO validation plus pharmacological confirmation, multiple orthogonal methods","pmids":["29490055"],"is_preprint":false},{"year":2019,"finding":"TNF-α induces p38-dependent phosphorylation of ATF7 in mouse testicular germ cells, causing release of ATF7 from the TERRA gene promoter in the subtelomeric region, disrupting heterochromatin and inducing TERRA (telomere repeat-containing RNA). This TERRA is transgenerationally transmitted to zygotes via sperm and causes telomere shortening in offspring.","method":"ChIP (ATF7 at TERRA promoter, H3K9me2 levels), p38 inhibitor treatment, ATF7 KO mouse model, TERRA measurement, sperm RNA analysis","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP plus genetic KO plus pharmacological inhibition plus sperm RNA analysis, multiple orthogonal methods in single study","pmids":["30407559"],"is_preprint":false},{"year":2019,"finding":"In C. elegans, PMK-1-ATF-7 signaling regulates a majority of all genes induced by P. aeruginosa infection. ATF-7 occupies regulatory regions of pathogen-induced genes in a PMK-1-dependent manner (ChIP-Seq). A subset of ATF-7-regulated pathogen-induced target genes directly contribute to host defense.","method":"RNA-seq, ChIP-Seq (ATF-7 genome-wide occupancy), functional analysis of target gene knockdowns","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide ChIP-Seq plus RNA-seq plus functional validation of targets, builds on prior genetic epistasis work","pmids":["30789901"],"is_preprint":false},{"year":2019,"finding":"ATF7 is required for adipocyte differentiation; it interacts with histone dimethyltransferase G9a in adipocytes to repress interferon-stimulated genes (which suppress adipogenesis). ATF7 binds transcriptional regulatory regions of the UCP1 gene and silences it by controlling H3K9 dimethylation. Ablation of ATF7 promotes beige fat biogenesis in inguinal white adipose tissue.","method":"ATF7 KO mouse model, ChIP (ATF7 at UCP1 promoter, H3K9me2 levels), co-immunoprecipitation (ATF7-G9a), differentiation assays","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus Co-IP plus KO mouse with specific phenotypic readout, single lab","pmids":["30826729"],"is_preprint":false},{"year":2019,"finding":"ATF7 binds the p16Ink4a gene promoter and recruits H3K9 di- and trimethyltransferases to silence p16Ink4a expression. With age or oxidative stress, p38-mediated phosphorylation of ATF7 increases and ATF7 is released from the promoter, leading to decreased H3K9me2 at the locus and accelerated p16Ink4a accumulation. Atf7-/- mice have shorter lifespans than wild-type mice.","method":"ChIP (ATF7 occupancy and H3K9me2 at p16Ink4a promoter), ATF7 KO mice (lifespan and p16 mRNA quantification), MEF culture with oxidative stress, p38 phosphorylation assays","journal":"Genes to cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus KO mouse with molecular phenotype plus mechanistic phosphorylation data, single lab","pmids":["31294895"],"is_preprint":false},{"year":2020,"finding":"ATF7 binds the promoter regions of ~2,300 genes including cholesterol biosynthesis-related and tRNA genes in testicular germ cells (TGCs). A paternal low-protein diet (LPD) induces ROS, which activates p38 to phosphorylate ATF7 in TGCs; this leads to ATF7 release from chromatin, decreased H3K9me2 on target genes, and increased tRNA fragment expression in spermatozoa. These epigenetic changes are transmitted to offspring and alter liver gene expression and metabolism. Atf7+/- mutation phenocopies paternal LPD effects.","method":"ChIP-seq (ATF7 genome-wide binding in TGCs, H3K9me2 levels), Atf7+/- mouse genetics, dietary intervention (LPD), ROS measurement, spermatozoa small RNA profiling, offspring liver transcriptomics","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide ChIP-Seq plus genetic mouse model plus dietary intervention plus multi-generation analysis, multiple orthogonal methods","pmids":["32197065"],"is_preprint":false},{"year":2020,"finding":"ATF2 and ATF7 are required for intestinal epithelial repair but dispensable for homeostasis. Activating phosphorylation of ATF2 and ATF7 occurs mainly in intestinal crypts. Intestine-specific double-mutant mice show impaired regenerative response to DSS or irradiation, with increased apoptosis, severe ulceration, and failure to regenerate colonic crypts. Organoids from double-mutant epithelium show growth disadvantage and impaired wound healing.","method":"Conditional KO mouse model (Villin-CreERT2), DSS colitis model, irradiation model, organoid culture, phospho-specific antibodies (IHC), scratch assay","journal":"Cellular and molecular gastroenterology and hepatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with multiple injury models plus organoid functional assays, single lab","pmids":["31958521"],"is_preprint":false},{"year":2022,"finding":"ATF7 accumulates in the nucleus of porcine embryos and localizes to pericentromeric heterochromatin after the late 4-cell stage, co-localizing with HP1. ATF7 knockdown reduces blastocyst rate and cell number, and decreases HP1 and H3K9me2 levels. High temperature induces p38 phosphorylation of ATF7, reducing H3K9me2 and HP1 levels; inhibition of p38 activity alleviates these effects.","method":"siRNA knockdown, immunofluorescence (ATF7 localization, HP1, H3K9me2), p38 inhibitor treatment, blastocyst rate and cell count","journal":"Cell proliferation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct imaging of localization plus functional KD plus pharmacological inhibition with specific molecular readouts, single lab","pmids":["36254813"],"is_preprint":false},{"year":2023,"finding":"ATF7 inhibits NF-κB signaling and increases H3K9 dimethylation (H3K9me2) to suppress cellular senescence and SASP secretion. Loss of ATF7 induces cellular senescence while overexpression delays it. In C. elegans, ATF7 overexpression suppresses aging biomarkers and extends lifespan.","method":"ATF7 overexpression and knockdown, H3K9me2 ChIP, NF-κB reporter assays, senescence assays (SA-β-gal, p21 levels), C. elegans lifespan assay","journal":"Aging and disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus functional KO/OE plus reporter assays across two model systems, single lab","pmids":["37163432"],"is_preprint":false},{"year":2023,"finding":"HNEAP (a piRNA) interacts with DNMT1 and reduces m5C methylation of Atf7 mRNA, increasing ATF7 protein levels. Elevated ATF7 then downregulates transcription of Chmp2a (an inhibitor of necroptosis), reducing CHMP2A levels and promoting cardiomyocyte necroptosis. Loss of HNEAP inhibits necroptosis and improves cardiac function in I/R-injured mice.","method":"RNA pulldown (HNEAP-DNMT1 interaction), m5C methylation assay, ATF7 ChIP (binding to Chmp2a promoter), luciferase reporter assay, ATF7 knockdown/overexpression, HNEAP KO mouse model","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP of ATF7 at Chmp2a promoter plus RNA pulldown plus m5C assay plus in vivo KO, single lab with multiple orthogonal methods","pmids":["37870216"],"is_preprint":false},{"year":2024,"finding":"ATF7 forms an AP-1 heterodimer with JDP2 in AML cells; IRF2BP2 is recruited by the ATF7/JDP2 dimer to chromatin and counteracts its gene-activating function on inflammatory pathway genes. Loss of IRF2BP2 leads to overactivation of inflammatory pathways and strongly reduced cell proliferation.","method":"Co-immunoprecipitation (ATF7/JDP2/IRF2BP2 complex), ChIP (IRF2BP2 recruitment by ATF7/JDP2), IRF2BP2 knockdown/KO with transcriptomic and proliferation readouts","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus ChIP plus functional KO with defined phenotype, single lab","pmids":["38801077"],"is_preprint":false},{"year":2025,"finding":"ATF7 directly binds to and transcriptionally activates the PINK1 promoter (a master mitophagy regulator) as demonstrated by ChIP-seq and luciferase reporter assays. Loss of ATF7 or PINK1 in intestinal epithelial cells impairs mitophagy, disrupts mitochondrial membrane potential, increases ROS, and exacerbates DSS-induced colitis in vivo.","method":"ChIP-seq, luciferase reporter assay, IEC-specific ATF7 KO mouse model, mitophagy assays (electron microscopy, mitochondrial membrane potential), DSS colitis model","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq plus luciferase reporter plus IEC-specific KO with functional readouts, single lab","pmids":["40586859"],"is_preprint":false}],"current_model":"ATF7 is a stress-responsive bZIP transcription factor that binds CRE/AP-1 elements as homodimers or heterodimers with Jun/Fos proteins, and functions predominantly as a chromatin-based epigenetic repressor: in its basal (unphosphorylated) state, ATF7 recruits H3K9 dimethyltransferases (G9a, ESET) and trimethyltransferases to silence target genes (including innate immunity genes, Htr5b, UCP1, p16Ink4a, TERRA, PINK1, and Chmp2a) by promoting H3K9me2/me3; upon stress or cytokine stimulation (TNF-α, LPS, social isolation, dietary stress, high temperature), p38 MAPK phosphorylates ATF7 at conserved N-terminal threonine residues (Thr51/Thr53), causing its release from chromatin, reduction of repressive histone marks, and gene derepression—a mechanism that underlies innate immunological memory, stress-induced telomere shortening, intergenerational epigenetic inheritance, cellular senescence, and adipocyte differentiation. ATF7 transcriptional activity is further modulated by: CDK1-mediated phosphorylation at Thr51/Thr53 and Thr112 during mitosis (stabilizing ATF7 and enabling G2/M progression and cyclin D1 expression), SUMO modification (inhibiting nuclear entry and TAF12 association), interaction with TAF12/TFIID (mediating transcriptional activation), association with JNK2 as a docking platform for substrate kinase delivery, dephosphorylation by PRL-1 phosphatase, and dominant inhibition by a cytoplasmic splice isoform (ATF7-4) that sequesters the activating kinase."},"narrative":{"mechanistic_narrative":"ATF7 (ATFa) is a stress-responsive bZIP transcription factor that binds CRE/AP-1 elements as homodimers or as heterodimers with Jun proteins (c-Jun, Jun-B, Jun-D), and operates predominantly as a chromatin-based epigenetic repressor whose activity is gated by stress-activated phosphorylation [PMID:8290251, PMID:26322480]. In its basal unphosphorylated state, ATF7 occupies target promoters and recruits H3K9 methyltransferases — G9a and ESET — to deposit repressive H3K9me2/me3 marks and silence genes including Htr5b, UCP1, p16Ink4a, and subtelomeric TERRA loci [PMID:19893493, PMID:26322480, PMID:30826729, PMID:31294895]. Upon stress or cytokine input (LPS, TNF-α, oxidative or dietary stress, high temperature), p38 MAPK phosphorylates conserved N-terminal threonines (Thr51/Thr53) in a sequential two-step mechanism, releasing ATF7 from chromatin, lowering repressive marks, and derepressing targets — a switch that underlies innate immunological memory in macrophages, stress-induced and intergenerational telomere shortening transmitted through sperm, cellular senescence, and adipocyte differentiation [PMID:18950637, PMID:26322480, PMID:29490055, PMID:30407559, PMID:32197065]. This repressor-to-activator switch is conserved in C. elegans, where the ortholog ATF-7 represses PMK-1 p38 MAPK-regulated innate immunity genes basally and is converted to an activator of pathogen-induced genes upon direct PMK-1 phosphorylation [PMID:20369020, PMID:30789901]. ATF7 activity is further tuned by SUMO modification — which delays nuclear entry and is mutually exclusive with Thr51/53 phosphorylation [PMID:17264123, PMID:18950637] — by interaction with TAF12/TFIID that potentiates activation [PMID:15735663], by CDK1/cyclin-B phosphorylation at Thr51/53 and Thr112 during mitosis that stabilizes ATF7 and supports G2/M progression and cyclin D1 expression [PMID:25545367, PMID:26101806], and by a cytoplasmic splice isoform (ATF7-4) that sequesters the activating kinase [PMID:21858082]. Beyond repression, ATF7 directly activates target promoters such as PINK1 to support mitophagy and intestinal epithelial repair [PMID:31958521, PMID:40586859].","teleology":[{"year":1994,"claim":"Established ATF7 as a bZIP dimerizing factor, defining its DNA-binding partners and a built-in negative regulatory architecture.","evidence":"Reciprocal Co-IP, EMSA and reporter assays showing ATFa/c-Jun heterodimers binding ATF/CRE/AP1 sites; a dominant-inhibitory splice form lacking the transactivation domain blocks full-length ATFa and binds NF-κB p50","pmids":["8290251","8288576"],"confidence":"High","gaps":["Endogenous target genes not yet identified","Functional consequence of NF-κB p50 binding unresolved"]},{"year":1995,"claim":"Mapped the dimerization determinant and distinguished ATF7 functionally from its relative ATF2.","evidence":"GST pulldown with domain deletion localizing the leucine zipper requirement; reporter assays showing pRb differentially inhibits ATFa versus ATF2","pmids":["7702840","7786026"],"confidence":"Medium","gaps":["pRb effect shown only in reporter context with no direct binding","In vivo relevance of pRb modulation unaddressed"]},{"year":1996,"claim":"Defined ATF7's nuclear localization and revealed a stable association with JNK2, framing the N-terminus as a regulatory hub.","evidence":"Chromosomal mapping, nuclear localization by transfection imaging, and Co-IP identifying associated 54/55 kDa JNK2 with domain-mapped binding sites","pmids":["8939888","8649858"],"confidence":"Medium","gaps":["Whether JNK2 binding regulates ATF7 transcription directly unclear","NLS mapping not validated by mutagenesis"]},{"year":1999,"claim":"Showed the N-terminal Thr51/Thr53 region functions as a kinase-docking platform rather than a kinase substrate, identifying the residues central to ATF7 regulation.","evidence":"Site-directed mutagenesis of Thr51/Thr53, in vivo phosphorylation and reporter assays demonstrating JNK2 docking delivers kinase to ATF7 partners such as JunD","pmids":["10376527"],"confidence":"Medium","gaps":["The kinase ultimately phosphorylating Thr51/53 not defined here","Physiological signals engaging docking unknown"]},{"year":2000,"claim":"Identified mAM as an ATF7-associated modulator linking ATF7 to the basal transcription machinery.","evidence":"Yeast two-hybrid, Co-IP, co-localization and ATPase/reporter assays showing mAM downregulates activity via TFIIE/TFIIH/Pol II contacts","pmids":["10777215"],"confidence":"Medium","gaps":["Single lab; mechanism of repression not reconstituted","Endogenous role of mAM-ATF7 axis untested"]},{"year":2001,"claim":"Connected ATF7 to a phosphatase, indicating its activity is reversibly controlled by phosphorylation.","evidence":"Yeast two-hybrid, Co-IP and in vitro dephosphorylation mapping the PRL-1 interaction to the ATF7 bZIP region","pmids":["11278933"],"confidence":"Medium","gaps":["Which ATF7 phospho-sites PRL-1 targets in vivo unknown","Cellular outcome of dephosphorylation not shown"]},{"year":2005,"claim":"Defined TAF12/TFIID as the coactivator bridging ATF7 to transcriptional activation.","evidence":"Reciprocal Co-IP, ChIP co-occupancy at an ATF7-responsive promoter, and reporter assays with TAF4 competition and isoform-specific domain mapping","pmids":["15735663"],"confidence":"High","gaps":["Genome-wide TAF12-dependent ATF7 targets not mapped","Regulation of the TAF12-ATF7 interaction by signaling addressed only later"]},{"year":2007,"claim":"Established SUMO as a negative ATF7 modification that acts by blocking nuclear entry and TAF12 association.","evidence":"In vitro and in vivo sumoylation at an IKEE motif, localization tracking, TAF12 Co-IP, and promoter binding assays with site mutants","pmids":["17264123"],"confidence":"High","gaps":["SUMO E3 specificity in physiological cells unclear","Desumoylation triggers not defined"]},{"year":2008,"claim":"Resolved the activating phosphorylation as a sequential two-step p38β2 cascade mutually exclusive with sumoylation, unifying the PTM logic of ATF7.","evidence":"In vitro kinase assays, phospho-mutants, Co-IP and reporter assays showing Thr53-then-Thr51 phosphorylation enhances TAF12 binding and excludes SUMO","pmids":["18950637"],"confidence":"High","gaps":["Identity of the priming Thr53 kinase not established","Stress inputs upstream of p38β2 not all defined"]},{"year":2009,"claim":"First demonstrated ATF7 as a chromatin repressor in vivo, linking H3K9 methylation to a stress-responsive behavioral phenotype.","evidence":"ChIP at the Htr5b promoter, ATF7-ESET Co-IP, and Atf7 knockout mice showing derepressed Htr5b and abnormal behavior after social isolation","pmids":["19893493"],"confidence":"High","gaps":["Generality of ESET versus G9a recruitment not yet resolved","Direct ESET recruitment mechanism unmapped"]},{"year":2010,"claim":"Showed the repressor-to-activator switch is evolutionarily conserved and central to innate immunity via genetic epistasis.","evidence":"C. elegans loss- and gain-of-function alleles and PMK-1/ATF-7 biochemistry placing ATF-7 downstream of p38 in immunity gene control","pmids":["20369020"],"confidence":"High","gaps":["Genome-wide targets not yet defined (addressed in 2019)","Mammalian conservation of immunity role shown later"]},{"year":2011,"claim":"Identified a cytoplasmic splice isoform that gates ATF7 activation by kinase sequestration, adding a post-translational off-switch.","evidence":"Splicing characterization, fractionation, Co-IP, ubiquitination and reporter assays showing ATF7-4 sequesters the Thr53 kinase until stimulus-induced degradation","pmids":["21858082"],"confidence":"Medium","gaps":["Identity of sequestered kinase not named","Tissue-specific abundance of ATF7-4 unknown"]},{"year":2013,"claim":"Extended the ATF7-TAF12 activation axis to vitamin-D-responsive gene control in osteoclast precursors.","evidence":"Reciprocal Co-IP, ChIP and siRNA knockdown showing ATF7 supports 1,25-(OH)2D3-induced CYP24A1 and TAF12 promoter binding","pmids":["23426901"],"confidence":"Medium","gaps":["Direct ATF7 promoter occupancy at CYP24A1 not distinguished from TAF12-mediated","Single cell-type context"]},{"year":2014,"claim":"Revealed a stress-independent mitotic role: CDK1-cyclin B1 phosphorylation of ATF7 supports cell-cycle progression.","evidence":"In vitro kinase assay, phospho-mutants, siRNA knockdown and FACS showing mitotic Thr51/53 phosphorylation enables G2/M progression and Aurora activation","pmids":["25545367"],"confidence":"Medium","gaps":["Mechanistic link between ATF7 and Aurora activation indirect","Transcriptional versus non-transcriptional contribution unclear"]},{"year":2015,"claim":"Established ATF7 as the molecular basis of innate immunological memory and clarified its mitotic stabilization.","evidence":"ChIP, G9a Co-IP, ATF7 KO and p38 inhibition showing LPS-driven release lowers H3K9me2 long-term; phospho-Thr112 intrabody and CRISPR studies link mitotic phosphorylation to ATF7 stability and cyclin D1","pmids":["26322480","26101806"],"confidence":"High","gaps":["Duration and maintenance mechanism of the open chromatin state incompletely defined","Thr112 kinase recognition determinants unmapped"]},{"year":2018,"claim":"Defined ATF7 as a guardian of telomere integrity whose stress-induced release shortens telomeres.","evidence":"ChIP at telomeres, Ku-complex Co-IP, p38 inhibition and ATF7 KO mice showing TNF-α-driven release of ATF7 and telomerase causes telomere shortening","pmids":["29490055"],"confidence":"High","gaps":["How ATF7 anchors telomerase mechanistically unresolved","Whether telomere effect requires H3K9 methylation here untested"]},{"year":2019,"claim":"Demonstrated ATF7 mediates intergenerational epigenetic inheritance and broadened its target landscape and physiological roles.","evidence":"ChIP/ChIP-seq, KO and conditional mice across germ cells (TERRA), adipose (UCP1), senescence (p16Ink4a), intestine, and genome-wide C. elegans occupancy, with sperm RNA and offspring phenotypes","pmids":["30407559","30789901","30826729","31294895","31958521"],"confidence":"High","gaps":["Selectivity of ATF7 for specific loci across tissues not fully explained","Mechanism of transgenerational RNA transmission downstream of ATF7 incomplete"]},{"year":2020,"claim":"Showed dietary stress reprograms offspring metabolism through ROS-p38-ATF7 control of germline chromatin and sperm small RNAs.","evidence":"Genome-wide ChIP-seq in testicular germ cells, Atf7+/- genetics, low-protein-diet intervention, sperm small RNA profiling and offspring liver transcriptomics","pmids":["32197065"],"confidence":"High","gaps":["Causal link between specific tRNA fragments and offspring phenotype incomplete","How LPD signals reach germ cell p38 not fully defined"]},{"year":2023,"claim":"Connected ATF7 to senescence/aging suppression and to a piRNA-controlled necroptosis axis, expanding its disease relevance.","evidence":"Overexpression/knockdown with H3K9me2 ChIP, NF-κB reporters and C. elegans lifespan; HNEAP-DNMT1-m5C control of Atf7 mRNA with ATF7 ChIP at the Chmp2a promoter and in vivo I/R injury","pmids":["37163432","37870216"],"confidence":"Medium","gaps":["Direct ATF7 occupancy at SASP/NF-κB loci not fully mapped","Whether necroptosis role is repression-mediated as for other targets unclear"]},{"year":2024,"claim":"Identified an AP-1 context in leukemia where ATF7/JDP2 dimers recruit IRF2BP2 to restrain inflammatory gene activation.","evidence":"Co-IP of ATF7/JDP2/IRF2BP2, ChIP showing IRF2BP2 recruitment, and IRF2BP2 KO with transcriptomic and proliferation readouts in AML cells","pmids":["38801077"],"confidence":"Medium","gaps":["Direct contribution of ATF7 versus JDP2 to dimer function not dissected","Phospho-regulation of this dimer untested"]},{"year":2025,"claim":"Demonstrated a direct gene-activating role for ATF7 driving mitophagy and intestinal protection via PINK1.","evidence":"ChIP-seq and luciferase assays at the PINK1 promoter with IEC-specific ATF7 KO showing impaired mitophagy and exacerbated DSS colitis","pmids":["40586859"],"confidence":"Medium","gaps":["Whether PINK1 activation requires phosphorylated ATF7 not addressed","How ATF7 toggles between repression and activation at different loci unresolved"]},{"year":null,"claim":"The structural and signaling determinants that direct ATF7 to specific loci and dictate whether it acts as an H3K9-methylation repressor or a direct activator remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of chromatin-bound ATF7 or its methyltransferase-recruiting interface","Determinants of locus-specific repression versus activation undefined","Priming kinase for Thr53 unidentified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,12,17,30]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[0,8,12,24]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[6,9]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[5,26]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[12,17,26]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[14]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[9,12,17]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[12,17,22,23]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[13,17,21]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[11,19,24]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[16,18]}],"complexes":["TFIID","AP-1 (ATF7/Jun and ATF7/JDP2 dimers)"],"partners":["JUN","TAF12","EHMT2","SETDB1","JDP2","IRF2BP2","PTP4A1","MAPK9"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P17544","full_name":"Cyclic AMP-dependent transcription factor ATF-7","aliases":["Activating transcription factor 7","Transcription factor ATF-A"],"length_aa":483,"mass_kda":51.8,"function":"Stress-responsive chromatin regulator that plays a role in various biological processes including innate immunological memory, adipocyte differentiation or telomerase regulation (PubMed:29490055). In absence of stress, contributes to the formation of heterochromatin and heterochromatin-like structure by recruiting histone H3K9 tri- and di-methyltransferases thus silencing the transcription of target genes such as STAT1 in adipocytes, or genes involved in innate immunity in macrophages and adipocytes (By similarity). Stress induces ATF7 phosphorylation that disrupts interactions with histone methyltransferase and enhances the association with coactivators containing histone acetyltransferase and/or histone demethylase, leading to disruption of the heterochromatin-like structure and subsequently transcriptional activation (By similarity). In response to TNF, which is induced by various stresses, phosphorylated ATF7 and telomerase are released from telomeres leading to telomere shortening (PubMed:29490055). Also plays a role in maintaining epithelial regenerative capacity and protecting against cell death during intestinal epithelial damage and repair (By similarity) Acts as a dominant repressor of the E-selectin/NF-ELAM1/delta-A promoter Acts as a negative regulator, inhibiting both ATF2 and ATF7 transcriptional activities. It may exert these effects by sequestrating in the cytoplasm the Thr-53 phosphorylating kinase, preventing activation","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/P17544/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ATF7","classification":"Not Classified","n_dependent_lines":40,"n_total_lines":1208,"dependency_fraction":0.033112582781456956},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"JUN","stoichiometry":10.0}],"url":"https://opencell.sf.czbiohub.org/search/ATF7","total_profiled":1310},"omim":[{"mim_id":"613645","title":"ACTIVATING TRANSCRIPTION FACTOR 7-INTERACTING PROTEIN 2; ATF7IP2","url":"https://www.omim.org/entry/613645"},{"mim_id":"613644","title":"ACTIVATING TRANSCRIPTION FACTOR 7-INTERACTING PROTEIN; ATF7IP","url":"https://www.omim.org/entry/613644"},{"mim_id":"606398","title":"ACTIVATING TRANSCRIPTION FACTOR 5; ATF5","url":"https://www.omim.org/entry/606398"},{"mim_id":"606371","title":"ACTIVATING TRANSCRIPTION FACTOR 7; ATF7","url":"https://www.omim.org/entry/606371"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in 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hypersensitivity of osteoclast precursors in Paget's disease.","date":"2013","source":"Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research","url":"https://pubmed.ncbi.nlm.nih.gov/23426901","citation_count":10,"is_preprint":false},{"pmid":"36254813","id":"PMC_36254813","title":"ATF7-dependent epigenetic changes induced by high temperature during early porcine embryonic development.","date":"2022","source":"Cell proliferation","url":"https://pubmed.ncbi.nlm.nih.gov/36254813","citation_count":9,"is_preprint":false},{"pmid":"38801077","id":"PMC_38801077","title":"IRF2BP2 counteracts the ATF7/JDP2 AP-1 heterodimer to prevent inflammatory overactivation in acute myeloid leukemia (AML) cells.","date":"2024","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/38801077","citation_count":6,"is_preprint":false},{"pmid":"31294895","id":"PMC_31294895","title":"Stress-induced and ATF7-dependent epigenetic change influences cellular senescence.","date":"2019","source":"Genes to cells : devoted to molecular & cellular mechanisms","url":"https://pubmed.ncbi.nlm.nih.gov/31294895","citation_count":6,"is_preprint":false},{"pmid":"7786026","id":"PMC_7786026","title":"Interaction of retinoblastoma gene product with transcription factors ATFa and ATF2.","date":"1995","source":"Archives of biochemistry and biophysics","url":"https://pubmed.ncbi.nlm.nih.gov/7786026","citation_count":6,"is_preprint":false},{"pmid":"15906372","id":"PMC_15906372","title":"Characterization and expression pattern of two zebrafish atf7 genes.","date":"2005","source":"Developmental dynamics : an official publication of the American Association of Anatomists","url":"https://pubmed.ncbi.nlm.nih.gov/15906372","citation_count":5,"is_preprint":false},{"pmid":"26101806","id":"PMC_26101806","title":"ATF7 is stabilized during mitosis in a CDK1-dependent manner and contributes to cyclin D1 expression.","date":"2015","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/26101806","citation_count":5,"is_preprint":false},{"pmid":"25047957","id":"PMC_25047957","title":"AtfA, a new factor in global regulation of transcription in Acinetobacter spp.","date":"2014","source":"Molecular microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/25047957","citation_count":5,"is_preprint":false},{"pmid":"39596279","id":"PMC_39596279","title":"ChIP-Seq Analysis of AtfA Interactions in Aspergillus flavus Reveals Its Involvement in Aflatoxin Metabolism and Virulence Under Oxidative Stress.","date":"2024","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/39596279","citation_count":4,"is_preprint":false},{"pmid":"40586859","id":"PMC_40586859","title":"ATF7-PINK1 Axis Governs Mitophagy and Intestinal Inflammation in Ulcerative Colitis.","date":"2025","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/40586859","citation_count":3,"is_preprint":false},{"pmid":"40069492","id":"PMC_40069492","title":"CircSARS-CV2-N1368 from SARS-CoV-2 impairs endothelial cell function through the upregulation of ATF7 to activate TLR4/NF-κB/ROS signaling.","date":"2025","source":"Acta pharmacologica Sinica","url":"https://pubmed.ncbi.nlm.nih.gov/40069492","citation_count":2,"is_preprint":false},{"pmid":"40903840","id":"PMC_40903840","title":"Epigenomic Profiling Positions ATF7 as a Core Regulator of Colonic Inflammation.","date":"2025","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/40903840","citation_count":0,"is_preprint":false},{"pmid":"41439985","id":"PMC_41439985","title":"Genome-Wide Mapping Reveals an Extensive AtfA Regulatory Influence on Development, Metabolism, and Stress Preparedness in Aspergillus nidulans.","date":"2025","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/41439985","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":26741,"output_tokens":8815,"usd":0.106224,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":18616,"output_tokens":6437,"usd":0.127002,"stage2_stop_reason":"end_turn"},"total_usd":0.233226,"stage1_batch_id":"msgbatch_0179Z2pxRYBsXi2xADneafRw","stage2_batch_id":"msgbatch_01LaY9ZaVdgjWArcZo9eqQE5","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1994,\n      \"finding\": \"ATF7 (ATFa) proteins heterodimerize with c-Jun, Jun-B, and Jun-D (but not effectively with c-Fos for DNA binding), and ATFa/c-Jun heterodimers bind ATF, CRE, and AP1 sites; coexpression of c-Jun stimulates ATFa-dependent reporter activity. A C-terminal element negatively interferes with ATFa intrinsic activation. These interactions were confirmed by reciprocal co-immunoprecipitation and EMSA with in vitro synthesized proteins, and ATFa/c-Jun complexes were detected in HeLa cell extracts.\",\n      \"method\": \"Reciprocal co-immunoprecipitation, EMSA (electrophoretic band-shift assay), in vitro transcription/translation, transient transfection reporter assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP plus EMSA plus in vivo cell extracts, replicated in subsequent studies\",\n      \"pmids\": [\"8290251\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"ATF-a0, a splice variant of ATF7 (ATFa) lacking the P/S/T-rich transactivation domain, has no transactivating function on the E-selectin NF-ELAM1/deltaA element and acts as a dominant inhibitor when heterodimerized with full-length ATFa, completely blocking its transactivating activity. Both ATFa forms bind the p50 subunit of NF-κB as shown by affinity chromatography.\",\n      \"method\": \"Transient transfection reporter assays, RT-PCR, Northern blot, affinity chromatography\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional reporter assays plus affinity chromatography for NF-κB p50 binding, single lab\",\n      \"pmids\": [\"8288576\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"ATFa interacts with c-Jun and c-Fos in vivo; complexes containing ATFa and either c-Jun or c-Fos were specifically retained on glutathione-agarose beads from crude extracts of transfected cells expressing GST-ATFa fusions. The leucine zipper domain of ATFa is essential for this interaction.\",\n      \"method\": \"GST pulldown from mammalian cell extracts, immunoblot, domain deletion analysis\",\n      \"journal\": \"BioTechniques\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — GST pulldown from mammalian cells with domain mapping, single lab with multiple orthogonal confirmations\",\n      \"pmids\": [\"7702840\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"The retinoblastoma gene product (pRb) differentially modulates ATFa and ATF2: co-expression of pRb strongly inhibits ATFa transcriptional activity on the TGF-β2 promoter CRE element, while it has additive or greater stimulatory effects with ATF2, revealing a functional distinction between these two related factors.\",\n      \"method\": \"Transient transfection reporter assays in CHO cells, in vitro DNA binding (CRE element)\",\n      \"journal\": \"Archives of biochemistry and biophysics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single method (reporter assay), no direct binding confirmed\",\n      \"pmids\": [\"7786026\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"ATF7 (ATFa) is associated in vivo with JNK/SAP kinase activity (identified as 54/55 kDa JNK2) as revealed by co-immunoprecipitation from whole cell extracts. Two independent regions mediate kinase binding: the major site is within N-terminal residues 1–82 (containing the metal-chelating element); a weaker site is in the basic region preceding the leucine zipper.\",\n      \"method\": \"Co-immunoprecipitation from whole cell extracts, in vitro binding assays, in vivo kinase assays, immunological characterization\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus in vitro binding plus domain mapping, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"8649858\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"The ATFa gene maps to chromosome 12 (band 12q13); ATFa isoforms are generated by alternative splice donor site usage; ATFa protein accumulates in the nucleus of transfected cells and the nuclear localization signal was mapped to the region adjacent to the leucine zipper domain. A minimal promoter of ~200 bp retains near-full transcriptional activity.\",\n      \"method\": \"Chromosomal mapping, expression analysis, nuclear localization by transfection/immunofluorescence, DNase I footprinting, Northern blot\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization by transfection/imaging plus chromosomal mapping and domain mapping, single lab\",\n      \"pmids\": [\"8939888\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"The N-terminal activation domain of ATF7 (ATFa) requires specific threonine residues (Thr51 and Thr53) in addition to the metal-binding domain for transcriptional activation. Although the N-terminal domain stably binds JNK2, ATFa is not itself a JNK2 substrate in vivo; instead, the N-terminal domain serves as a JNK2-docking site, allowing ATFa-associated partners such as JunD to be phosphorylated by the bound kinase.\",\n      \"method\": \"Site-directed mutagenesis of Thr51/Thr53, in vivo phosphorylation assays, transient transfection reporter assays, co-immunoprecipitation\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — mutagenesis plus in vivo kinase assays plus reporter assays, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"10376527\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"A novel protein mAM (mouse ATFa-associated Modulator, 1306 residues) was identified by yeast two-hybrid screening using the N-terminal half of ATF7 as bait. mAM colocalizes and interacts with ATFa in mammalian cells, contains a bipartite NLS, possesses ATPase activity, and downregulates transcriptional activity in an ATPase-independent manner by interacting with components of the basal transcription machinery (TFIIE, TFIIH, and RNA Pol II itself).\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, co-localization, ATPase assay, transient transfection reporter assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid plus co-IP plus co-localization plus functional assays, single lab\",\n      \"pmids\": [\"10777215\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"ATF-7 physically interacts with the PRL-1 protein-tyrosine phosphatase; the interaction was initially identified by yeast two-hybrid and confirmed biochemically. The interaction maps to ATF-7's bZIP region and PRL-1's phosphatase domain. PRL-1 is able to dephosphorylate ATF-7 in vitro. ATF-7 homodimers bind CRE elements specifically.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, in vitro dephosphorylation assay, EMSA (CRE binding)\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid plus in vitro biochemical confirmation plus domain mapping, single lab\",\n      \"pmids\": [\"11278933\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"ATF7 interacts directly with TAF12 (hsTAF12, a subunit of TFIID), and this interaction potentiates ATF7-induced transcriptional activation. Overexpression of hsTAF12 stimulates ATF7-dependent transcription; ChIP confirms ATF7-TAF12 co-occupancy at an ATF7-responsive promoter in vivo. TAF12-mediated activation is competitively inhibited by TAF4. Both TAF12 isoforms (TAF12-1 and -2) interact with the ATF7 activation region through their histone-fold domain, but only TAF12-1 mediates activation through its N-terminal region.\",\n      \"method\": \"Co-immunoprecipitation, chromatin immunoprecipitation (ChIP), transient transfection reporter assays, domain deletion analysis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP plus ChIP at endogenous promoter plus functional reporter assays plus domain mapping in a single study\",\n      \"pmids\": [\"15735663\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"ATF7 is sumoylated in vitro (using RanBP2 as E3 SUMO ligase) and in vivo at a consensus IKEE motif within its N-terminal activation domain. Sumoylation delays ATF7 nuclear entry and inhibits its transcriptional activity by (i) impairing its association with TAF12 and (ii) blocking binding to specific sequences within target promoters.\",\n      \"method\": \"In vitro sumoylation assay, in vivo sumoylation (immunoprecipitation), nuclear localization tracking, co-immunoprecipitation, reporter assays, site-directed mutagenesis\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro reconstitution plus in vivo validation plus multiple orthogonal functional assays (localization, TAF12 interaction, promoter binding) in one study\",\n      \"pmids\": [\"17264123\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"p38β2 MAPK phosphorylates ATF7 at Thr51 in a sequential two-step mechanism: an unknown kinase first phosphorylates Thr53, which then permits p38β2 to phosphorylate Thr51. EGF treatment triggers this cascade. Phosphorylation at Thr51/53 and sumoylation of ATF7 are mutually exclusive modifications; phosphorylation increases ATF7 transcriptional activity via enhanced TAF12 association, while excluding sumoylation.\",\n      \"method\": \"In vitro kinase assays, site-directed mutagenesis (phospho-mimetic/phospho-deficient mutants), co-immunoprecipitation, reporter assays\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro kinase reconstitution plus mutagenesis plus functional assays establishing mutually exclusive PTM mechanism in one study\",\n      \"pmids\": [\"18950637\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"ATF7 silences transcription of the serotonin receptor 5B gene (Htr5b) by directly binding its 5'-regulatory region and mediating histone H3-K9 trimethylation via interaction with the ESET histone methyltransferase. Upon social isolation stress, ATF7 is phosphorylated via p38 and released from the Htr5b promoter, upregulating Htr5b. Atf7-deficient mice exhibit abnormal behavior and increased Htr5b mRNA in the dorsal raphe nucleus.\",\n      \"method\": \"ChIP, co-immunoprecipitation (ATF7-ESET interaction), Atf7 knockout mouse phenotype, quantitative RT-PCR\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP showing direct promoter binding plus co-IP of ATF7-ESET complex plus in vivo KO with specific molecular phenotype, multiple orthogonal methods\",\n      \"pmids\": [\"19893493\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"C. elegans ATF-7, an ortholog of mammalian ATF2/ATF7, functions as a repressor of PMK-1 p38 MAPK-regulated innate immunity genes in the basal state and switches to an activator upon direct phosphorylation by PMK-1. Loss-of-function mutations in atf-7 restore basal expression of PMK-1-regulated genes in pmk-1 null mutants (genetic epistasis), but pathogen-induced gene induction by P. aeruginosa PA14 is abrogated in atf-7 loss-of-function animals.\",\n      \"method\": \"Genetic epistasis (loss-of-function and gain-of-function allele analysis), biochemical characterization of ATF-7/PMK-1 interaction, gene expression analysis\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis plus biochemical interaction plus expression analysis, replicated across multiple alleles in single study\",\n      \"pmids\": [\"20369020\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"A cytoplasmic alternatively spliced isoform of ATF7, named ATF7-4, inhibits both ATF7 and ATF2 transcriptional activity by blocking the first phosphorylation event on Thr53/Thr71 residues. ATF7-4 sequesters the Thr53-phosphorylating kinase in the cytoplasm. Upon stimulus-induced phosphorylation, ATF7-4 is poly-ubiquitinated and degraded, releasing the kinase and enabling ATF7/ATF2 activation.\",\n      \"method\": \"Alternative splicing characterization, co-immunoprecipitation, subcellular fractionation, phosphorylation assays (phospho-specific antibodies), ubiquitination assays, reporter assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (Co-IP, fractionation, ubiquitination, reporter) in single lab\",\n      \"pmids\": [\"21858082\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"ATF7 physically interacts with TAF12 in osteoclast (OCL) precursors (confirmed by reciprocal co-immunoprecipitation). ATF7 contributes to 1,25-(OH)2D3-induced CYP24A1 (24-hydroxylase) gene expression; knockdown of ATF7 in MVNP-expressing OCL precursors decreases CYP24A1 induction by 1,25-(OH)2D3 and reduces TAF12 binding to the CYP24A1 promoter (by ChIP).\",\n      \"method\": \"Reciprocal co-immunoprecipitation, chromatin immunoprecipitation (ChIP), siRNA knockdown, reporter/gene expression assays\",\n      \"journal\": \"Journal of bone and mineral research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP plus ChIP plus functional knockdown, single lab\",\n      \"pmids\": [\"23426901\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Cdk1-cyclin B1 phosphorylates ATF7 at Thr51/Thr53 from early prophase to anaphase during mitosis (in the absence of stress). Knockdown of ATF7 decreases cell proliferation rate and M-phase cell number. Expression of a mitotically non-phosphorylatable ATF7 mutant inhibits G2/M progression despite endogenous ATF7 presence. Mitotic phosphorylation of ATF7 promotes activation of Aurora kinases.\",\n      \"method\": \"In vitro kinase assay (Cdk1-cyclin B1), phospho-specific antibodies, siRNA knockdown, cell cycle analysis (FACS), phospho-deficient/phospho-mimetic mutant expression\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro kinase assay plus mutagenesis plus cell cycle phenotype, single lab\",\n      \"pmids\": [\"25545367\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ATF7 mediates innate immunological memory in macrophages by suppressing innate immunity genes through recruitment of the histone H3K9 dimethyltransferase G9a to chromatin. LPS treatment induces p38-mediated phosphorylation of ATF7, causing its release from chromatin and a decrease in repressive H3K9me2 marks; the partially open chromatin structure and increased basal expression of target genes are maintained long-term.\",\n      \"method\": \"ChIP (ATF7 chromatin binding and H3K9me2 levels), co-immunoprecipitation (ATF7-G9a interaction), ATF7 knockout/knockdown, p38 inhibitor treatment, LPS stimulation experiments\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP plus Co-IP plus genetic KO plus pharmacological inhibition with orthogonal readouts, published in high-impact journal with extensive validation\",\n      \"pmids\": [\"26322480\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ATF7 phosphorylation on residue Thr112 occurs exclusively during mitosis and is CDK1/cyclin B-dependent. ATF7 is excluded from condensed chromatin during mitosis. Thr112 phosphorylation protects ATF7 from proteasomal degradation (demonstrated using a transduced neutralizing intrabody), but does not affect displacement from condensed chromatin. ATF7 silencing by CRISPR/Cas9 decreases cyclin D1 protein levels, suggesting ATF7 re-localizes to chromatin after telophase to drive cyclin D1 expression.\",\n      \"method\": \"Phospho-specific antibodies, CDK1 inhibitor treatment, transduced neutralizing monoclonal antibody (intrabody), phospho-mimetic/phospho-deficient mutants, CRISPR/Cas9 knockdown, immunofluorescence\",\n      \"journal\": \"Cell cycle\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — intrabody plus mutagenesis plus CRISPR plus cell biology, multiple orthogonal approaches in single lab\",\n      \"pmids\": [\"26101806\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ATF7 and telomerase are localized on telomeres via interactions with the Ku complex. In response to TNF-α, ATF7 is phosphorylated by p38, leading to the release of ATF7 and telomerase from telomeres and resulting in telomere shortening. ATF7-deficient mice show telomere shortening consistent with this mechanism.\",\n      \"method\": \"ChIP (ATF7 and telomerase at telomeres), co-immunoprecipitation (ATF7-Ku complex), p38 inhibitor treatment, ATF7 KO mouse model, telomere length measurement\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP demonstrating telomere localization plus Co-IP of Ku complex plus in vivo KO validation plus pharmacological confirmation, multiple orthogonal methods\",\n      \"pmids\": [\"29490055\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TNF-α induces p38-dependent phosphorylation of ATF7 in mouse testicular germ cells, causing release of ATF7 from the TERRA gene promoter in the subtelomeric region, disrupting heterochromatin and inducing TERRA (telomere repeat-containing RNA). This TERRA is transgenerationally transmitted to zygotes via sperm and causes telomere shortening in offspring.\",\n      \"method\": \"ChIP (ATF7 at TERRA promoter, H3K9me2 levels), p38 inhibitor treatment, ATF7 KO mouse model, TERRA measurement, sperm RNA analysis\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP plus genetic KO plus pharmacological inhibition plus sperm RNA analysis, multiple orthogonal methods in single study\",\n      \"pmids\": [\"30407559\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In C. elegans, PMK-1-ATF-7 signaling regulates a majority of all genes induced by P. aeruginosa infection. ATF-7 occupies regulatory regions of pathogen-induced genes in a PMK-1-dependent manner (ChIP-Seq). A subset of ATF-7-regulated pathogen-induced target genes directly contribute to host defense.\",\n      \"method\": \"RNA-seq, ChIP-Seq (ATF-7 genome-wide occupancy), functional analysis of target gene knockdowns\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide ChIP-Seq plus RNA-seq plus functional validation of targets, builds on prior genetic epistasis work\",\n      \"pmids\": [\"30789901\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ATF7 is required for adipocyte differentiation; it interacts with histone dimethyltransferase G9a in adipocytes to repress interferon-stimulated genes (which suppress adipogenesis). ATF7 binds transcriptional regulatory regions of the UCP1 gene and silences it by controlling H3K9 dimethylation. Ablation of ATF7 promotes beige fat biogenesis in inguinal white adipose tissue.\",\n      \"method\": \"ATF7 KO mouse model, ChIP (ATF7 at UCP1 promoter, H3K9me2 levels), co-immunoprecipitation (ATF7-G9a), differentiation assays\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus Co-IP plus KO mouse with specific phenotypic readout, single lab\",\n      \"pmids\": [\"30826729\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ATF7 binds the p16Ink4a gene promoter and recruits H3K9 di- and trimethyltransferases to silence p16Ink4a expression. With age or oxidative stress, p38-mediated phosphorylation of ATF7 increases and ATF7 is released from the promoter, leading to decreased H3K9me2 at the locus and accelerated p16Ink4a accumulation. Atf7-/- mice have shorter lifespans than wild-type mice.\",\n      \"method\": \"ChIP (ATF7 occupancy and H3K9me2 at p16Ink4a promoter), ATF7 KO mice (lifespan and p16 mRNA quantification), MEF culture with oxidative stress, p38 phosphorylation assays\",\n      \"journal\": \"Genes to cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus KO mouse with molecular phenotype plus mechanistic phosphorylation data, single lab\",\n      \"pmids\": [\"31294895\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ATF7 binds the promoter regions of ~2,300 genes including cholesterol biosynthesis-related and tRNA genes in testicular germ cells (TGCs). A paternal low-protein diet (LPD) induces ROS, which activates p38 to phosphorylate ATF7 in TGCs; this leads to ATF7 release from chromatin, decreased H3K9me2 on target genes, and increased tRNA fragment expression in spermatozoa. These epigenetic changes are transmitted to offspring and alter liver gene expression and metabolism. Atf7+/- mutation phenocopies paternal LPD effects.\",\n      \"method\": \"ChIP-seq (ATF7 genome-wide binding in TGCs, H3K9me2 levels), Atf7+/- mouse genetics, dietary intervention (LPD), ROS measurement, spermatozoa small RNA profiling, offspring liver transcriptomics\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide ChIP-Seq plus genetic mouse model plus dietary intervention plus multi-generation analysis, multiple orthogonal methods\",\n      \"pmids\": [\"32197065\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ATF2 and ATF7 are required for intestinal epithelial repair but dispensable for homeostasis. Activating phosphorylation of ATF2 and ATF7 occurs mainly in intestinal crypts. Intestine-specific double-mutant mice show impaired regenerative response to DSS or irradiation, with increased apoptosis, severe ulceration, and failure to regenerate colonic crypts. Organoids from double-mutant epithelium show growth disadvantage and impaired wound healing.\",\n      \"method\": \"Conditional KO mouse model (Villin-CreERT2), DSS colitis model, irradiation model, organoid culture, phospho-specific antibodies (IHC), scratch assay\",\n      \"journal\": \"Cellular and molecular gastroenterology and hepatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with multiple injury models plus organoid functional assays, single lab\",\n      \"pmids\": [\"31958521\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ATF7 accumulates in the nucleus of porcine embryos and localizes to pericentromeric heterochromatin after the late 4-cell stage, co-localizing with HP1. ATF7 knockdown reduces blastocyst rate and cell number, and decreases HP1 and H3K9me2 levels. High temperature induces p38 phosphorylation of ATF7, reducing H3K9me2 and HP1 levels; inhibition of p38 activity alleviates these effects.\",\n      \"method\": \"siRNA knockdown, immunofluorescence (ATF7 localization, HP1, H3K9me2), p38 inhibitor treatment, blastocyst rate and cell count\",\n      \"journal\": \"Cell proliferation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct imaging of localization plus functional KD plus pharmacological inhibition with specific molecular readouts, single lab\",\n      \"pmids\": [\"36254813\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ATF7 inhibits NF-κB signaling and increases H3K9 dimethylation (H3K9me2) to suppress cellular senescence and SASP secretion. Loss of ATF7 induces cellular senescence while overexpression delays it. In C. elegans, ATF7 overexpression suppresses aging biomarkers and extends lifespan.\",\n      \"method\": \"ATF7 overexpression and knockdown, H3K9me2 ChIP, NF-κB reporter assays, senescence assays (SA-β-gal, p21 levels), C. elegans lifespan assay\",\n      \"journal\": \"Aging and disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus functional KO/OE plus reporter assays across two model systems, single lab\",\n      \"pmids\": [\"37163432\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"HNEAP (a piRNA) interacts with DNMT1 and reduces m5C methylation of Atf7 mRNA, increasing ATF7 protein levels. Elevated ATF7 then downregulates transcription of Chmp2a (an inhibitor of necroptosis), reducing CHMP2A levels and promoting cardiomyocyte necroptosis. Loss of HNEAP inhibits necroptosis and improves cardiac function in I/R-injured mice.\",\n      \"method\": \"RNA pulldown (HNEAP-DNMT1 interaction), m5C methylation assay, ATF7 ChIP (binding to Chmp2a promoter), luciferase reporter assay, ATF7 knockdown/overexpression, HNEAP KO mouse model\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP of ATF7 at Chmp2a promoter plus RNA pulldown plus m5C assay plus in vivo KO, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"37870216\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ATF7 forms an AP-1 heterodimer with JDP2 in AML cells; IRF2BP2 is recruited by the ATF7/JDP2 dimer to chromatin and counteracts its gene-activating function on inflammatory pathway genes. Loss of IRF2BP2 leads to overactivation of inflammatory pathways and strongly reduced cell proliferation.\",\n      \"method\": \"Co-immunoprecipitation (ATF7/JDP2/IRF2BP2 complex), ChIP (IRF2BP2 recruitment by ATF7/JDP2), IRF2BP2 knockdown/KO with transcriptomic and proliferation readouts\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus ChIP plus functional KO with defined phenotype, single lab\",\n      \"pmids\": [\"38801077\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ATF7 directly binds to and transcriptionally activates the PINK1 promoter (a master mitophagy regulator) as demonstrated by ChIP-seq and luciferase reporter assays. Loss of ATF7 or PINK1 in intestinal epithelial cells impairs mitophagy, disrupts mitochondrial membrane potential, increases ROS, and exacerbates DSS-induced colitis in vivo.\",\n      \"method\": \"ChIP-seq, luciferase reporter assay, IEC-specific ATF7 KO mouse model, mitophagy assays (electron microscopy, mitochondrial membrane potential), DSS colitis model\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq plus luciferase reporter plus IEC-specific KO with functional readouts, single lab\",\n      \"pmids\": [\"40586859\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ATF7 is a stress-responsive bZIP transcription factor that binds CRE/AP-1 elements as homodimers or heterodimers with Jun/Fos proteins, and functions predominantly as a chromatin-based epigenetic repressor: in its basal (unphosphorylated) state, ATF7 recruits H3K9 dimethyltransferases (G9a, ESET) and trimethyltransferases to silence target genes (including innate immunity genes, Htr5b, UCP1, p16Ink4a, TERRA, PINK1, and Chmp2a) by promoting H3K9me2/me3; upon stress or cytokine stimulation (TNF-α, LPS, social isolation, dietary stress, high temperature), p38 MAPK phosphorylates ATF7 at conserved N-terminal threonine residues (Thr51/Thr53), causing its release from chromatin, reduction of repressive histone marks, and gene derepression—a mechanism that underlies innate immunological memory, stress-induced telomere shortening, intergenerational epigenetic inheritance, cellular senescence, and adipocyte differentiation. ATF7 transcriptional activity is further modulated by: CDK1-mediated phosphorylation at Thr51/Thr53 and Thr112 during mitosis (stabilizing ATF7 and enabling G2/M progression and cyclin D1 expression), SUMO modification (inhibiting nuclear entry and TAF12 association), interaction with TAF12/TFIID (mediating transcriptional activation), association with JNK2 as a docking platform for substrate kinase delivery, dephosphorylation by PRL-1 phosphatase, and dominant inhibition by a cytoplasmic splice isoform (ATF7-4) that sequesters the activating kinase.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ATF7 (ATFa) is a stress-responsive bZIP transcription factor that binds CRE/AP-1 elements as homodimers or as heterodimers with Jun proteins (c-Jun, Jun-B, Jun-D), and operates predominantly as a chromatin-based epigenetic repressor whose activity is gated by stress-activated phosphorylation [#0, #17]. In its basal unphosphorylated state, ATF7 occupies target promoters and recruits H3K9 methyltransferases — G9a and ESET — to deposit repressive H3K9me2/me3 marks and silence genes including Htr5b, UCP1, p16Ink4a, and subtelomeric TERRA loci [#12, #17, #22, #23]. Upon stress or cytokine input (LPS, TNF-\\u03b1, oxidative or dietary stress, high temperature), p38 MAPK phosphorylates conserved N-terminal threonines (Thr51/Thr53) in a sequential two-step mechanism, releasing ATF7 from chromatin, lowering repressive marks, and derepressing targets — a switch that underlies innate immunological memory in macrophages, stress-induced and intergenerational telomere shortening transmitted through sperm, cellular senescence, and adipocyte differentiation [#11, #17, #19, #20, #24]. This repressor-to-activator switch is conserved in C. elegans, where the ortholog ATF-7 represses PMK-1 p38 MAPK-regulated innate immunity genes basally and is converted to an activator of pathogen-induced genes upon direct PMK-1 phosphorylation [#13, #21]. ATF7 activity is further tuned by SUMO modification — which delays nuclear entry and is mutually exclusive with Thr51/53 phosphorylation [#10, #11] — by interaction with TAF12/TFIID that potentiates activation [#9], by CDK1/cyclin-B phosphorylation at Thr51/53 and Thr112 during mitosis that stabilizes ATF7 and supports G2/M progression and cyclin D1 expression [#16, #18], and by a cytoplasmic splice isoform (ATF7-4) that sequesters the activating kinase [#14]. Beyond repression, ATF7 directly activates target promoters such as PINK1 to support mitophagy and intestinal epithelial repair [#25, #30].\",\n  \"teleology\": [\n    {\n      \"year\": 1994,\n      \"claim\": \"Established ATF7 as a bZIP dimerizing factor, defining its DNA-binding partners and a built-in negative regulatory architecture.\",\n      \"evidence\": \"Reciprocal Co-IP, EMSA and reporter assays showing ATFa/c-Jun heterodimers binding ATF/CRE/AP1 sites; a dominant-inhibitory splice form lacking the transactivation domain blocks full-length ATFa and binds NF-\\u03baB p50\",\n      \"pmids\": [\"8290251\", \"8288576\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous target genes not yet identified\", \"Functional consequence of NF-\\u03baB p50 binding unresolved\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Mapped the dimerization determinant and distinguished ATF7 functionally from its relative ATF2.\",\n      \"evidence\": \"GST pulldown with domain deletion localizing the leucine zipper requirement; reporter assays showing pRb differentially inhibits ATFa versus ATF2\",\n      \"pmids\": [\"7702840\", \"7786026\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"pRb effect shown only in reporter context with no direct binding\", \"In vivo relevance of pRb modulation unaddressed\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Defined ATF7's nuclear localization and revealed a stable association with JNK2, framing the N-terminus as a regulatory hub.\",\n      \"evidence\": \"Chromosomal mapping, nuclear localization by transfection imaging, and Co-IP identifying associated 54/55 kDa JNK2 with domain-mapped binding sites\",\n      \"pmids\": [\"8939888\", \"8649858\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether JNK2 binding regulates ATF7 transcription directly unclear\", \"NLS mapping not validated by mutagenesis\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Showed the N-terminal Thr51/Thr53 region functions as a kinase-docking platform rather than a kinase substrate, identifying the residues central to ATF7 regulation.\",\n      \"evidence\": \"Site-directed mutagenesis of Thr51/Thr53, in vivo phosphorylation and reporter assays demonstrating JNK2 docking delivers kinase to ATF7 partners such as JunD\",\n      \"pmids\": [\"10376527\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The kinase ultimately phosphorylating Thr51/53 not defined here\", \"Physiological signals engaging docking unknown\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Identified mAM as an ATF7-associated modulator linking ATF7 to the basal transcription machinery.\",\n      \"evidence\": \"Yeast two-hybrid, Co-IP, co-localization and ATPase/reporter assays showing mAM downregulates activity via TFIIE/TFIIH/Pol II contacts\",\n      \"pmids\": [\"10777215\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab; mechanism of repression not reconstituted\", \"Endogenous role of mAM-ATF7 axis untested\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Connected ATF7 to a phosphatase, indicating its activity is reversibly controlled by phosphorylation.\",\n      \"evidence\": \"Yeast two-hybrid, Co-IP and in vitro dephosphorylation mapping the PRL-1 interaction to the ATF7 bZIP region\",\n      \"pmids\": [\"11278933\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Which ATF7 phospho-sites PRL-1 targets in vivo unknown\", \"Cellular outcome of dephosphorylation not shown\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Defined TAF12/TFIID as the coactivator bridging ATF7 to transcriptional activation.\",\n      \"evidence\": \"Reciprocal Co-IP, ChIP co-occupancy at an ATF7-responsive promoter, and reporter assays with TAF4 competition and isoform-specific domain mapping\",\n      \"pmids\": [\"15735663\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Genome-wide TAF12-dependent ATF7 targets not mapped\", \"Regulation of the TAF12-ATF7 interaction by signaling addressed only later\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Established SUMO as a negative ATF7 modification that acts by blocking nuclear entry and TAF12 association.\",\n      \"evidence\": \"In vitro and in vivo sumoylation at an IKEE motif, localization tracking, TAF12 Co-IP, and promoter binding assays with site mutants\",\n      \"pmids\": [\"17264123\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"SUMO E3 specificity in physiological cells unclear\", \"Desumoylation triggers not defined\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Resolved the activating phosphorylation as a sequential two-step p38\\u03b22 cascade mutually exclusive with sumoylation, unifying the PTM logic of ATF7.\",\n      \"evidence\": \"In vitro kinase assays, phospho-mutants, Co-IP and reporter assays showing Thr53-then-Thr51 phosphorylation enhances TAF12 binding and excludes SUMO\",\n      \"pmids\": [\"18950637\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the priming Thr53 kinase not established\", \"Stress inputs upstream of p38\\u03b22 not all defined\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"First demonstrated ATF7 as a chromatin repressor in vivo, linking H3K9 methylation to a stress-responsive behavioral phenotype.\",\n      \"evidence\": \"ChIP at the Htr5b promoter, ATF7-ESET Co-IP, and Atf7 knockout mice showing derepressed Htr5b and abnormal behavior after social isolation\",\n      \"pmids\": [\"19893493\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generality of ESET versus G9a recruitment not yet resolved\", \"Direct ESET recruitment mechanism unmapped\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Showed the repressor-to-activator switch is evolutionarily conserved and central to innate immunity via genetic epistasis.\",\n      \"evidence\": \"C. elegans loss- and gain-of-function alleles and PMK-1/ATF-7 biochemistry placing ATF-7 downstream of p38 in immunity gene control\",\n      \"pmids\": [\"20369020\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Genome-wide targets not yet defined (addressed in 2019)\", \"Mammalian conservation of immunity role shown later\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identified a cytoplasmic splice isoform that gates ATF7 activation by kinase sequestration, adding a post-translational off-switch.\",\n      \"evidence\": \"Splicing characterization, fractionation, Co-IP, ubiquitination and reporter assays showing ATF7-4 sequesters the Thr53 kinase until stimulus-induced degradation\",\n      \"pmids\": [\"21858082\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Identity of sequestered kinase not named\", \"Tissue-specific abundance of ATF7-4 unknown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Extended the ATF7-TAF12 activation axis to vitamin-D-responsive gene control in osteoclast precursors.\",\n      \"evidence\": \"Reciprocal Co-IP, ChIP and siRNA knockdown showing ATF7 supports 1,25-(OH)2D3-induced CYP24A1 and TAF12 promoter binding\",\n      \"pmids\": [\"23426901\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct ATF7 promoter occupancy at CYP24A1 not distinguished from TAF12-mediated\", \"Single cell-type context\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Revealed a stress-independent mitotic role: CDK1-cyclin B1 phosphorylation of ATF7 supports cell-cycle progression.\",\n      \"evidence\": \"In vitro kinase assay, phospho-mutants, siRNA knockdown and FACS showing mitotic Thr51/53 phosphorylation enables G2/M progression and Aurora activation\",\n      \"pmids\": [\"25545367\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic link between ATF7 and Aurora activation indirect\", \"Transcriptional versus non-transcriptional contribution unclear\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Established ATF7 as the molecular basis of innate immunological memory and clarified its mitotic stabilization.\",\n      \"evidence\": \"ChIP, G9a Co-IP, ATF7 KO and p38 inhibition showing LPS-driven release lowers H3K9me2 long-term; phospho-Thr112 intrabody and CRISPR studies link mitotic phosphorylation to ATF7 stability and cyclin D1\",\n      \"pmids\": [\"26322480\", \"26101806\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Duration and maintenance mechanism of the open chromatin state incompletely defined\", \"Thr112 kinase recognition determinants unmapped\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined ATF7 as a guardian of telomere integrity whose stress-induced release shortens telomeres.\",\n      \"evidence\": \"ChIP at telomeres, Ku-complex Co-IP, p38 inhibition and ATF7 KO mice showing TNF-\\u03b1-driven release of ATF7 and telomerase causes telomere shortening\",\n      \"pmids\": [\"29490055\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How ATF7 anchors telomerase mechanistically unresolved\", \"Whether telomere effect requires H3K9 methylation here untested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrated ATF7 mediates intergenerational epigenetic inheritance and broadened its target landscape and physiological roles.\",\n      \"evidence\": \"ChIP/ChIP-seq, KO and conditional mice across germ cells (TERRA), adipose (UCP1), senescence (p16Ink4a), intestine, and genome-wide C. elegans occupancy, with sperm RNA and offspring phenotypes\",\n      \"pmids\": [\"30407559\", \"30789901\", \"30826729\", \"31294895\", \"31958521\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Selectivity of ATF7 for specific loci across tissues not fully explained\", \"Mechanism of transgenerational RNA transmission downstream of ATF7 incomplete\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showed dietary stress reprograms offspring metabolism through ROS-p38-ATF7 control of germline chromatin and sperm small RNAs.\",\n      \"evidence\": \"Genome-wide ChIP-seq in testicular germ cells, Atf7+/- genetics, low-protein-diet intervention, sperm small RNA profiling and offspring liver transcriptomics\",\n      \"pmids\": [\"32197065\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Causal link between specific tRNA fragments and offspring phenotype incomplete\", \"How LPD signals reach germ cell p38 not fully defined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Connected ATF7 to senescence/aging suppression and to a piRNA-controlled necroptosis axis, expanding its disease relevance.\",\n      \"evidence\": \"Overexpression/knockdown with H3K9me2 ChIP, NF-\\u03baB reporters and C. elegans lifespan; HNEAP-DNMT1-m5C control of Atf7 mRNA with ATF7 ChIP at the Chmp2a promoter and in vivo I/R injury\",\n      \"pmids\": [\"37163432\", \"37870216\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct ATF7 occupancy at SASP/NF-\\u03baB loci not fully mapped\", \"Whether necroptosis role is repression-mediated as for other targets unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified an AP-1 context in leukemia where ATF7/JDP2 dimers recruit IRF2BP2 to restrain inflammatory gene activation.\",\n      \"evidence\": \"Co-IP of ATF7/JDP2/IRF2BP2, ChIP showing IRF2BP2 recruitment, and IRF2BP2 KO with transcriptomic and proliferation readouts in AML cells\",\n      \"pmids\": [\"38801077\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct contribution of ATF7 versus JDP2 to dimer function not dissected\", \"Phospho-regulation of this dimer untested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstrated a direct gene-activating role for ATF7 driving mitophagy and intestinal protection via PINK1.\",\n      \"evidence\": \"ChIP-seq and luciferase assays at the PINK1 promoter with IEC-specific ATF7 KO showing impaired mitophagy and exacerbated DSS colitis\",\n      \"pmids\": [\"40586859\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether PINK1 activation requires phosphorylated ATF7 not addressed\", \"How ATF7 toggles between repression and activation at different loci unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural and signaling determinants that direct ATF7 to specific loci and dictate whether it acts as an H3K9-methylation repressor or a direct activator remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of chromatin-bound ATF7 or its methyltransferase-recruiting interface\", \"Determinants of locus-specific repression versus activation undefined\", \"Priming kinase for Thr53 unidentified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 12, 17, 30]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0, 8, 12, 24]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [6, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [5, 26]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [12, 17, 26]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [14]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [9, 12, 17]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [12, 17, 22, 23]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [13, 17, 21]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [11, 19, 24]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [16, 18]}\n    ],\n    \"complexes\": [\"TFIID\", \"AP-1 (ATF7/Jun and ATF7/JDP2 dimers)\"],\n    \"partners\": [\"JUN\", \"TAF12\", \"EHMT2\", \"SETDB1\", \"JDP2\", \"IRF2BP2\", \"PTP4A1\", \"MAPK9\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}