{"gene":"MAF","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":1996,"finding":"c-Maf, a basic region/leucine zipper transcription factor, directly binds a c-Maf response element (MARE) in the proximal IL-4 promoter and transactivates IL-4 expression in Th2 cells; it acts in synergy with NF-ATp to initiate endogenous IL-4 production.","method":"DNA binding assays (footprinting), reporter gene transactivation assays, ectopic expression in Th1 cells and B cells","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct DNA binding demonstrated by footprinting, transactivation confirmed by reporter assay across multiple cell types, replicated by loss-of-function studies (PMID:10403649)","pmids":["8674125"],"is_preprint":false},{"year":1999,"finding":"c-Maf is selectively required for IL-4 gene transcription in vivo; c-maf-/- CD4+ and NK T cells are markedly deficient in IL-4 production but produce normal levels of IL-13 and IgE, establishing that c-Maf's function is specific to IL-4 among Th2 cytokines.","method":"Gene knockout (c-maf-/- mice), cytokine measurement by ELISA and intracellular staining","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean loss-of-function genetic model with specific phenotypic readout, independently corroborated by PMID:8674125","pmids":["10403649"],"is_preprint":false},{"year":1999,"finding":"c-Maf is required for differentiation of lens fiber cells and crystallin gene expression; c-maf-null mice lack normal lenses due to defective fiber cell differentiation, and c-Maf transactivates crystallin gene promoters.","method":"Gene targeting/knockout (c-maf-null mice), histology, lacZ reporter for expression visualization, crystallin gene expression analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — loss-of-function in vivo with defined cellular phenotype, corroborated by three independent studies (PMID:10097114, PMID:10603348)","pmids":["10383433"],"is_preprint":false},{"year":1999,"finding":"c-Maf is required for posterior lens fiber cell elongation and crystallin gene expression in vivo; c-Maf protein binds to T-MARE sites in αA-, βB2-, and βA4-crystallin promoters, and a point mutation in the αA-crystallin promoter that abolishes promoter function also abolishes c-Maf binding.","method":"Gene targeting (Maf(lacZ) knock-in mice), recombinant protein binding to crystallin promoter T-MARE sites, reporter gene assays","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro DNA binding with mutagenesis combined with in vivo knockout phenotype","pmids":["10603348"],"is_preprint":false},{"year":1994,"finding":"c-Maf (and Nrl) bind specifically to AP-1 and CRE sites and form heterodimers with Fos and Jun in vitro; mutations in the leucine zipper or basic region inhibit heterodimer formation and DNA binding.","method":"In vitro binding assays with purified polypeptides, co-immunoprecipitation with antisera against each subunit, leucine zipper/basic region mutagenesis","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1 / Moderate — reconstituted in vitro dimerization and DNA binding with mutagenesis, single lab but multiple orthogonal methods","pmids":["8108109"],"is_preprint":false},{"year":2007,"finding":"GSK-3 phosphorylates Maf proteins (demonstrated sequentially on MafA residues S49, T53, T57, S61), triggering ubiquitination and proteasomal degradation; paradoxically, this phosphorylation also increases transcriptional activity through recruitment of the co-activator P/CAF, which in turn protects MafA from degradation.","method":"Microarray analysis, phosphorylation site mapping by mutagenesis, ubiquitination assays, co-activator (P/CAF) co-immunoprecipitation, reporter gene assays","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Moderate — sequential phosphorylation site mutagenesis, ubiquitination assays, and co-activator interaction established in one rigorous study","pmids":["18042454"],"is_preprint":false},{"year":2009,"finding":"c-Maf directly regulates IL-10 expression during Th17 polarization by binding to a MARE motif in the IL-10 promoter; retroviral transduction of c-Maf induces IL-10 in Stat6-deficient CD4 and CD8 T cells.","method":"Retroviral transduction, reporter gene assay with IL-10 promoter MARE, gene array analysis","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — retroviral gain-of-function with promoter binding evidence, single lab with two orthogonal methods","pmids":["19414776"],"is_preprint":false},{"year":2009,"finding":"c-Maf is required for F4/80 expression in macrophages in vivo; c-Maf directly binds to a half-MARE site in the F4/80 promoter to activate transcription, as shown by luciferase reporter assays and EMSA.","method":"c-Maf knockout mice (null mutant phenotype), luciferase reporter assay, EMSA","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo knockout combined with direct DNA-binding (EMSA) and reporter assays, single lab","pmids":["19539733"],"is_preprint":false},{"year":2009,"finding":"Combined MafB and c-Maf deficiency enables self-renewal of mature macrophages without loss of differentiated phenotype; this requires concomitant up-regulation of KLF4 and c-Myc, as shown by shRNA inactivation.","method":"Gene knockout (MafB/c-Maf double-deficient cells), shRNA knockdown of KLF4 and c-Myc, transplantation assay","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 / Strong — double-knockout combined with shRNA epistasis and transplantation, multiple orthogonal methods","pmids":["19892988"],"is_preprint":false},{"year":2009,"finding":"Crystal structure of MafG-DNA complex reveals that two conserved residues Arg57 and Asn61 in the basic region mediate Maf-specific recognition of the extended GC sequences flanking the MARE core, an alternative DNA recognition mechanism relative to other bZIP factors.","method":"X-ray crystallography of MafG-DNA complex","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with functional validation of specific residues; definitive structural mechanism","pmids":["19797082"],"is_preprint":false},{"year":1998,"finding":"c-Maf physically associates with c-Myb to form inhibitory complexes that repress c-Myb-dependent CD13/APN transcription in myeloid cells in a developmentally regulated manner; complex levels peak at the promyelocyte stage.","method":"Reporter gene assays, physical interaction (co-immunoprecipitation), developmental stage analysis of complex levels","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP demonstrating physical interaction with functional reporter assay, single lab","pmids":["9566892"],"is_preprint":false},{"year":1999,"finding":"c-Maf overexpression in bipotent myeloid progenitors drives monocytic differentiation followed by apoptosis, linked to c-Maf/c-Myb complex formation inhibiting c-Myb targets including Bcl-2 and CD13/APN.","method":"Inducible c-Maf overexpression in myeloid progenitor cell lines, flow cytometric lineage analysis, complex formation assays","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain-of-function with lineage and molecular readouts, extends PMID:9566892 mechanism","pmids":["10477683"],"is_preprint":false},{"year":2002,"finding":"c-Maf negatively regulates ARE-mediated detoxifying enzyme gene expression (NQO1, GST Ya) by binding to the ARE as homodimers and heterodimers with small Maf proteins, but not as heterodimers with Nrf2; the transcriptional activation domain of c-Maf is not required for this repression.","method":"Reporter gene assays, EMSA (band and supershift assays), in vitro translated protein binding, mutational analysis of ARE, deletion constructs","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro binding with mutagenesis combined with reporter assays, multiple orthogonal methods in single study","pmids":["12149651"],"is_preprint":false},{"year":2012,"finding":"c-Maf is essential for development and function of several rapidly adapting mechanoreceptor types in mice; Pacinian corpuscles are severely atrophied in c-Maf mutant mice, and humans carrying a dominant MAF mutation show reduced sensitivity to high-frequency vibration.","method":"c-Maf knockout mice (phenotypic analysis of mechanoreceptors), human genetic mutation analysis, electrophysiological measurements","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 / Strong — mouse loss-of-function with defined cellular phenotype corroborated by human dominant mutation with matching sensory phenotype","pmids":["22345400"],"is_preprint":false},{"year":2012,"finding":"c-Maf is required for development of dorsal horn laminae III/IV interneurons and for differentiation of MafA+/Ret+/GFRα2+ low-threshold mechanoreceptors in DRG, as well as for proper central and peripheral projections of mechanoreceptive DRG neurons.","method":"c-Maf conditional knockout mice, immunohistochemistry, marker gene expression analysis","journal":"The Journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean loss-of-function in vivo with defined cellular and molecular phenotypes, single lab","pmids":["22514301"],"is_preprint":false},{"year":2012,"finding":"Bcl6 and c-Maf (Maf) cooperate in human Tfh cell differentiation: Maf introduction induces IL-21 expression and CXCR5, while co-expression of Bcl6 and Maf cooperatively induces CXCR4, PD-1, and ICOS.","method":"Retroviral introduction of Bcl6 and/or Maf into primary human CD4 T cells, flow cytometry, gene expression analysis","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain-of-function in primary human cells with defined gene expression readouts, single lab","pmids":["22427637"],"is_preprint":false},{"year":2014,"finding":"Sox5 physically associates with c-Maf via the HMG domain of Sox5 and the DNA-binding domain of c-Maf; Sox5 and c-Maf together directly activate the RORγt promoter in CD4+ T cells and cooperatively induce Th17 cell differentiation downstream of Stat3 and upstream of RORγt.","method":"Retrovirus-mediated co-expression in Stat3-deficient and RORγt-deficient CD4+ T cells (epistasis), physical interaction mapping, promoter reporter assay","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — physical interaction domain mapping, genetic epistasis with multiple knockout backgrounds, and direct promoter activation, multiple orthogonal methods","pmids":["25073789"],"is_preprint":false},{"year":2017,"finding":"USP5 (deubiquitinase) interacts with c-Maf and prevents its proteasomal degradation by decreasing K48-linked polyubiquitination; the cryptic ZnF domain and C-box domain of USP5 interact with c-Maf, while the UBA1/UBA2 domain partly increases c-Maf stability; lysines K308 and K347 of c-Maf are critical for USP5-mediated deubiquitination.","method":"Co-immunoprecipitation, ubiquitination assays, domain deletion/mapping, site-directed mutagenesis (K308R, K347R), shRNA knockdown, luciferase assay","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 1 / Moderate — site-directed mutagenesis of ubiquitination sites, domain mapping of interaction, multiple orthogonal assays in single study","pmids":["28933784"],"is_preprint":false},{"year":2017,"finding":"UBE2O (ubiquitin-conjugating enzyme) interacts with c-Maf and mediates its K48-linked polyubiquitination and subsequent proteasomal degradation, reducing c-Maf transcriptional activity and cyclin D2 expression in myeloma cells.","method":"Mass spectrometry, co-immunoprecipitation, ubiquitination assays, luciferase transcriptional activity assay, shRNA/overexpression in myeloma cell lines and xenografts","journal":"Journal of hematology & oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — affinity purification/MS plus co-IP and functional assays, single lab","pmids":["28673317"],"is_preprint":false},{"year":2018,"finding":"c-MAF transcription factor is required for induction of RORγt+FOXP3+ regulatory T cells in the large intestine in response to Helicobacter hepaticus; c-MAF-deficient Treg cells fail to differentiate and produce IL-10, leading to expansion of colitogenic TH17 cells and spontaneous colitis.","method":"Conditional knockout of c-MAF in Treg compartment, colitis model, flow cytometry, cytokine measurement","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional cell-type specific knockout with defined cellular and molecular phenotypes, high-impact venue","pmids":["29414937"],"is_preprint":false},{"year":2018,"finding":"c-Maf is a negative regulator of IL-2 transcription in CD4+ T cells; bivariate genomic footprinting identified enhanced NFAT activity in c-Maf-deficient cells; reduced RORγt expression upon c-Maf deficiency is IL-2-dependent.","method":"T cell-specific c-Maf knockout mice, in vivo disease models (malaria, allergy, autoimmunity), bivariate genomic footprinting, cytokine and transcription factor expression analysis","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional knockout in multiple disease contexts with genomic footprinting revealing transcription factor network, multiple orthogonal methods","pmids":["29662170"],"is_preprint":false},{"year":2018,"finding":"c-Maf is an essential commitment factor for IL-17-producing γδ T cells (Tγδ17); Maf deficiency causes an absolute lineage block at the CD24+CD45RBlo γδ thymocyte stage; c-Maf promotes chromatin accessibility at Rorc and Blk while antagonizing TCF1 to prevent IFN-γ-producing γδ T cell fate.","method":"Conditional c-Maf knockout mice, ATAC-seq (chromatin accessibility), transcriptomics, flow cytometry","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional knockout with ATAC-seq chromatin profiling and transcriptomics establishing mechanistic pathway","pmids":["30538336"],"is_preprint":false},{"year":2018,"finding":"SUMOylation of c-Maf at lysine-33 attenuates its IL-4 transcriptional activity by reducing its recruitment to the Il4 promoter without altering subcellular localization or protein stability; c-Maf interacts with Ubc9 and PIAS1 (SUMO pathway enzymes).","method":"Yeast two-hybrid (interaction with Ubc9/PIAS1), in vitro and in vivo SUMOylation assays, site-directed mutagenesis (K33R), chromatin immunoprecipitation, retroviral transduction in c-Maf-deficient Th2 cells","journal":"European journal of immunology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — site-directed mutagenesis of SUMO acceptor site combined with ChIP and functional rescue, multiple orthogonal methods","pmids":["20127678"],"is_preprint":false},{"year":2018,"finding":"SUMO-defective c-Maf (K→R mutation at SUMOylation site) preferentially transactivates Il21 over Il4 by selectively inhibiting recruitment of Daxx/HDAC2 to the Il21 promoter and enhancing CBP/p300-mediated histone acetylation at that locus.","method":"Transgenic NOD mice (wild-type vs. SUMOylation-mutant c-Maf), promoter ChIP assays, pharmacological CBP/p300 inhibition","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — transgenic mouse comparison with ChIP mechanistic evidence and pharmacological validation, multiple orthogonal methods","pmids":["30059018"],"is_preprint":false},{"year":2019,"finding":"Otub1 (OTU deubiquitinase) interacts with c-Maf (identified by mass spectrometry), abrogates K48-linked polyubiquitination of c-Maf and prevents its degradation, enhancing its transcriptional activity; this activity requires Otub1 Lys71 and its N-terminus but is independent of UBE2O.","method":"Mass spectrometry identification, co-immunoprecipitation, ubiquitination assays, domain mutagenesis (Lys71), luciferase assay, shRNA knockdown, xenograft models","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1 / Moderate — MS identification plus domain mutagenesis, ubiquitination assays, and in vivo xenograft validation","pmids":["32842143"],"is_preprint":false},{"year":2019,"finding":"USP7 (deubiquitinase) interacts with c-Maf, MafA, and MafB and blocks their polyubiquitination and proteasomal degradation, thereby promoting Maf transcriptional activity and myeloma cell survival.","method":"Mass spectrometry (MafB interactome), co-immunoprecipitation, ubiquitination assays, luciferase assay, shRNA knockdown, pharmacological inhibition (P5091)","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS-based identification plus co-IP and functional assays, single lab","pmids":["31822558"],"is_preprint":false},{"year":2014,"finding":"c-MAF ubiquitination is mediated by multiple lysine residues; no single lysine alone is sufficient, but K85 and K350 together are sufficient (though not the only pair); c-MAF is also degraded by lysosomes in addition to proteasomes.","method":"Systematic lysine-to-arginine mutagenesis, cell-based ubiquitination assays, luciferase reporter assay for transcriptional activity, lysosomal inhibitor treatment","journal":"The international journal of biochemistry & cell biology","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — systematic mutagenesis with functional readouts, single lab","pmids":["25448412"],"is_preprint":false},{"year":2016,"finding":"MAF overexpression (as in t(14;16) multiple myeloma) confers innate resistance to proteasome inhibitors (bortezomib, carfilzomib) by stabilizing MAF protein; proteasome inhibitor exposure blocks GSK3β-mediated MAF degradation, increasing MAF protein stability.","method":"Cell line models with t(14;16) translocation, loss-of-function (MAF silencing) and gain-of-function (MAF overexpression), PI sensitivity assays, apoptosis/caspase assays","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal gain/loss-of-function with biochemical mechanism (GSK3β pathway), single lab","pmids":["27793878"],"is_preprint":false},{"year":2006,"finding":"c-Maf's cell-transforming activity requires transactivation through MARE (replacement of transactivation domain with VP16 enhances transformation; fusion with transcriptional repressor abolishes it); c-Maf and Jun share downstream target genes for transformation; heterodimer formation with other bZIP factors is not required for Maf-induced transformation.","method":"Chicken embryo fibroblast transformation assay, domain swap/fusion constructs (VP16 activation domain, Mxi1 repressor domain, GCN4 leucine zipper), dominant-negative Jun","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — structure-function analysis with multiple constructs in transformation assay, single lab","pmids":["16247450"],"is_preprint":false},{"year":2006,"finding":"c-Maf overexpression in T cells drives T-cell lymphoma in transgenic mice, with upregulation of cyclin D2, integrin β7, and ARK5 as downstream target genes.","method":"T-cell-specific c-Maf transgenic mice, gene expression analysis of lymphoma cells","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transgenic mouse model with target gene identification, single lab","pmids":["16424013"],"is_preprint":false},{"year":2018,"finding":"c-Maf is required for Treg specialization: it is essential for generation of RORγt+ Tregs and T follicular regulatory cells in mice, but not for adipose-resident Tregs; c-Maf is induced in Tregs by IL-6 and TGF-β.","method":"Conditional c-Maf knockout in Tregs, flow cytometric analysis of Treg subsets, cytokine stimulation experiments","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional knockout with defined cellular phenotype, single lab","pmids":["29127150"],"is_preprint":false},{"year":2019,"finding":"c-Maf-dependent intestinal Treg cells constrain microbiota-dependent TH17 and IgA responses; c-Maf deficiency in Tregs leads to dysbiosis sufficient to induce exacerbated intestinal TH17 responses upon germ-free transfer; c-Maf controls IL-10 production and prevents excessive PI3K/Akt/mTORC1 signaling in intestinal Tregs.","method":"Conditional c-Maf knockout in Treg compartment, germ-free mouse transfer experiments, cytokine and signaling pathway analysis","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional knockout plus germ-free transfer epistasis establishing mechanistic pathway in vivo","pmids":["30778241"],"is_preprint":false},{"year":2020,"finding":"c-Maf is a critical controller of immunosuppressive (M2-like) macrophage polarization in cancer; it has direct binding sites within a conserved noncoding sequence of the Csf-1r gene; c-Maf also acts as a metabolic checkpoint regulating the TCA cycle and UDP-GlcNAc biosynthesis; myeloid-specific deletion reduces tumor burden with enhanced T cell immunity.","method":"Myeloid-specific c-Maf knockout mice, ChIP (Csf-1r binding sites), metabolomics, tumor models, T cell functional assays","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional knockout in vivo with ChIP validation of direct target, metabolomic evidence of metabolic checkpoint function, multiple orthogonal methods","pmids":["31945018"],"is_preprint":false},{"year":2020,"finding":"c-Maf enforces ILC3 identity by promoting RORγt activity and type 3 effector gene expression while directly restraining T-bet expression; c-Maf and T-bet form a negative feedback loop in CCR6- ILC3s.","method":"c-Maf conditional knockout, transcriptomics, ATAC-seq (chromatin accessibility and TF motif enrichment), flow cytometry","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional knockout with ATAC-seq and transcriptomics revealing direct molecular mechanism","pmids":["31570496"],"is_preprint":false},{"year":2021,"finding":"MAF directly activates β/γ-crystallin gene promoters and activates TGF-β1-Smad signaling to upregulate crystallins in high myopia lenses; mechanistic studies identify a MAF-TGF-β1-crystallin axis.","method":"Mechanistic studies in myopia mouse models and human high myopic lenses, promoter activation assays, Smad signaling analysis","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct promoter activation and signaling pathway evidence in mouse models, single lab","pmids":["33833231"],"is_preprint":false},{"year":2021,"finding":"c-Maf is a critical perinatal transcriptional switch for hepatic sinusoidal endothelial cell identity; endothelium-restricted c-Maf deletion disrupts liver sinusoidal development, expands postnatal hematopoiesis, and increases pro-fibrotic sensitivity; enforced c-Maf expression in generic human endothelial cells activates a liver sinusoidal transcriptional program.","method":"Endothelium-restricted c-Maf knockout mice, scRNA-seq, enforced c-Maf overexpression in human endothelial cells, functional hepatocyte co-culture assays","journal":"Cell stem cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional knockout plus gain-of-function in human cells with scRNA-seq, multiple orthogonal methods","pmids":["35364013"],"is_preprint":false},{"year":2021,"finding":"c-MAF-dependent perivascular macrophages in white adipose tissue regulate metabolic syndrome; conditional c-MAF deletion in macrophage lineages ablates perivascular macrophages and alters muscularis macrophage program, with macrophage-specific c-MAF deletion improving metabolic parameters under high-fat diet.","method":"Macrophage lineage-specific c-MAF conditional knockout, single-cell RNA-seq, metabolic phenotyping (glucose tolerance, weight, adipose inflammation)","journal":"Science immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional knockout with scRNA-seq and defined metabolic phenotype, multiple orthogonal methods","pmids":["34597123"],"is_preprint":false},{"year":2022,"finding":"c-Maf is required for optimal type 2 cytokine production and memory-like (trained) responses in group-2 innate lymphoid cells (ILC2s); c-Maf is induced by IL-33/IL-25 and allergen (papain) exposure; c-Maf-deficient mouse and human ILC2s fail to show trained immunity upon repeated challenge.","method":"c-Maf deletion in ILCs (mouse), transcriptomic analysis, knockdown in human ILC2s, repeated allergen challenge model","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mouse and human loss-of-function with transcriptomic and functional readouts, single lab","pmids":["35467036"],"is_preprint":false},{"year":2024,"finding":"TGF-β induces CXCR5 expression in mouse CD4+ T cells to drive TFH differentiation via c-Maf, but independently of Bcl6; c-Maf acts as a switch factor for TFH versus TH17 cell fates in TGF-β-rich environments both in vitro and in vivo.","method":"In vitro TFH differentiation protocol, Bcl6 and c-Maf conditional knockouts, CXCR5 expression analysis, in vivo immunization experiments","journal":"Science immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional knockouts establishing epistasis (TFH independent of Bcl6 but dependent on c-Maf), in vitro and in vivo validation","pmids":["38427718"],"is_preprint":false},{"year":2018,"finding":"Maf acts downstream of Neuregulin1 (Nrg1) signaling in Schwann cells to directly bind enhancers of cholesterol synthesis genes, promoting cholesterol biosynthesis required for myelination; Nrg1-calmodulin-dependent kinases regulate Maf transcription, while Nrg1-MAPK signaling stabilizes Maf protein.","method":"Genetic ablation of Maf in Schwann cells, ChIP (Maf binding to cholesterol synthesis gene enhancers), epistasis with Nrg1 signaling, kinase inhibition experiments","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional knockout plus ChIP establishing direct binding, genetic epistasis with Nrg1 pathway, multiple orthogonal methods","pmids":["29748249"],"is_preprint":false},{"year":2007,"finding":"c-maf is required for AhR-dependent β7-integrin induction in macrophages by benzo(a)pyrene; c-Maf binds to a Maf-responsive element in the β7-integrin promoter (demonstrated by ChIP and EMSA), and c-maf knockdown impairs induction.","method":"shRNA knockdown of c-maf, chromatin immunoprecipitation (ChIP), EMSA, chemical inhibition of AhR","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct DNA binding shown by ChIP and EMSA combined with knockdown, single lab","pmids":["17490615"],"is_preprint":false},{"year":2010,"finding":"IL-2 induces STAT5 binding to specific sites in the c-MAF promoter, thereby promoting c-MAF expression in human CD4 T cells; IL-2 and IL-6 synergistically induce c-MAF expression; blockade of IL-2 signaling (daclizumab or JAK3 inhibitor) reduces c-MAF and IL-4 expression.","method":"Chromatin immunoprecipitation (STAT5 binding to c-MAF promoter), cytokine stimulation experiments, pharmacological inhibition (daclizumab, R333), primary human CD4 T cells","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP establishes direct STAT5 binding to c-MAF promoter with functional validation, single lab","pmids":["21876034"],"is_preprint":false},{"year":2007,"finding":"c-Maf interacts with c-Myb in CD4 T cells to reduce Bcl-2 expression and increase susceptibility to apoptosis; c-Maf/c-Myb complex formation is enhanced following TCR engagement and prevents c-Myb binding to the Bcl-2 promoter; Bcl-2 overexpression corrects the apoptosis defect.","method":"c-Maf transgenic mice, co-immunoprecipitation, chromatin immunoprecipitation (c-Myb at Bcl-2 promoter), reporter gene assay, Bcl-2 rescue transgene","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP for physical interaction, ChIP for promoter occupancy, and Bcl-2 rescue experiment, single lab","pmids":["17823980"],"is_preprint":false},{"year":2001,"finding":"Maf's transforming activity requires transactivation through MARE; heterodimer formation with other bZIP factors is dispensable for transformation; Maf and Jun share downstream MARE-regulated target genes for cell transformation, as a Jun dominant-negative construct blocks both Jun- and Maf-induced transformation.","method":"Chicken embryo fibroblast transformation assays, domain swap constructs (VP16 activator, Mxi1 repressor, GCN4 leucine zipper), dominant-negative Jun constructs","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — structure-function transformation assays with multiple constructs establishing shared target gene mechanism, single lab","pmids":["11461901"],"is_preprint":false},{"year":2023,"finding":"Intestinal commensal-specific Th17 cells acquire an anti-inflammatory, IL-10-producing phenotype driven by c-MAF; these cells suppress effector T cell activity in an IL-10-dependent and c-MAF-dependent manner in vitro and in vivo.","method":"Conditional c-MAF deletion in T cells, antigen-specific T cell tracking, in vitro and in vivo suppression assays, cytokine measurement","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional knockout with both in vitro and in vivo functional suppression assays, replicated across multiple experimental settings","pmids":["38039966"],"is_preprint":false},{"year":2006,"finding":"c-Maf regulates the alphaA-crystallin locus through binding to the promoter and distal control regions (DCR3), associated with broad histone H3K9-hyperacetylation and increased abundance of chromatin remodeling enzymes Brg1 and Snf2h at the locus.","method":"Chromatin immunoprecipitation (ChIP) for c-Maf, CREB, Pax6 binding, histone acetylation marks, and chromatin remodeling enzymes; reporter gene assays in lens explants","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP across multiple targets at the alphaA-crystallin locus with functional reporter assays, single lab","pmids":["16675956"],"is_preprint":false},{"year":2019,"finding":"CRISPR-mediated deletion of MAF abrogates the ability of PD-1hiCXCR5- T peripheral helper (Tph) cells to induce memory B cell differentiation into plasmablasts in vitro.","method":"CRISPR-Cas9 deletion of MAF in human Tph cells, B cell differentiation co-culture assay","journal":"JCI insight","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR loss-of-function with defined functional readout in human primary cells, single lab","pmids":["31536480"],"is_preprint":false},{"year":2015,"finding":"MAF and MAFB are necessary and sufficient for epidermal progenitor differentiation; MAF:MAFB regulate 393 genes including downstream transcription factors GRHL3, ZNF750, KLF4, and PRDM1; ChIP-seq confirms MAF:MAFB binding to these TF gene loci.","method":"ChIP-seq (MAF:MAFB binding genome-wide), siRNA knockdown and overexpression, kinetic transcriptome analysis, organotypic epidermal regeneration","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP-seq combined with necessary and sufficient functional tests in primary human epidermal cells, multiple orthogonal methods","pmids":["25805135"],"is_preprint":false}],"current_model":"c-MAF is a basic leucine zipper (bZIP) transcription factor that binds Maf recognition elements (MAREs) as homodimers or heterodimers (with Fos, Jun, NF-AT, Sox5, or small Maf proteins), directly activating or repressing target genes across diverse tissues; it is the essential Th2-specific transactivator of IL-4, a selective inducer of IL-10 and IL-21 in multiple T cell and innate lymphoid cell subsets, a determinant of lens fiber cell differentiation and crystallin gene expression, a regulator of macrophage identity (F4/80, M2 polarization, perivascular identity), a specifier of mechanoreceptor and interneuron development, and a myeloma oncogene whose stability is controlled by GSK-3-mediated phosphorylation-dependent ubiquitination countered by deubiquitinases USP5, USP7, and Otub1, and by SUMOylation at K33 which selectively attenuates IL-4 (but not IL-21) transactivation."},"narrative":{"mechanistic_narrative":"MAF (c-Maf) is a basic region/leucine zipper transcription factor that binds Maf recognition elements (MAREs) to control cell-type-specific gene programs across the immune system, lens, neural, vascular, and myeloid lineages [PMID:8674125, PMID:10383433]. Maf-specific DNA recognition is structurally encoded by conserved basic-region residues (Arg57, Asn61) that read the extended GC sequences flanking the MARE core [PMID:19797082], and MAF can act as a homodimer or heterodimerize with Fos and Jun at AP-1/CRE-related sites [PMID:8108109]. In the immune system MAF is the IL-4-specific transactivator that initiates Th2 cytokine production in synergy with NF-ATp [PMID:8674125, PMID:10403649], and it directly drives IL-10 and IL-21 programs to enforce regulatory and follicular helper phenotypes: it induces intestinal RORγt+ Treg and IL-10-producing commensal-specific Th17 cells that constrain colitogenic responses [PMID:29414937, PMID:38039966, PMID:30778241], cooperates with Sox5 to activate the RORγt promoter for Th17 differentiation [PMID:25073789], and serves as a Bcl6-independent switch factor for TFH versus TH17 fate in TGF-β-rich settings [PMID:38427718]. MAF specifies γδ17 and ILC3/ILC2 effector identity by remodeling chromatin at Rorc while antagonizing the opposing TCF1/T-bet fate [PMID:30538336, PMID:31570496]. Beyond immunity, MAF directs lens fiber cell differentiation by binding T-MARE sites in crystallin promoters [PMID:10383433, PMID:10603348, PMID:16675956], controls macrophage identity, M2/perivascular polarization, and metabolic programming via direct CSF1R regulation [PMID:19539733, PMID:31945018, PMID:34597123], specifies mechanoreceptor and dorsal-horn interneuron development [PMID:22345400, PMID:22514301], acts downstream of Neuregulin1 to drive Schwann-cell cholesterol biosynthesis for myelination [PMID:29748249], and sets hepatic sinusoidal endothelial and epidermal progenitor identity [PMID:35364013, PMID:25805135]. As a myeloma oncogene, MAF transforming activity requires MARE-dependent transactivation [PMID:11461901, PMID:16247450], and its abundance is governed by a phosphodegron axis: GSK-3 phosphorylation triggers ubiquitination and proteasomal degradation [PMID:18042454], opposed by the deubiquitinases USP5, USP7, and Otub1 [PMID:28933784, PMID:31822558, PMID:32842143] and promoted by the E2 enzyme UBE2O [PMID:28673317]; SUMOylation at K33 selectively attenuates IL-4 (but not IL-21) transactivation by altering promoter recruitment and coactivator engagement [PMID:20127678, PMID:30059018]. A dominant human MAF mutation causes reduced high-frequency vibration sensitivity, linking MAF to mechanosensory function [PMID:22345400].","teleology":[{"year":1994,"claim":"Established the biochemical basis of MAF as a bZIP factor capable of dimerizing with AP-1 family proteins, defining its DNA-binding modality.","evidence":"In vitro binding/co-IP with purified polypeptides and leucine-zipper/basic-region mutagenesis","pmids":["8108109"],"confidence":"High","gaps":["Did not address in vivo target genes","Cellular function not assigned"]},{"year":1996,"claim":"Identified the first direct MAF target and function: it answered how Th2 cells transcriptionally activate IL-4, establishing MAF as a MARE-binding transactivator acting with NF-ATp.","evidence":"Footprinting, reporter transactivation, ectopic expression in Th1/B cells","pmids":["8674125"],"confidence":"High","gaps":["Specificity among Th2 cytokines not yet defined","In vivo requirement not tested"]},{"year":1999,"claim":"Genetic loss-of-function resolved whether MAF is specifically required for IL-4 in vivo and revealed a parallel essential role in lens fiber differentiation, defining its tissue breadth.","evidence":"c-maf-null mice with cytokine readouts; lens histology and crystallin promoter binding/reporter assays","pmids":["10403649","10383433","10603348"],"confidence":"High","gaps":["Mechanism of crystallin locus activation not detailed","How IL-4 specificity versus IL-13 is enforced unresolved"]},{"year":2006,"claim":"Defined how MAF transforms cells, showing transformation requires MARE-dependent transactivation rather than obligate heterodimerization, and identified shared MAF/Jun target genes.","evidence":"Chicken embryo fibroblast transformation with domain-swap and dominant-negative Jun constructs; T-cell transgenic lymphoma model","pmids":["11461901","16247450","16424013"],"confidence":"Medium","gaps":["Direct oncogenic target genes in human myeloma not yet mapped","Single-lab transformation assays"]},{"year":2009,"claim":"Provided the structural mechanism for MARE recognition, explaining how Maf-family basic-region residues read extended flanking GC sequences distinct from other bZIP factors.","evidence":"X-ray crystallography of MafG-DNA complex with functional residue validation","pmids":["19797082"],"confidence":"High","gaps":["Structure solved for MafG, not c-Maf directly","Heterodimer DNA complexes not crystallized"]},{"year":2009,"claim":"Extended MAF's transcriptional repertoire to IL-10 and macrophage identity, broadening it from a Th2-specific factor to a multilineage regulator.","evidence":"Retroviral transduction with promoter MARE reporters (IL-10); knockout plus EMSA/reporter (F4/80); double-knockout with shRNA epistasis (macrophage self-renewal)","pmids":["19414776","19539733","19892988"],"confidence":"High","gaps":["Direct genome-wide targets not yet defined","Relationship between repressive and activating modes unclear"]},{"year":2012,"claim":"Established MAF's role in nervous-system development and human sensory function, linking it to mechanoreceptor and interneuron differentiation and a dominant human vibration-sensitivity phenotype.","evidence":"Constitutive and conditional knockout mice with electrophysiology and IHC; human dominant MAF mutation analysis","pmids":["22345400","22514301"],"confidence":"High","gaps":["Direct neuronal target genes not identified","Molecular basis of the dominant human allele not dissected"]},{"year":2014,"claim":"Identified MAF cofactors and a key post-translational stabilizer, showing Sox5 cooperation for Th17 fate and USP5 deubiquitination controlling MAF abundance.","evidence":"Domain-mapped physical interaction with Sox5 plus epistasis; co-IP, ubiquitination assays, and site-directed mutagenesis (K308/K347) for USP5; systematic lysine mutagenesis of degradation sites","pmids":["25073789","28933784","25448412"],"confidence":"High","gaps":["Full E3 ligase responsible for K48 chains not fully defined","Lysosomal versus proteasomal balance unresolved"]},{"year":2018,"claim":"Defined MAF as a master regulator of regulatory and effector lymphocyte programs and dissected SUMOylation as a switch tuning IL-4 versus IL-21 output.","evidence":"Conditional knockouts across Treg, γδ17, and disease contexts with ATAC-seq/genomic footprinting; K33 SUMO-site mutagenesis with ChIP and transgenic mice","pmids":["29414937","29662170","30538336","29127150","20127678","30059018"],"confidence":"High","gaps":["How a single factor selects opposing programs context-dependently is incompletely mapped","Coactivator/corepressor switching at additional loci not characterized"]},{"year":2019,"claim":"Expanded MAF's deubiquitinase network (Otub1, USP7) and its oncogenic stabilization, while defining intestinal Treg metabolic control and Tph helper function.","evidence":"MS, co-IP, ubiquitination and domain mutagenesis, xenografts (DUBs); germ-free transfer epistasis (intestinal Treg); CRISPR deletion in human Tph cells","pmids":["32842143","31822558","30778241","31536480","31570496"],"confidence":"High","gaps":["Relative contributions of USP5/USP7/Otub1 in vivo unresolved","Direct ILC3 target genes beyond Rorc/T-bet not fully mapped"]},{"year":2020,"claim":"Defined MAF as a metabolic and identity checkpoint in tissue macrophages and endothelium, including direct CSF1R regulation and immunosuppressive polarization in cancer.","evidence":"Myeloid- and endothelium-restricted knockouts with ChIP, metabolomics, scRNA-seq, and tumor models","pmids":["31945018","34597123","35364013"],"confidence":"High","gaps":["Upstream signals inducing MAF in each niche differ and are not unified","Direct metabolic-gene targets only partially mapped"]},{"year":2024,"claim":"Resolved MAF as the Bcl6-independent TFH/TH17 switch factor in TGF-β environments, clarifying its decision-making logic in helper T cell fate.","evidence":"In vitro TFH differentiation and in vivo immunization with Bcl6 and c-Maf conditional knockouts","pmids":["38427718"],"confidence":"High","gaps":["Genome-wide CXCR5/TFH targets of MAF not detailed","Interplay with SUMO/DUB regulation in this context untested"]},{"year":null,"claim":"How a single MARE-binding factor is wired to select among opposing transcriptional programs (e.g., activation vs repression, IL-4 vs IL-21, RORγt vs T-bet) in a cell-type-specific manner remains the central open question.","evidence":"","pmids":[],"confidence":"High","gaps":["No unified model of context-dependent cofactor/PTM selection","Genome-wide direct target maps incomplete across most lineages"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,2,6,7,16,32,47]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[3,4,9,12,40,45]},{"term_id":"GO:0140097","term_label":"catalytic activity, acting on DNA","supporting_discovery_ids":[9]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[22,45]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,1,6,19,21,33]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,3,9,47]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[2,13,35,47]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[5,17,24,25]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[27,28,29]}],"complexes":[],"partners":["FOS","JUN","MYB","SOX5","BCL6","USP7","OTUB1","USP5"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O75444","full_name":"Transcription factor Maf","aliases":["Proto-oncogene c-Maf","V-maf musculoaponeurotic fibrosarcoma oncogene homolog"],"length_aa":373,"mass_kda":38.5,"function":"Acts as a transcriptional activator or repressor. Involved in embryonic lens fiber cell development. Recruits the transcriptional coactivators CREBBP and/or EP300 to crystallin promoters leading to up-regulation of crystallin gene during lens fiber cell differentiation. Activates the expression of IL4 in T helper 2 (Th2) cells. Increases T-cell susceptibility to apoptosis by interacting with MYB and decreasing BCL2 expression. Together with PAX6, transactivates strongly the glucagon gene promoter through the G1 element. Activates transcription of the CD13 proximal promoter in endothelial cells. Represses transcription of the CD13 promoter in early stages of myelopoiesis by affecting the ETS1 and MYB cooperative interaction. Involved in the initial chondrocyte terminal differentiation and the disappearance of hypertrophic chondrocytes during endochondral bone development. Binds to the sequence 5'-[GT]G[GC]N[GT]NCTCAGNN-3' in the L7 promoter. Binds to the T-MARE (Maf response element) sites of lens-specific alpha- and beta-crystallin gene promoters. Binds element G1 on the glucagon promoter. Binds an AT-rich region adjacent to the TGC motif (atypical Maf response element) in the CD13 proximal promoter in endothelial cells (By similarity). When overexpressed, represses anti-oxidant response element (ARE)-mediated transcription. Involved either as an oncogene or as a tumor suppressor, depending on the cell context. Binds to the ARE sites of detoxifying enzyme gene promoters","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/O75444/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MAF","classification":"Not Classified","n_dependent_lines":19,"n_total_lines":1208,"dependency_fraction":0.015728476821192054},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/MAF","total_profiled":1310},"omim":[{"mim_id":"621376","title":"CILIA- AND FLAGELLA-ASSOCIATED PROTEIN 206; CFAP206","url":"https://www.omim.org/entry/621376"},{"mim_id":"620931","title":"IMMUNODEFICIENCY 126, SUSCEPTIBILITY TO; IMD126","url":"https://www.omim.org/entry/620931"},{"mim_id":"620923","title":"PARKINSON DISEASE 26, AUTOSOMAL DOMINANT, SUSCEPTIBILITY TO; PARK26","url":"https://www.omim.org/entry/620923"},{"mim_id":"620718","title":"OROFACIODIGITAL SYNDROME XX; OFD20","url":"https://www.omim.org/entry/620718"},{"mim_id":"620635","title":"CARDIOMYOPATHY, DILATED, 2J; CMD2J","url":"https://www.omim.org/entry/620635"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Nuclear bodies","reliability":"Approved"},{"location":"Golgi apparatus","reliability":"Additional"},{"location":"Vesicles","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/MAF"},"hgnc":{"alias_symbol":["c-MAF"],"prev_symbol":[]},"alphafold":{"accession":"O75444","domains":[{"cath_id":"1.20.5.170","chopping":"258-353","consensus_level":"medium","plddt":96.1322,"start":258,"end":353}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O75444","model_url":"https://alphafold.ebi.ac.uk/files/AF-O75444-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O75444-F1-predicted_aligned_error_v6.png","plddt_mean":59.34},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MAF","jax_strain_url":"https://www.jax.org/strain/search?query=MAF"},"sequence":{"accession":"O75444","fasta_url":"https://rest.uniprot.org/uniprotkb/O75444.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O75444/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O75444"}},"corpus_meta":[{"pmid":"8674125","id":"PMC_8674125","title":"The proto-oncogene c-maf is responsible for tissue-specific expression of interleukin-4.","date":"1996","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/8674125","citation_count":541,"is_preprint":false},{"pmid":"29414937","id":"PMC_29414937","title":"c-MAF-dependent regulatory T cells mediate immunological tolerance to a gut pathobiont.","date":"2018","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/29414937","citation_count":426,"is_preprint":false},{"pmid":"12234662","id":"PMC_12234662","title":"Integration and diversity of the regulatory network composed of Maf and CNC families of transcription factors.","date":"2002","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/12234662","citation_count":393,"is_preprint":false},{"pmid":"10403649","id":"PMC_10403649","title":"The transcription factor c-Maf controls the production of interleukin-4 but not other Th2 cytokines.","date":"1999","source":"Immunity","url":"https://pubmed.ncbi.nlm.nih.gov/10403649","citation_count":318,"is_preprint":false},{"pmid":"22427637","id":"PMC_22427637","title":"Bcl6 and Maf cooperate to instruct human follicular helper CD4 T cell differentiation.","date":"2012","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/22427637","citation_count":300,"is_preprint":false},{"pmid":"31536480","id":"PMC_31536480","title":"PD-1hiCXCR5- T peripheral helper cells promote B cell responses in lupus via MAF and IL-21.","date":"2019","source":"JCI insight","url":"https://pubmed.ncbi.nlm.nih.gov/31536480","citation_count":249,"is_preprint":false},{"pmid":"9224592","id":"PMC_9224592","title":"The world according to Maf.","date":"1997","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/9224592","citation_count":237,"is_preprint":false},{"pmid":"19892988","id":"PMC_19892988","title":"MafB/c-Maf deficiency enables self-renewal of differentiated functional macrophages.","date":"2009","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/19892988","citation_count":237,"is_preprint":false},{"pmid":"10383433","id":"PMC_10383433","title":"Regulation of lens fiber cell differentiation by transcription factor c-Maf.","date":"1999","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10383433","citation_count":215,"is_preprint":false},{"pmid":"10603348","id":"PMC_10603348","title":"Regulation of mouse lens fiber cell development and differentiation by the Maf gene.","date":"2000","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/10603348","citation_count":205,"is_preprint":false},{"pmid":"19414776","id":"PMC_19414776","title":"c-Maf regulates IL-10 expression during Th17 polarization.","date":"2009","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/19414776","citation_count":200,"is_preprint":false},{"pmid":"10097114","id":"PMC_10097114","title":"Requirement for the c-Maf transcription factor in crystallin gene regulation and lens development.","date":"1999","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/10097114","citation_count":200,"is_preprint":false},{"pmid":"27058431","id":"PMC_27058431","title":"Small Maf proteins (MafF, MafG, MafK): History, structure and function.","date":"2016","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/27058431","citation_count":199,"is_preprint":false},{"pmid":"8108109","id":"PMC_8108109","title":"Maf and Nrl can bind to AP-1 sites and form heterodimers with Fos and Jun.","date":"1994","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/8108109","citation_count":172,"is_preprint":false},{"pmid":"25805135","id":"PMC_25805135","title":"A LncRNA-MAF:MAFB transcription factor network regulates epidermal differentiation.","date":"2015","source":"Developmental cell","url":"https://pubmed.ncbi.nlm.nih.gov/25805135","citation_count":162,"is_preprint":false},{"pmid":"30778241","id":"PMC_30778241","title":"c-Maf-dependent Treg cell control of intestinal TH17 cells and IgA establishes host-microbiota homeostasis.","date":"2019","source":"Nature immunology","url":"https://pubmed.ncbi.nlm.nih.gov/30778241","citation_count":154,"is_preprint":false},{"pmid":"31945018","id":"PMC_31945018","title":"Transcription factor c-Maf is a checkpoint that programs macrophages in lung cancer.","date":"2020","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/31945018","citation_count":148,"is_preprint":false},{"pmid":"22345400","id":"PMC_22345400","title":"The transcription factor c-Maf controls touch receptor development and function.","date":"2012","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/22345400","citation_count":142,"is_preprint":false},{"pmid":"18201722","id":"PMC_18201722","title":"Small Maf proteins in mammalian gene control: mere dimerization partners or dynamic transcriptional regulators?","date":"2007","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/18201722","citation_count":131,"is_preprint":false},{"pmid":"22721719","id":"PMC_22721719","title":"The small MAF transcription factors MAFF, MAFG and MAFK: current knowledge and perspectives.","date":"2012","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/22721719","citation_count":127,"is_preprint":false},{"pmid":"29662170","id":"PMC_29662170","title":"c-Maf controls immune responses by regulating disease-specific gene networks and repressing IL-2 in CD4+ T cells.","date":"2018","source":"Nature immunology","url":"https://pubmed.ncbi.nlm.nih.gov/29662170","citation_count":124,"is_preprint":false},{"pmid":"25073789","id":"PMC_25073789","title":"Sox5 and c-Maf cooperatively induce Th17 cell differentiation via RORγt induction as downstream targets of Stat3.","date":"2014","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/25073789","citation_count":109,"is_preprint":false},{"pmid":"7706310","id":"PMC_7706310","title":"Activity and expression of murine small Maf family protein MafK.","date":"1995","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/7706310","citation_count":106,"is_preprint":false},{"pmid":"30538336","id":"PMC_30538336","title":"The transcription factor c-Maf is essential for the commitment of IL-17-producing γδ T cells.","date":"2018","source":"Nature immunology","url":"https://pubmed.ncbi.nlm.nih.gov/30538336","citation_count":106,"is_preprint":false},{"pmid":"18042454","id":"PMC_18042454","title":"GSK-3-mediated phosphorylation enhances Maf-transforming activity.","date":"2007","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/18042454","citation_count":99,"is_preprint":false},{"pmid":"16675956","id":"PMC_16675956","title":"Regulation of alphaA-crystallin via Pax6, c-Maf, CREB and a broad domain of lens-specific chromatin.","date":"2006","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/16675956","citation_count":93,"is_preprint":false},{"pmid":"9038383","id":"PMC_9038383","title":"Rat maf related genes: specific expression in chondrocytes, lens and spinal cord.","date":"1997","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/9038383","citation_count":88,"is_preprint":false},{"pmid":"38039966","id":"PMC_38039966","title":"Intestinal microbiota-specific Th17 cells possess regulatory properties and suppress effector T cells via c-MAF and IL-10.","date":"2023","source":"Immunity","url":"https://pubmed.ncbi.nlm.nih.gov/38039966","citation_count":82,"is_preprint":false},{"pmid":"30201991","id":"PMC_30201991","title":"An immunoregulatory and tissue-residency program modulated by c-MAF in human TH17 cells.","date":"2018","source":"Nature immunology","url":"https://pubmed.ncbi.nlm.nih.gov/30201991","citation_count":81,"is_preprint":false},{"pmid":"32281173","id":"PMC_32281173","title":"CncC/Maf-mediated xenobiotic response pathway in insects.","date":"2020","source":"Archives of insect biochemistry and physiology","url":"https://pubmed.ncbi.nlm.nih.gov/32281173","citation_count":79,"is_preprint":false},{"pmid":"28933784","id":"PMC_28933784","title":"Inhibition of the deubiquitinase USP5 leads to c-Maf protein degradation and myeloma cell apoptosis.","date":"2017","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/28933784","citation_count":75,"is_preprint":false},{"pmid":"9566892","id":"PMC_9566892","title":"c-Maf interacts with c-Myb to regulate transcription of an early myeloid gene during differentiation.","date":"1998","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/9566892","citation_count":72,"is_preprint":false},{"pmid":"17569705","id":"PMC_17569705","title":"Multiple mechanisms and functions of maf transcription factors in the regulation of tissue-specific genes.","date":"2007","source":"Journal of biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/17569705","citation_count":71,"is_preprint":false},{"pmid":"12149651","id":"PMC_12149651","title":"c-Maf negatively regulates ARE-mediated detoxifying enzyme genes expression and anti-oxidant induction.","date":"2002","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/12149651","citation_count":69,"is_preprint":false},{"pmid":"10477683","id":"PMC_10477683","title":"c-Maf induces monocytic differentiation and apoptosis in bipotent myeloid progenitors.","date":"1999","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/10477683","citation_count":69,"is_preprint":false},{"pmid":"28496444","id":"PMC_28496444","title":"The Transcription Factor c-Maf Promotes the Differentiation of Follicular Helper T Cells.","date":"2017","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/28496444","citation_count":69,"is_preprint":false},{"pmid":"33833231","id":"PMC_33833231","title":"Aberrant TGF-β1 signaling activation by MAF underlies pathological lens growth in high myopia.","date":"2021","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/33833231","citation_count":68,"is_preprint":false},{"pmid":"19797082","id":"PMC_19797082","title":"Structural basis of alternative DNA recognition by Maf transcription factors.","date":"2009","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/19797082","citation_count":68,"is_preprint":false},{"pmid":"16424013","id":"PMC_16424013","title":"Overexpression of c-Maf contributes to T-cell lymphoma in both mice and human.","date":"2006","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/16424013","citation_count":66,"is_preprint":false},{"pmid":"31570496","id":"PMC_31570496","title":"c-Maf regulates the plasticity of group 3 innate lymphoid cells by restraining the type 1 program.","date":"2020","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/31570496","citation_count":65,"is_preprint":false},{"pmid":"32512455","id":"PMC_32512455","title":"Xenobiotic transcription factors CncC and maf regulate expression of CYP321A16 and CYP332A1 that mediate chlorpyrifos resistance in Spodoptera exigua.","date":"2020","source":"Journal of hazardous materials","url":"https://pubmed.ncbi.nlm.nih.gov/32512455","citation_count":62,"is_preprint":false},{"pmid":"29314435","id":"PMC_29314435","title":"Mutation update of transcription factor genes FOXE3, HSF4, MAF, and PITX3 causing cataracts and other developmental ocular defects.","date":"2018","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/29314435","citation_count":61,"is_preprint":false},{"pmid":"27793878","id":"PMC_27793878","title":"MAF protein mediates innate resistance to proteasome inhibition therapy in multiple myeloma.","date":"2016","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/27793878","citation_count":61,"is_preprint":false},{"pmid":"35364013","id":"PMC_35364013","title":"Specification of fetal liver endothelial progenitors to functional zonated adult sinusoids requires c-Maf induction.","date":"2022","source":"Cell stem cell","url":"https://pubmed.ncbi.nlm.nih.gov/35364013","citation_count":59,"is_preprint":false},{"pmid":"32321759","id":"PMC_32321759","title":"Malat1 Suppresses Immunity to Infection through Promoting Expression of Maf and IL-10 in Th Cells.","date":"2020","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/32321759","citation_count":58,"is_preprint":false},{"pmid":"29127150","id":"PMC_29127150","title":"Cutting Edge: c-Maf Is Required for Regulatory T Cells To Adopt RORγt+ and Follicular Phenotypes.","date":"2017","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/29127150","citation_count":56,"is_preprint":false},{"pmid":"32117317","id":"PMC_32117317","title":"c-MAF, a Swiss Army Knife for Tolerance in Lymphocytes.","date":"2020","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/32117317","citation_count":55,"is_preprint":false},{"pmid":"34597123","id":"PMC_34597123","title":"c-MAF-dependent perivascular macrophages regulate diet-induced metabolic syndrome.","date":"2021","source":"Science immunology","url":"https://pubmed.ncbi.nlm.nih.gov/34597123","citation_count":52,"is_preprint":false},{"pmid":"14991699","id":"PMC_14991699","title":"Roles of Maf family proteins in lens development.","date":"2004","source":"Developmental dynamics : an official publication of the American Association of Anatomists","url":"https://pubmed.ncbi.nlm.nih.gov/14991699","citation_count":52,"is_preprint":false},{"pmid":"32842143","id":"PMC_32842143","title":"Targeting the Otub1/c-Maf axis for the treatment of multiple myeloma.","date":"2021","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/32842143","citation_count":51,"is_preprint":false},{"pmid":"30699346","id":"PMC_30699346","title":"Mafb and c-Maf Have Prenatal Compensatory and Postnatal Antagonistic Roles in Cortical Interneuron Fate and Function.","date":"2019","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/30699346","citation_count":49,"is_preprint":false},{"pmid":"16247450","id":"PMC_16247450","title":"Cell context reveals a dual role for Maf in oncogenesis.","date":"2006","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/16247450","citation_count":48,"is_preprint":false},{"pmid":"9375588","id":"PMC_9375588","title":"Differential expression of maf-1 and maf-2 genes in the developing rat lens.","date":"1997","source":"Investigative ophthalmology & visual science","url":"https://pubmed.ncbi.nlm.nih.gov/9375588","citation_count":47,"is_preprint":false},{"pmid":"26719333","id":"PMC_26719333","title":"Regulation of c-Maf and αA-Crystallin in Ocular Lens by Fibroblast Growth Factor Signaling.","date":"2015","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/26719333","citation_count":44,"is_preprint":false},{"pmid":"34403373","id":"PMC_34403373","title":"Circular RNA cia-MAF drives self-renewal and metastasis of liver tumor-initiating cells via transcription factor MAFF.","date":"2021","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/34403373","citation_count":44,"is_preprint":false},{"pmid":"35343082","id":"PMC_35343082","title":"The IL-21-TET2-AIM2-c-MAF pathway drives the T follicular helper cell response in lupus-like disease.","date":"2022","source":"Clinical and translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/35343082","citation_count":43,"is_preprint":false},{"pmid":"31822558","id":"PMC_31822558","title":"The deubiquitinase USP7 stabilizes Maf proteins to promote myeloma cell survival.","date":"2019","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/31822558","citation_count":43,"is_preprint":false},{"pmid":"28673317","id":"PMC_28673317","title":"The ubiquitin-conjugating enzyme UBE2O modulates c-Maf stability and induces myeloma cell apoptosis.","date":"2017","source":"Journal of hematology & oncology","url":"https://pubmed.ncbi.nlm.nih.gov/28673317","citation_count":42,"is_preprint":false},{"pmid":"15845902","id":"PMC_15845902","title":"Impaired IL-4 and c-Maf expression and enhanced Th1-cell development in Vav1-deficient mice.","date":"2005","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/15845902","citation_count":41,"is_preprint":false},{"pmid":"18059226","id":"PMC_18059226","title":"c-Maf expression in angioimmunoblastic T-cell lymphoma.","date":"2007","source":"The American journal of surgical pathology","url":"https://pubmed.ncbi.nlm.nih.gov/18059226","citation_count":40,"is_preprint":false},{"pmid":"31197245","id":"PMC_31197245","title":"Mebendazole elicits potent antimyeloma activity by inhibiting the USP5/c-Maf axis.","date":"2019","source":"Acta pharmacologica Sinica","url":"https://pubmed.ncbi.nlm.nih.gov/31197245","citation_count":38,"is_preprint":false},{"pmid":"31422869","id":"PMC_31422869","title":"A Thpok-Directed Transcriptional Circuitry Promotes Bcl6 and Maf Expression to Orchestrate T Follicular Helper Differentiation.","date":"2019","source":"Immunity","url":"https://pubmed.ncbi.nlm.nih.gov/31422869","citation_count":38,"is_preprint":false},{"pmid":"17129360","id":"PMC_17129360","title":"Carcinogenesis and transcriptional regulation through Maf recognition elements.","date":"2006","source":"Cancer science","url":"https://pubmed.ncbi.nlm.nih.gov/17129360","citation_count":37,"is_preprint":false},{"pmid":"22514301","id":"PMC_22514301","title":"c-Maf is required for the development of dorsal horn laminae III/IV neurons and mechanoreceptive DRG axon projections.","date":"2012","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/22514301","citation_count":35,"is_preprint":false},{"pmid":"12081646","id":"PMC_12081646","title":"Characterization of the chicken L-Maf, MafB and c-Maf in crystallin gene regulation and lens differentiation.","date":"2002","source":"Genes to cells : devoted to molecular & cellular mechanisms","url":"https://pubmed.ncbi.nlm.nih.gov/12081646","citation_count":34,"is_preprint":false},{"pmid":"24509877","id":"PMC_24509877","title":"MAF mediates crosstalk between Ras-MAPK and mTOR signaling in NF1.","date":"2014","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/24509877","citation_count":33,"is_preprint":false},{"pmid":"35359922","id":"PMC_35359922","title":"Molecular Mechanisms Driving IL-10- Producing B Cells Functions: STAT3 and c-MAF as Underestimated Central Key Regulators?","date":"2022","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/35359922","citation_count":33,"is_preprint":false},{"pmid":"32039762","id":"PMC_32039762","title":"c-Maf restrains T-bet-driven programming of CCR6-negative group 3 innate lymphoid cells.","date":"2020","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/32039762","citation_count":32,"is_preprint":false},{"pmid":"26996125","id":"PMC_26996125","title":"Differential expression patterns of MafB and c-Maf in macrophages in vivo and in vitro.","date":"2016","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/26996125","citation_count":31,"is_preprint":false},{"pmid":"9571165","id":"PMC_9571165","title":"Rat maf-related factors: the specificities of DNA binding and heterodimer formation.","date":"1998","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/9571165","citation_count":31,"is_preprint":false},{"pmid":"32452758","id":"PMC_32452758","title":"Maf and Mafb control mouse pallial interneuron fate and maturation through neuropsychiatric disease gene regulation.","date":"2020","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/32452758","citation_count":30,"is_preprint":false},{"pmid":"33312178","id":"PMC_33312178","title":"MAFB and MAF Transcription Factors as Macrophage Checkpoints for COVID-19 Severity.","date":"2020","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/33312178","citation_count":29,"is_preprint":false},{"pmid":"19539733","id":"PMC_19539733","title":"c-Maf is essential for the F4/80 expression in macrophages in vivo.","date":"2009","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/19539733","citation_count":29,"is_preprint":false},{"pmid":"26496036","id":"PMC_26496036","title":"c-Maf regulates pluripotency genes, proliferation/self-renewal, and lineage commitment in ROS-mediated senescence of human mesenchymal stem cells.","date":"2015","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/26496036","citation_count":29,"is_preprint":false},{"pmid":"25448412","id":"PMC_25448412","title":"Ubiquitination of the transcription factor c-MAF is mediated by multiple lysine residues.","date":"2014","source":"The international journal of biochemistry & cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/25448412","citation_count":29,"is_preprint":false},{"pmid":"21876034","id":"PMC_21876034","title":"IL-2 regulates expression of C-MAF in human CD4 T cells.","date":"2011","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/21876034","citation_count":28,"is_preprint":false},{"pmid":"29748249","id":"PMC_29748249","title":"Maf links Neuregulin1 signaling to cholesterol synthesis in myelinating Schwann cells.","date":"2018","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/29748249","citation_count":28,"is_preprint":false},{"pmid":"17490615","id":"PMC_17490615","title":"AhR- and c-maf-dependent induction of beta7-integrin expression in human macrophages in response to environmental polycyclic aromatic hydrocarbons.","date":"2007","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/17490615","citation_count":28,"is_preprint":false},{"pmid":"29245136","id":"PMC_29245136","title":"Small Maf functions in the maintenance of germline stem cells in the Drosophila testis.","date":"2017","source":"Redox biology","url":"https://pubmed.ncbi.nlm.nih.gov/29245136","citation_count":28,"is_preprint":false},{"pmid":"38427718","id":"PMC_38427718","title":"TGF-β specifies TFH versus TH17 cell fates in murine CD4+ T cells through c-Maf.","date":"2024","source":"Science immunology","url":"https://pubmed.ncbi.nlm.nih.gov/38427718","citation_count":27,"is_preprint":false},{"pmid":"22827438","id":"PMC_22827438","title":"The tumor suppressor p53 regulates c-Maf and Prox-1 to control lens differentiation.","date":"2012","source":"Current molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/22827438","citation_count":27,"is_preprint":false},{"pmid":"35169232","id":"PMC_35169232","title":"A Notch/STAT3-driven Blimp-1/c-Maf-dependent molecular switch induces IL-10 expression in human CD4+ T cells and is defective in Crohn´s disease patients.","date":"2022","source":"Mucosal immunology","url":"https://pubmed.ncbi.nlm.nih.gov/35169232","citation_count":27,"is_preprint":false},{"pmid":"11842109","id":"PMC_11842109","title":"c-Maf, the gammaD-crystallin Maf-responsive element and growth factor regulation.","date":"2002","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/11842109","citation_count":26,"is_preprint":false},{"pmid":"35467036","id":"PMC_35467036","title":"c-Maf enforces cytokine production and promotes memory-like responses in mouse and human type 2 innate lymphoid cells.","date":"2022","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/35467036","citation_count":26,"is_preprint":false},{"pmid":"36750911","id":"PMC_36750911","title":"The role and regulation of Maf proteins in cancer.","date":"2023","source":"Biomarker research","url":"https://pubmed.ncbi.nlm.nih.gov/36750911","citation_count":25,"is_preprint":false},{"pmid":"33627137","id":"PMC_33627137","title":"Inhibition of the Otub1/c-Maf axis by the herbal acevaltrate induces myeloma cell apoptosis.","date":"2021","source":"Cell communication and signaling : CCS","url":"https://pubmed.ncbi.nlm.nih.gov/33627137","citation_count":25,"is_preprint":false},{"pmid":"17823980","id":"PMC_17823980","title":"c-Maf interacts with c-Myb to down-regulate Bcl-2 expression and increase apoptosis in peripheral CD4 cells.","date":"2007","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/17823980","citation_count":25,"is_preprint":false},{"pmid":"11461901","id":"PMC_11461901","title":"Maf and Jun nuclear oncoproteins share downstream target genes for inducing cell transformation.","date":"2001","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11461901","citation_count":25,"is_preprint":false},{"pmid":"26122665","id":"PMC_26122665","title":"Multiple functions of Maf in the regulation of cellular development and differentiation.","date":"2015","source":"Diabetes/metabolism research and reviews","url":"https://pubmed.ncbi.nlm.nih.gov/26122665","citation_count":24,"is_preprint":false},{"pmid":"30059018","id":"PMC_30059018","title":"SUMO-defective c-Maf preferentially transactivates Il21 to exacerbate autoimmune diabetes.","date":"2018","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/30059018","citation_count":24,"is_preprint":false},{"pmid":"12938159","id":"PMC_12938159","title":"Mitogen-activated protein kinase pathway mediates DBP-maf-induced apoptosis in RAW 264.7 macrophages.","date":"2003","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12938159","citation_count":24,"is_preprint":false},{"pmid":"14998484","id":"PMC_14998484","title":"c-maf in multiple myeloma: an oncogene enhancing tumor-stroma interactions.","date":"2004","source":"Cancer cell","url":"https://pubmed.ncbi.nlm.nih.gov/14998484","citation_count":23,"is_preprint":false},{"pmid":"30899058","id":"PMC_30899058","title":"IL-27 promotes NK cell effector functions via Maf-Nrf2 pathway during influenza infection.","date":"2019","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/30899058","citation_count":23,"is_preprint":false},{"pmid":"37838657","id":"PMC_37838657","title":"Cancer stem cell-derived CHI3L1 activates the MAF/CTLA4 signaling pathway to promote immune escape in triple-negative breast cancer.","date":"2023","source":"Journal of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/37838657","citation_count":21,"is_preprint":false},{"pmid":"14521912","id":"PMC_14521912","title":"Regulation and differential expression of the c-maf gene in differentiating cultured cells.","date":"2003","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/14521912","citation_count":21,"is_preprint":false},{"pmid":"24821970","id":"PMC_24821970","title":"KLF13 cooperates with c-Maf to regulate IL-4 expression in CD4+ T cells.","date":"2014","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/24821970","citation_count":20,"is_preprint":false},{"pmid":"11147792","id":"PMC_11147792","title":"Variable effects of transgenic c-Maf on autoimmune diabetes.","date":"2001","source":"Diabetes","url":"https://pubmed.ncbi.nlm.nih.gov/11147792","citation_count":20,"is_preprint":false},{"pmid":"33762508","id":"PMC_33762508","title":"Functional analysis of large MAF transcription factors and elucidation of their relationships with human diseases.","date":"2021","source":"Experimental animals","url":"https://pubmed.ncbi.nlm.nih.gov/33762508","citation_count":20,"is_preprint":false},{"pmid":"20127678","id":"PMC_20127678","title":"SUMOylation attenuates c-Maf-dependent IL-4 expression.","date":"2010","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/20127678","citation_count":19,"is_preprint":false},{"pmid":"28604806","id":"PMC_28604806","title":"Prostaglandin E2 inhibits Tr1 cell differentiation through suppression of c-Maf.","date":"2017","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/28604806","citation_count":19,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":45842,"output_tokens":10907,"usd":0.150565,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":21729,"output_tokens":4364,"usd":0.108872,"stage2_stop_reason":"end_turn"},"total_usd":0.259437,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1996,\n      \"finding\": \"c-Maf, a basic region/leucine zipper transcription factor, directly binds a c-Maf response element (MARE) in the proximal IL-4 promoter and transactivates IL-4 expression in Th2 cells; it acts in synergy with NF-ATp to initiate endogenous IL-4 production.\",\n      \"method\": \"DNA binding assays (footprinting), reporter gene transactivation assays, ectopic expression in Th1 cells and B cells\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct DNA binding demonstrated by footprinting, transactivation confirmed by reporter assay across multiple cell types, replicated by loss-of-function studies (PMID:10403649)\",\n      \"pmids\": [\"8674125\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"c-Maf is selectively required for IL-4 gene transcription in vivo; c-maf-/- CD4+ and NK T cells are markedly deficient in IL-4 production but produce normal levels of IL-13 and IgE, establishing that c-Maf's function is specific to IL-4 among Th2 cytokines.\",\n      \"method\": \"Gene knockout (c-maf-/- mice), cytokine measurement by ELISA and intracellular staining\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean loss-of-function genetic model with specific phenotypic readout, independently corroborated by PMID:8674125\",\n      \"pmids\": [\"10403649\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"c-Maf is required for differentiation of lens fiber cells and crystallin gene expression; c-maf-null mice lack normal lenses due to defective fiber cell differentiation, and c-Maf transactivates crystallin gene promoters.\",\n      \"method\": \"Gene targeting/knockout (c-maf-null mice), histology, lacZ reporter for expression visualization, crystallin gene expression analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — loss-of-function in vivo with defined cellular phenotype, corroborated by three independent studies (PMID:10097114, PMID:10603348)\",\n      \"pmids\": [\"10383433\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"c-Maf is required for posterior lens fiber cell elongation and crystallin gene expression in vivo; c-Maf protein binds to T-MARE sites in αA-, βB2-, and βA4-crystallin promoters, and a point mutation in the αA-crystallin promoter that abolishes promoter function also abolishes c-Maf binding.\",\n      \"method\": \"Gene targeting (Maf(lacZ) knock-in mice), recombinant protein binding to crystallin promoter T-MARE sites, reporter gene assays\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro DNA binding with mutagenesis combined with in vivo knockout phenotype\",\n      \"pmids\": [\"10603348\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"c-Maf (and Nrl) bind specifically to AP-1 and CRE sites and form heterodimers with Fos and Jun in vitro; mutations in the leucine zipper or basic region inhibit heterodimer formation and DNA binding.\",\n      \"method\": \"In vitro binding assays with purified polypeptides, co-immunoprecipitation with antisera against each subunit, leucine zipper/basic region mutagenesis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstituted in vitro dimerization and DNA binding with mutagenesis, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"8108109\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"GSK-3 phosphorylates Maf proteins (demonstrated sequentially on MafA residues S49, T53, T57, S61), triggering ubiquitination and proteasomal degradation; paradoxically, this phosphorylation also increases transcriptional activity through recruitment of the co-activator P/CAF, which in turn protects MafA from degradation.\",\n      \"method\": \"Microarray analysis, phosphorylation site mapping by mutagenesis, ubiquitination assays, co-activator (P/CAF) co-immunoprecipitation, reporter gene assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — sequential phosphorylation site mutagenesis, ubiquitination assays, and co-activator interaction established in one rigorous study\",\n      \"pmids\": [\"18042454\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"c-Maf directly regulates IL-10 expression during Th17 polarization by binding to a MARE motif in the IL-10 promoter; retroviral transduction of c-Maf induces IL-10 in Stat6-deficient CD4 and CD8 T cells.\",\n      \"method\": \"Retroviral transduction, reporter gene assay with IL-10 promoter MARE, gene array analysis\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — retroviral gain-of-function with promoter binding evidence, single lab with two orthogonal methods\",\n      \"pmids\": [\"19414776\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"c-Maf is required for F4/80 expression in macrophages in vivo; c-Maf directly binds to a half-MARE site in the F4/80 promoter to activate transcription, as shown by luciferase reporter assays and EMSA.\",\n      \"method\": \"c-Maf knockout mice (null mutant phenotype), luciferase reporter assay, EMSA\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo knockout combined with direct DNA-binding (EMSA) and reporter assays, single lab\",\n      \"pmids\": [\"19539733\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Combined MafB and c-Maf deficiency enables self-renewal of mature macrophages without loss of differentiated phenotype; this requires concomitant up-regulation of KLF4 and c-Myc, as shown by shRNA inactivation.\",\n      \"method\": \"Gene knockout (MafB/c-Maf double-deficient cells), shRNA knockdown of KLF4 and c-Myc, transplantation assay\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — double-knockout combined with shRNA epistasis and transplantation, multiple orthogonal methods\",\n      \"pmids\": [\"19892988\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Crystal structure of MafG-DNA complex reveals that two conserved residues Arg57 and Asn61 in the basic region mediate Maf-specific recognition of the extended GC sequences flanking the MARE core, an alternative DNA recognition mechanism relative to other bZIP factors.\",\n      \"method\": \"X-ray crystallography of MafG-DNA complex\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with functional validation of specific residues; definitive structural mechanism\",\n      \"pmids\": [\"19797082\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"c-Maf physically associates with c-Myb to form inhibitory complexes that repress c-Myb-dependent CD13/APN transcription in myeloid cells in a developmentally regulated manner; complex levels peak at the promyelocyte stage.\",\n      \"method\": \"Reporter gene assays, physical interaction (co-immunoprecipitation), developmental stage analysis of complex levels\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP demonstrating physical interaction with functional reporter assay, single lab\",\n      \"pmids\": [\"9566892\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"c-Maf overexpression in bipotent myeloid progenitors drives monocytic differentiation followed by apoptosis, linked to c-Maf/c-Myb complex formation inhibiting c-Myb targets including Bcl-2 and CD13/APN.\",\n      \"method\": \"Inducible c-Maf overexpression in myeloid progenitor cell lines, flow cytometric lineage analysis, complex formation assays\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain-of-function with lineage and molecular readouts, extends PMID:9566892 mechanism\",\n      \"pmids\": [\"10477683\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"c-Maf negatively regulates ARE-mediated detoxifying enzyme gene expression (NQO1, GST Ya) by binding to the ARE as homodimers and heterodimers with small Maf proteins, but not as heterodimers with Nrf2; the transcriptional activation domain of c-Maf is not required for this repression.\",\n      \"method\": \"Reporter gene assays, EMSA (band and supershift assays), in vitro translated protein binding, mutational analysis of ARE, deletion constructs\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro binding with mutagenesis combined with reporter assays, multiple orthogonal methods in single study\",\n      \"pmids\": [\"12149651\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"c-Maf is essential for development and function of several rapidly adapting mechanoreceptor types in mice; Pacinian corpuscles are severely atrophied in c-Maf mutant mice, and humans carrying a dominant MAF mutation show reduced sensitivity to high-frequency vibration.\",\n      \"method\": \"c-Maf knockout mice (phenotypic analysis of mechanoreceptors), human genetic mutation analysis, electrophysiological measurements\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mouse loss-of-function with defined cellular phenotype corroborated by human dominant mutation with matching sensory phenotype\",\n      \"pmids\": [\"22345400\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"c-Maf is required for development of dorsal horn laminae III/IV interneurons and for differentiation of MafA+/Ret+/GFRα2+ low-threshold mechanoreceptors in DRG, as well as for proper central and peripheral projections of mechanoreceptive DRG neurons.\",\n      \"method\": \"c-Maf conditional knockout mice, immunohistochemistry, marker gene expression analysis\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean loss-of-function in vivo with defined cellular and molecular phenotypes, single lab\",\n      \"pmids\": [\"22514301\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Bcl6 and c-Maf (Maf) cooperate in human Tfh cell differentiation: Maf introduction induces IL-21 expression and CXCR5, while co-expression of Bcl6 and Maf cooperatively induces CXCR4, PD-1, and ICOS.\",\n      \"method\": \"Retroviral introduction of Bcl6 and/or Maf into primary human CD4 T cells, flow cytometry, gene expression analysis\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain-of-function in primary human cells with defined gene expression readouts, single lab\",\n      \"pmids\": [\"22427637\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Sox5 physically associates with c-Maf via the HMG domain of Sox5 and the DNA-binding domain of c-Maf; Sox5 and c-Maf together directly activate the RORγt promoter in CD4+ T cells and cooperatively induce Th17 cell differentiation downstream of Stat3 and upstream of RORγt.\",\n      \"method\": \"Retrovirus-mediated co-expression in Stat3-deficient and RORγt-deficient CD4+ T cells (epistasis), physical interaction mapping, promoter reporter assay\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — physical interaction domain mapping, genetic epistasis with multiple knockout backgrounds, and direct promoter activation, multiple orthogonal methods\",\n      \"pmids\": [\"25073789\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"USP5 (deubiquitinase) interacts with c-Maf and prevents its proteasomal degradation by decreasing K48-linked polyubiquitination; the cryptic ZnF domain and C-box domain of USP5 interact with c-Maf, while the UBA1/UBA2 domain partly increases c-Maf stability; lysines K308 and K347 of c-Maf are critical for USP5-mediated deubiquitination.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, domain deletion/mapping, site-directed mutagenesis (K308R, K347R), shRNA knockdown, luciferase assay\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — site-directed mutagenesis of ubiquitination sites, domain mapping of interaction, multiple orthogonal assays in single study\",\n      \"pmids\": [\"28933784\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"UBE2O (ubiquitin-conjugating enzyme) interacts with c-Maf and mediates its K48-linked polyubiquitination and subsequent proteasomal degradation, reducing c-Maf transcriptional activity and cyclin D2 expression in myeloma cells.\",\n      \"method\": \"Mass spectrometry, co-immunoprecipitation, ubiquitination assays, luciferase transcriptional activity assay, shRNA/overexpression in myeloma cell lines and xenografts\",\n      \"journal\": \"Journal of hematology & oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — affinity purification/MS plus co-IP and functional assays, single lab\",\n      \"pmids\": [\"28673317\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"c-MAF transcription factor is required for induction of RORγt+FOXP3+ regulatory T cells in the large intestine in response to Helicobacter hepaticus; c-MAF-deficient Treg cells fail to differentiate and produce IL-10, leading to expansion of colitogenic TH17 cells and spontaneous colitis.\",\n      \"method\": \"Conditional knockout of c-MAF in Treg compartment, colitis model, flow cytometry, cytokine measurement\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional cell-type specific knockout with defined cellular and molecular phenotypes, high-impact venue\",\n      \"pmids\": [\"29414937\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"c-Maf is a negative regulator of IL-2 transcription in CD4+ T cells; bivariate genomic footprinting identified enhanced NFAT activity in c-Maf-deficient cells; reduced RORγt expression upon c-Maf deficiency is IL-2-dependent.\",\n      \"method\": \"T cell-specific c-Maf knockout mice, in vivo disease models (malaria, allergy, autoimmunity), bivariate genomic footprinting, cytokine and transcription factor expression analysis\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional knockout in multiple disease contexts with genomic footprinting revealing transcription factor network, multiple orthogonal methods\",\n      \"pmids\": [\"29662170\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"c-Maf is an essential commitment factor for IL-17-producing γδ T cells (Tγδ17); Maf deficiency causes an absolute lineage block at the CD24+CD45RBlo γδ thymocyte stage; c-Maf promotes chromatin accessibility at Rorc and Blk while antagonizing TCF1 to prevent IFN-γ-producing γδ T cell fate.\",\n      \"method\": \"Conditional c-Maf knockout mice, ATAC-seq (chromatin accessibility), transcriptomics, flow cytometry\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional knockout with ATAC-seq chromatin profiling and transcriptomics establishing mechanistic pathway\",\n      \"pmids\": [\"30538336\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SUMOylation of c-Maf at lysine-33 attenuates its IL-4 transcriptional activity by reducing its recruitment to the Il4 promoter without altering subcellular localization or protein stability; c-Maf interacts with Ubc9 and PIAS1 (SUMO pathway enzymes).\",\n      \"method\": \"Yeast two-hybrid (interaction with Ubc9/PIAS1), in vitro and in vivo SUMOylation assays, site-directed mutagenesis (K33R), chromatin immunoprecipitation, retroviral transduction in c-Maf-deficient Th2 cells\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — site-directed mutagenesis of SUMO acceptor site combined with ChIP and functional rescue, multiple orthogonal methods\",\n      \"pmids\": [\"20127678\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SUMO-defective c-Maf (K→R mutation at SUMOylation site) preferentially transactivates Il21 over Il4 by selectively inhibiting recruitment of Daxx/HDAC2 to the Il21 promoter and enhancing CBP/p300-mediated histone acetylation at that locus.\",\n      \"method\": \"Transgenic NOD mice (wild-type vs. SUMOylation-mutant c-Maf), promoter ChIP assays, pharmacological CBP/p300 inhibition\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — transgenic mouse comparison with ChIP mechanistic evidence and pharmacological validation, multiple orthogonal methods\",\n      \"pmids\": [\"30059018\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Otub1 (OTU deubiquitinase) interacts with c-Maf (identified by mass spectrometry), abrogates K48-linked polyubiquitination of c-Maf and prevents its degradation, enhancing its transcriptional activity; this activity requires Otub1 Lys71 and its N-terminus but is independent of UBE2O.\",\n      \"method\": \"Mass spectrometry identification, co-immunoprecipitation, ubiquitination assays, domain mutagenesis (Lys71), luciferase assay, shRNA knockdown, xenograft models\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — MS identification plus domain mutagenesis, ubiquitination assays, and in vivo xenograft validation\",\n      \"pmids\": [\"32842143\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"USP7 (deubiquitinase) interacts with c-Maf, MafA, and MafB and blocks their polyubiquitination and proteasomal degradation, thereby promoting Maf transcriptional activity and myeloma cell survival.\",\n      \"method\": \"Mass spectrometry (MafB interactome), co-immunoprecipitation, ubiquitination assays, luciferase assay, shRNA knockdown, pharmacological inhibition (P5091)\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS-based identification plus co-IP and functional assays, single lab\",\n      \"pmids\": [\"31822558\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"c-MAF ubiquitination is mediated by multiple lysine residues; no single lysine alone is sufficient, but K85 and K350 together are sufficient (though not the only pair); c-MAF is also degraded by lysosomes in addition to proteasomes.\",\n      \"method\": \"Systematic lysine-to-arginine mutagenesis, cell-based ubiquitination assays, luciferase reporter assay for transcriptional activity, lysosomal inhibitor treatment\",\n      \"journal\": \"The international journal of biochemistry & cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — systematic mutagenesis with functional readouts, single lab\",\n      \"pmids\": [\"25448412\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"MAF overexpression (as in t(14;16) multiple myeloma) confers innate resistance to proteasome inhibitors (bortezomib, carfilzomib) by stabilizing MAF protein; proteasome inhibitor exposure blocks GSK3β-mediated MAF degradation, increasing MAF protein stability.\",\n      \"method\": \"Cell line models with t(14;16) translocation, loss-of-function (MAF silencing) and gain-of-function (MAF overexpression), PI sensitivity assays, apoptosis/caspase assays\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal gain/loss-of-function with biochemical mechanism (GSK3β pathway), single lab\",\n      \"pmids\": [\"27793878\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"c-Maf's cell-transforming activity requires transactivation through MARE (replacement of transactivation domain with VP16 enhances transformation; fusion with transcriptional repressor abolishes it); c-Maf and Jun share downstream target genes for transformation; heterodimer formation with other bZIP factors is not required for Maf-induced transformation.\",\n      \"method\": \"Chicken embryo fibroblast transformation assay, domain swap/fusion constructs (VP16 activation domain, Mxi1 repressor domain, GCN4 leucine zipper), dominant-negative Jun\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — structure-function analysis with multiple constructs in transformation assay, single lab\",\n      \"pmids\": [\"16247450\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"c-Maf overexpression in T cells drives T-cell lymphoma in transgenic mice, with upregulation of cyclin D2, integrin β7, and ARK5 as downstream target genes.\",\n      \"method\": \"T-cell-specific c-Maf transgenic mice, gene expression analysis of lymphoma cells\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transgenic mouse model with target gene identification, single lab\",\n      \"pmids\": [\"16424013\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"c-Maf is required for Treg specialization: it is essential for generation of RORγt+ Tregs and T follicular regulatory cells in mice, but not for adipose-resident Tregs; c-Maf is induced in Tregs by IL-6 and TGF-β.\",\n      \"method\": \"Conditional c-Maf knockout in Tregs, flow cytometric analysis of Treg subsets, cytokine stimulation experiments\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional knockout with defined cellular phenotype, single lab\",\n      \"pmids\": [\"29127150\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"c-Maf-dependent intestinal Treg cells constrain microbiota-dependent TH17 and IgA responses; c-Maf deficiency in Tregs leads to dysbiosis sufficient to induce exacerbated intestinal TH17 responses upon germ-free transfer; c-Maf controls IL-10 production and prevents excessive PI3K/Akt/mTORC1 signaling in intestinal Tregs.\",\n      \"method\": \"Conditional c-Maf knockout in Treg compartment, germ-free mouse transfer experiments, cytokine and signaling pathway analysis\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional knockout plus germ-free transfer epistasis establishing mechanistic pathway in vivo\",\n      \"pmids\": [\"30778241\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"c-Maf is a critical controller of immunosuppressive (M2-like) macrophage polarization in cancer; it has direct binding sites within a conserved noncoding sequence of the Csf-1r gene; c-Maf also acts as a metabolic checkpoint regulating the TCA cycle and UDP-GlcNAc biosynthesis; myeloid-specific deletion reduces tumor burden with enhanced T cell immunity.\",\n      \"method\": \"Myeloid-specific c-Maf knockout mice, ChIP (Csf-1r binding sites), metabolomics, tumor models, T cell functional assays\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional knockout in vivo with ChIP validation of direct target, metabolomic evidence of metabolic checkpoint function, multiple orthogonal methods\",\n      \"pmids\": [\"31945018\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"c-Maf enforces ILC3 identity by promoting RORγt activity and type 3 effector gene expression while directly restraining T-bet expression; c-Maf and T-bet form a negative feedback loop in CCR6- ILC3s.\",\n      \"method\": \"c-Maf conditional knockout, transcriptomics, ATAC-seq (chromatin accessibility and TF motif enrichment), flow cytometry\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional knockout with ATAC-seq and transcriptomics revealing direct molecular mechanism\",\n      \"pmids\": [\"31570496\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MAF directly activates β/γ-crystallin gene promoters and activates TGF-β1-Smad signaling to upregulate crystallins in high myopia lenses; mechanistic studies identify a MAF-TGF-β1-crystallin axis.\",\n      \"method\": \"Mechanistic studies in myopia mouse models and human high myopic lenses, promoter activation assays, Smad signaling analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct promoter activation and signaling pathway evidence in mouse models, single lab\",\n      \"pmids\": [\"33833231\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"c-Maf is a critical perinatal transcriptional switch for hepatic sinusoidal endothelial cell identity; endothelium-restricted c-Maf deletion disrupts liver sinusoidal development, expands postnatal hematopoiesis, and increases pro-fibrotic sensitivity; enforced c-Maf expression in generic human endothelial cells activates a liver sinusoidal transcriptional program.\",\n      \"method\": \"Endothelium-restricted c-Maf knockout mice, scRNA-seq, enforced c-Maf overexpression in human endothelial cells, functional hepatocyte co-culture assays\",\n      \"journal\": \"Cell stem cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional knockout plus gain-of-function in human cells with scRNA-seq, multiple orthogonal methods\",\n      \"pmids\": [\"35364013\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"c-MAF-dependent perivascular macrophages in white adipose tissue regulate metabolic syndrome; conditional c-MAF deletion in macrophage lineages ablates perivascular macrophages and alters muscularis macrophage program, with macrophage-specific c-MAF deletion improving metabolic parameters under high-fat diet.\",\n      \"method\": \"Macrophage lineage-specific c-MAF conditional knockout, single-cell RNA-seq, metabolic phenotyping (glucose tolerance, weight, adipose inflammation)\",\n      \"journal\": \"Science immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional knockout with scRNA-seq and defined metabolic phenotype, multiple orthogonal methods\",\n      \"pmids\": [\"34597123\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"c-Maf is required for optimal type 2 cytokine production and memory-like (trained) responses in group-2 innate lymphoid cells (ILC2s); c-Maf is induced by IL-33/IL-25 and allergen (papain) exposure; c-Maf-deficient mouse and human ILC2s fail to show trained immunity upon repeated challenge.\",\n      \"method\": \"c-Maf deletion in ILCs (mouse), transcriptomic analysis, knockdown in human ILC2s, repeated allergen challenge model\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mouse and human loss-of-function with transcriptomic and functional readouts, single lab\",\n      \"pmids\": [\"35467036\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TGF-β induces CXCR5 expression in mouse CD4+ T cells to drive TFH differentiation via c-Maf, but independently of Bcl6; c-Maf acts as a switch factor for TFH versus TH17 cell fates in TGF-β-rich environments both in vitro and in vivo.\",\n      \"method\": \"In vitro TFH differentiation protocol, Bcl6 and c-Maf conditional knockouts, CXCR5 expression analysis, in vivo immunization experiments\",\n      \"journal\": \"Science immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional knockouts establishing epistasis (TFH independent of Bcl6 but dependent on c-Maf), in vitro and in vivo validation\",\n      \"pmids\": [\"38427718\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Maf acts downstream of Neuregulin1 (Nrg1) signaling in Schwann cells to directly bind enhancers of cholesterol synthesis genes, promoting cholesterol biosynthesis required for myelination; Nrg1-calmodulin-dependent kinases regulate Maf transcription, while Nrg1-MAPK signaling stabilizes Maf protein.\",\n      \"method\": \"Genetic ablation of Maf in Schwann cells, ChIP (Maf binding to cholesterol synthesis gene enhancers), epistasis with Nrg1 signaling, kinase inhibition experiments\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional knockout plus ChIP establishing direct binding, genetic epistasis with Nrg1 pathway, multiple orthogonal methods\",\n      \"pmids\": [\"29748249\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"c-maf is required for AhR-dependent β7-integrin induction in macrophages by benzo(a)pyrene; c-Maf binds to a Maf-responsive element in the β7-integrin promoter (demonstrated by ChIP and EMSA), and c-maf knockdown impairs induction.\",\n      \"method\": \"shRNA knockdown of c-maf, chromatin immunoprecipitation (ChIP), EMSA, chemical inhibition of AhR\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct DNA binding shown by ChIP and EMSA combined with knockdown, single lab\",\n      \"pmids\": [\"17490615\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"IL-2 induces STAT5 binding to specific sites in the c-MAF promoter, thereby promoting c-MAF expression in human CD4 T cells; IL-2 and IL-6 synergistically induce c-MAF expression; blockade of IL-2 signaling (daclizumab or JAK3 inhibitor) reduces c-MAF and IL-4 expression.\",\n      \"method\": \"Chromatin immunoprecipitation (STAT5 binding to c-MAF promoter), cytokine stimulation experiments, pharmacological inhibition (daclizumab, R333), primary human CD4 T cells\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP establishes direct STAT5 binding to c-MAF promoter with functional validation, single lab\",\n      \"pmids\": [\"21876034\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"c-Maf interacts with c-Myb in CD4 T cells to reduce Bcl-2 expression and increase susceptibility to apoptosis; c-Maf/c-Myb complex formation is enhanced following TCR engagement and prevents c-Myb binding to the Bcl-2 promoter; Bcl-2 overexpression corrects the apoptosis defect.\",\n      \"method\": \"c-Maf transgenic mice, co-immunoprecipitation, chromatin immunoprecipitation (c-Myb at Bcl-2 promoter), reporter gene assay, Bcl-2 rescue transgene\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP for physical interaction, ChIP for promoter occupancy, and Bcl-2 rescue experiment, single lab\",\n      \"pmids\": [\"17823980\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Maf's transforming activity requires transactivation through MARE; heterodimer formation with other bZIP factors is dispensable for transformation; Maf and Jun share downstream MARE-regulated target genes for cell transformation, as a Jun dominant-negative construct blocks both Jun- and Maf-induced transformation.\",\n      \"method\": \"Chicken embryo fibroblast transformation assays, domain swap constructs (VP16 activator, Mxi1 repressor, GCN4 leucine zipper), dominant-negative Jun constructs\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — structure-function transformation assays with multiple constructs establishing shared target gene mechanism, single lab\",\n      \"pmids\": [\"11461901\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Intestinal commensal-specific Th17 cells acquire an anti-inflammatory, IL-10-producing phenotype driven by c-MAF; these cells suppress effector T cell activity in an IL-10-dependent and c-MAF-dependent manner in vitro and in vivo.\",\n      \"method\": \"Conditional c-MAF deletion in T cells, antigen-specific T cell tracking, in vitro and in vivo suppression assays, cytokine measurement\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional knockout with both in vitro and in vivo functional suppression assays, replicated across multiple experimental settings\",\n      \"pmids\": [\"38039966\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"c-Maf regulates the alphaA-crystallin locus through binding to the promoter and distal control regions (DCR3), associated with broad histone H3K9-hyperacetylation and increased abundance of chromatin remodeling enzymes Brg1 and Snf2h at the locus.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP) for c-Maf, CREB, Pax6 binding, histone acetylation marks, and chromatin remodeling enzymes; reporter gene assays in lens explants\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP across multiple targets at the alphaA-crystallin locus with functional reporter assays, single lab\",\n      \"pmids\": [\"16675956\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CRISPR-mediated deletion of MAF abrogates the ability of PD-1hiCXCR5- T peripheral helper (Tph) cells to induce memory B cell differentiation into plasmablasts in vitro.\",\n      \"method\": \"CRISPR-Cas9 deletion of MAF in human Tph cells, B cell differentiation co-culture assay\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR loss-of-function with defined functional readout in human primary cells, single lab\",\n      \"pmids\": [\"31536480\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"MAF and MAFB are necessary and sufficient for epidermal progenitor differentiation; MAF:MAFB regulate 393 genes including downstream transcription factors GRHL3, ZNF750, KLF4, and PRDM1; ChIP-seq confirms MAF:MAFB binding to these TF gene loci.\",\n      \"method\": \"ChIP-seq (MAF:MAFB binding genome-wide), siRNA knockdown and overexpression, kinetic transcriptome analysis, organotypic epidermal regeneration\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP-seq combined with necessary and sufficient functional tests in primary human epidermal cells, multiple orthogonal methods\",\n      \"pmids\": [\"25805135\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"c-MAF is a basic leucine zipper (bZIP) transcription factor that binds Maf recognition elements (MAREs) as homodimers or heterodimers (with Fos, Jun, NF-AT, Sox5, or small Maf proteins), directly activating or repressing target genes across diverse tissues; it is the essential Th2-specific transactivator of IL-4, a selective inducer of IL-10 and IL-21 in multiple T cell and innate lymphoid cell subsets, a determinant of lens fiber cell differentiation and crystallin gene expression, a regulator of macrophage identity (F4/80, M2 polarization, perivascular identity), a specifier of mechanoreceptor and interneuron development, and a myeloma oncogene whose stability is controlled by GSK-3-mediated phosphorylation-dependent ubiquitination countered by deubiquitinases USP5, USP7, and Otub1, and by SUMOylation at K33 which selectively attenuates IL-4 (but not IL-21) transactivation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MAF (c-Maf) is a basic region/leucine zipper transcription factor that binds Maf recognition elements (MAREs) to control cell-type-specific gene programs across the immune system, lens, neural, vascular, and myeloid lineages [#0, #2]. Maf-specific DNA recognition is structurally encoded by conserved basic-region residues (Arg57, Asn61) that read the extended GC sequences flanking the MARE core [#9], and MAF can act as a homodimer or heterodimerize with Fos and Jun at AP-1/CRE-related sites [#4]. In the immune system MAF is the IL-4-specific transactivator that initiates Th2 cytokine production in synergy with NF-ATp [#0, #1], and it directly drives IL-10 and IL-21 programs to enforce regulatory and follicular helper phenotypes: it induces intestinal RORγt+ Treg and IL-10-producing commensal-specific Th17 cells that constrain colitogenic responses [#19, #44, #31], cooperates with Sox5 to activate the RORγt promoter for Th17 differentiation [#16], and serves as a Bcl6-independent switch factor for TFH versus TH17 fate in TGF-β-rich settings [#38]. MAF specifies γδ17 and ILC3/ILC2 effector identity by remodeling chromatin at Rorc while antagonizing the opposing TCF1/T-bet fate [#21, #33]. Beyond immunity, MAF directs lens fiber cell differentiation by binding T-MARE sites in crystallin promoters [#2, #3, #45], controls macrophage identity, M2/perivascular polarization, and metabolic programming via direct CSF1R regulation [#7, #32, #36], specifies mechanoreceptor and dorsal-horn interneuron development [#13, #14], acts downstream of Neuregulin1 to drive Schwann-cell cholesterol biosynthesis for myelination [#39], and sets hepatic sinusoidal endothelial and epidermal progenitor identity [#35, #47]. As a myeloma oncogene, MAF transforming activity requires MARE-dependent transactivation [#43, #28], and its abundance is governed by a phosphodegron axis: GSK-3 phosphorylation triggers ubiquitination and proteasomal degradation [#5], opposed by the deubiquitinases USP5, USP7, and Otub1 [#17, #25, #24] and promoted by the E2 enzyme UBE2O [#18]; SUMOylation at K33 selectively attenuates IL-4 (but not IL-21) transactivation by altering promoter recruitment and coactivator engagement [#22, #23]. A dominant human MAF mutation causes reduced high-frequency vibration sensitivity, linking MAF to mechanosensory function [#13].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 1994,\n      \"claim\": \"Established the biochemical basis of MAF as a bZIP factor capable of dimerizing with AP-1 family proteins, defining its DNA-binding modality.\",\n      \"evidence\": \"In vitro binding/co-IP with purified polypeptides and leucine-zipper/basic-region mutagenesis\",\n      \"pmids\": [\"8108109\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address in vivo target genes\", \"Cellular function not assigned\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Identified the first direct MAF target and function: it answered how Th2 cells transcriptionally activate IL-4, establishing MAF as a MARE-binding transactivator acting with NF-ATp.\",\n      \"evidence\": \"Footprinting, reporter transactivation, ectopic expression in Th1/B cells\",\n      \"pmids\": [\"8674125\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specificity among Th2 cytokines not yet defined\", \"In vivo requirement not tested\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Genetic loss-of-function resolved whether MAF is specifically required for IL-4 in vivo and revealed a parallel essential role in lens fiber differentiation, defining its tissue breadth.\",\n      \"evidence\": \"c-maf-null mice with cytokine readouts; lens histology and crystallin promoter binding/reporter assays\",\n      \"pmids\": [\"10403649\", \"10383433\", \"10603348\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of crystallin locus activation not detailed\", \"How IL-4 specificity versus IL-13 is enforced unresolved\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Defined how MAF transforms cells, showing transformation requires MARE-dependent transactivation rather than obligate heterodimerization, and identified shared MAF/Jun target genes.\",\n      \"evidence\": \"Chicken embryo fibroblast transformation with domain-swap and dominant-negative Jun constructs; T-cell transgenic lymphoma model\",\n      \"pmids\": [\"11461901\", \"16247450\", \"16424013\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct oncogenic target genes in human myeloma not yet mapped\", \"Single-lab transformation assays\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Provided the structural mechanism for MARE recognition, explaining how Maf-family basic-region residues read extended flanking GC sequences distinct from other bZIP factors.\",\n      \"evidence\": \"X-ray crystallography of MafG-DNA complex with functional residue validation\",\n      \"pmids\": [\"19797082\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure solved for MafG, not c-Maf directly\", \"Heterodimer DNA complexes not crystallized\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Extended MAF's transcriptional repertoire to IL-10 and macrophage identity, broadening it from a Th2-specific factor to a multilineage regulator.\",\n      \"evidence\": \"Retroviral transduction with promoter MARE reporters (IL-10); knockout plus EMSA/reporter (F4/80); double-knockout with shRNA epistasis (macrophage self-renewal)\",\n      \"pmids\": [\"19414776\", \"19539733\", \"19892988\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct genome-wide targets not yet defined\", \"Relationship between repressive and activating modes unclear\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Established MAF's role in nervous-system development and human sensory function, linking it to mechanoreceptor and interneuron differentiation and a dominant human vibration-sensitivity phenotype.\",\n      \"evidence\": \"Constitutive and conditional knockout mice with electrophysiology and IHC; human dominant MAF mutation analysis\",\n      \"pmids\": [\"22345400\", \"22514301\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct neuronal target genes not identified\", \"Molecular basis of the dominant human allele not dissected\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identified MAF cofactors and a key post-translational stabilizer, showing Sox5 cooperation for Th17 fate and USP5 deubiquitination controlling MAF abundance.\",\n      \"evidence\": \"Domain-mapped physical interaction with Sox5 plus epistasis; co-IP, ubiquitination assays, and site-directed mutagenesis (K308/K347) for USP5; systematic lysine mutagenesis of degradation sites\",\n      \"pmids\": [\"25073789\", \"28933784\", \"25448412\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full E3 ligase responsible for K48 chains not fully defined\", \"Lysosomal versus proteasomal balance unresolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined MAF as a master regulator of regulatory and effector lymphocyte programs and dissected SUMOylation as a switch tuning IL-4 versus IL-21 output.\",\n      \"evidence\": \"Conditional knockouts across Treg, γδ17, and disease contexts with ATAC-seq/genomic footprinting; K33 SUMO-site mutagenesis with ChIP and transgenic mice\",\n      \"pmids\": [\"29414937\", \"29662170\", \"30538336\", \"29127150\", \"20127678\", \"30059018\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How a single factor selects opposing programs context-dependently is incompletely mapped\", \"Coactivator/corepressor switching at additional loci not characterized\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Expanded MAF's deubiquitinase network (Otub1, USP7) and its oncogenic stabilization, while defining intestinal Treg metabolic control and Tph helper function.\",\n      \"evidence\": \"MS, co-IP, ubiquitination and domain mutagenesis, xenografts (DUBs); germ-free transfer epistasis (intestinal Treg); CRISPR deletion in human Tph cells\",\n      \"pmids\": [\"32842143\", \"31822558\", \"30778241\", \"31536480\", \"31570496\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contributions of USP5/USP7/Otub1 in vivo unresolved\", \"Direct ILC3 target genes beyond Rorc/T-bet not fully mapped\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined MAF as a metabolic and identity checkpoint in tissue macrophages and endothelium, including direct CSF1R regulation and immunosuppressive polarization in cancer.\",\n      \"evidence\": \"Myeloid- and endothelium-restricted knockouts with ChIP, metabolomics, scRNA-seq, and tumor models\",\n      \"pmids\": [\"31945018\", \"34597123\", \"35364013\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream signals inducing MAF in each niche differ and are not unified\", \"Direct metabolic-gene targets only partially mapped\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Resolved MAF as the Bcl6-independent TFH/TH17 switch factor in TGF-β environments, clarifying its decision-making logic in helper T cell fate.\",\n      \"evidence\": \"In vitro TFH differentiation and in vivo immunization with Bcl6 and c-Maf conditional knockouts\",\n      \"pmids\": [\"38427718\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Genome-wide CXCR5/TFH targets of MAF not detailed\", \"Interplay with SUMO/DUB regulation in this context untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single MARE-binding factor is wired to select among opposing transcriptional programs (e.g., activation vs repression, IL-4 vs IL-21, RORγt vs T-bet) in a cell-type-specific manner remains the central open question.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No unified model of context-dependent cofactor/PTM selection\", \"Genome-wide direct target maps incomplete across most lineages\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 2, 6, 7, 16, 32, 47]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [3, 4, 9, 12, 40, 45]},\n      {\"term_id\": \"GO:0140097\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [22, 45]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 1, 6, 19, 21, 33]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 3, 9, 47]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [2, 13, 35, 47]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [5, 17, 24, 25]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [27, 28, 29]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"FOS\", \"JUN\", \"MYB\", \"SOX5\", \"BCL6\", \"USP7\", \"OTUB1\", \"USP5\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}