{"gene":"MYRF","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":2013,"finding":"MYRF is synthesized as an ER/membrane-associated protein that undergoes autoproteolytic cleavage to separate its transmembrane-domain-containing C-terminal region from a nuclear-targeted N-terminal region; the N-terminal cleavage product directly binds enhancer regions of oligodendrocyte-specific and myelin genes via a defined DNA-binding consensus sequence to activate their transcription.","method":"Biochemical fractionation, ChIP-Seq, domain mutagenesis, reporter assays","journal":"PLoS biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — two independent labs (PMID 23966833 and 23966832) published simultaneously with multiple orthogonal methods including ChIP-Seq, mutagenesis, and functional assays; findings replicated across both papers","pmids":["23966833","23966832"],"is_preprint":false},{"year":2013,"finding":"MYRF contains a protein domain related to bacteriophage tailspike intramolecular chaperone (ICA) domains that facilitates MYRF trimerization and autoproteolytic self-cleavage; this chaperone domain-mediated autoproteolysis is essential for MYRF transcriptional activity and its ability to promote oligodendrocyte maturation. The proteolysis occurs constitutively and independent of cell- or tissue-type, as demonstrated by reconstitution in E. coli and yeast.","method":"Bioinformatics, biochemical reconstitution in E. coli and yeast, functional transcriptional assays, domain mutagenesis","journal":"PLoS biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution in heterologous systems plus mutagenesis plus functional validation in a single rigorous study, replicated in parallel by PMID 23966833","pmids":["23966832"],"is_preprint":false},{"year":2013,"finding":"Sox10 induces Myrf expression through a Sox10-responsive enhancer in intron 1 of the Myrf gene; once induced, Myrf physically interacts with Sox10 and they synergistically activate several myelin-specific genes.","method":"Reporter/enhancer assays, Co-immunoprecipitation (physical interaction), luciferase synergy assays, in vivo genetics","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal interaction confirmed by Co-IP, multiple functional assays including enhancer mapping and synergy, single lab but ≥2 orthogonal methods","pmids":["24204311"],"is_preprint":false},{"year":2017,"finding":"MYRF N-terminal fragments assemble into stable homo-trimers before ER release; homo-trimerization is essential for the biological function of the N-terminal fragment, and the region adjacent to the DNA-binding domain is pivotal for homo-trimerization. Homo-trimerization defines the DNA-binding specificity of Myrf N-terminal fragments, enabling binding to a novel homo-trimeric DNA motif.","method":"Biochemical fractionation, gel filtration, mutagenesis, C. elegans genetic rescue, computational DNA motif analysis","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — multiple orthogonal biochemical and genetic methods in a single study; mutagenesis tied to in vivo functional readout in C. elegans","pmids":["28160598"],"is_preprint":false},{"year":2018,"finding":"TMEM98, an ER-associated transmembrane protein, physically binds to the C-terminal region of MYRF and inhibits its self-cleavage and N-fragment nuclear translocation, thereby acting as a negative feedback regulator of MYRF activity during oligodendrocyte differentiation.","method":"Co-immunoprecipitation, overexpression in embryonic chicken spinal cord, Western blot for cleavage products, nuclear translocation assays","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP for physical interaction, in vivo functional assay (chicken spinal cord), and cleavage assay in a single study with multiple orthogonal methods","pmids":["30249802"],"is_preprint":false},{"year":2020,"finding":"TMEM98 inhibits the autoproteolytic self-cleavage of MYRF; in retinal pigment epithelium lacking TMEM98, MYRF is ectopically activated and abnormally localised to nuclei, demonstrating that TMEM98–MYRF interaction controls MYRF activation state and eye size.","method":"Proximity labeling (BioID) to identify interacting partners, conditional Tmem98 knockout mice (RPE-specific), immunofluorescence for MYRF nuclear localization, cleavage assays","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 / Moderate — proximity labeling plus conditional KO with localization readout, independent replication of TMEM98–MYRF interaction from PMID 30249802","pmids":["32236127"],"is_preprint":false},{"year":2018,"finding":"The SCF-FBXW7 E3 ubiquitin ligase complex directly binds the NH2-terminal cytoplasmic domain of MYRF and polyubiquitylates it in an in vitro ubiquitylation assay; GSK-3 kinase phosphorylates a putative phosphodegron in MYRF, and this phosphorylation is required for FBXW7-mediated degradation of MYRF.","method":"Co-immunoprecipitation, in vitro ubiquitylation assay with recombinant SCF-FBXW7, phosphodegron mutagenesis, GSK-3 inhibitor treatment","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstituted ubiquitylation with purified components, Co-IP, and mutagenesis in a single study","pmids":["29472293"],"is_preprint":false},{"year":2025,"finding":"FBXW7 directly binds and degrades the N-terminal fragment of MYRF (N-MYRF) to control the balance between oligodendrocyte myelin growth and homeostasis; loss of Fbxw7 in myelinating oligodendrocytes increases myelin sheath lengths and causes progressive myelin abnormalities including outfolds and ectopic ensheathment.","method":"Zebrafish genetics, conditional mouse KO in oligodendrocytes, primary OL cultures, biochemical Co-IP and degradation assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP plus in vivo conditional KO in two vertebrate models (zebrafish and mouse) with specific cellular phenotype readout; replicates and extends PMID 29472293","pmids":["40841354"],"is_preprint":false},{"year":2020,"finding":"Myrf cooperates with Sox10 in a bimodal manner: it co-activates differentiation genes by joint binding with Sox10 to the same regulatory regions, and it inhibits Sox10-dependent activation of OPC-stage genes by physical interaction with Sox10 leading to Sox10 sequestration on genes lacking Myrf binding sites.","method":"ChIP, EMSA, reporter assays, Co-immunoprecipitation, loss-of-function analysis","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (ChIP, EMSA, Co-IP, reporter assays) in a single study establishing two mechanistically distinct modes of cooperation/inhibition","pmids":["31828317"],"is_preprint":false},{"year":2018,"finding":"The N-terminal-most (NTM) domain of Myrf functions as its transactivation domain; when fused to Gal4 it activates transcription independently of trimerization. This NTM domain can be sumoylated at three lysine residues (K123, K208, K276), with K276 as the main acceptor; K276 sumoylation represses the transactivation function without affecting Myrf stability or nuclear localization.","method":"Gal4 fusion reporter assays, site-directed mutagenesis of sumoylation sites, Western blot, nuclear localization assays","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional reporter plus mutagenesis, single lab, no orthogonal structural validation","pmids":["30166609"],"is_preprint":false},{"year":2021,"finding":"Four disease-associated MYRF DNA-binding domain missense mutations (F387S, Q403H, G435R, L479V) abolish transcriptional activity by disrupting homo-trimerization through perturbation of DBD structure. Three mutations (F387S, Q403H, L479V) are tolerated as single copies within a homo-trimer (haploinsufficiency mechanism), while G435R acts as a dominant negative.","method":"Mutagenesis, transcriptional activity assays, trimerization biochemical assays, structural perturbation analysis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis linked to functional transcriptional and biochemical trimerization assays, single lab, clear mechanistic distinction between allele classes","pmids":["33798553"],"is_preprint":false},{"year":2021,"finding":"Crystal structure of the MyRF ICA domain with its upstream β-helical stalk (at 2.4 Å) reveals that a triple α-helical coiled-coil at the ICA domain C-terminus is the main driving force for trimerization; self-cleavage occurs via a conserved serine-lysine catalytic dyad and is activated only when ICA domains are organized as trimers.","method":"X-ray crystallography, structural analysis, mutagenesis of catalytic residues","journal":"International journal of biological sciences","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure determination with functional validation of catalytic mechanism by mutagenesis, single lab","pmids":["34345217"],"is_preprint":false},{"year":2017,"finding":"In C. elegans, the MYRF family members MYRF-1 and MYRF-2 localize to the ER membrane, undergo proteolytic cleavage to release active N-terminal fragments that translocate to the nucleus, and cooperatively regulate synaptic rewiring; overexpression of active forms of MYRF is sufficient to accelerate synaptic rewiring.","method":"Live imaging of GFP fusions, cleavage assays, genetic loss-of-function, overexpression rescue in C. elegans","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct localization by live imaging tied to functional genetic evidence; cleavage-to-nuclear-translocation mechanism confirmed in vivo in C. elegans","pmids":["28441531"],"is_preprint":false},{"year":2021,"finding":"In C. elegans, the LRR-TM protein PAN-1 localizes on the cell membrane, physically interacts with MYRF via extracellular domains, and is required for MYRF cell membrane localization; loss of PAN-1 abolishes MYRF membrane localization and consequently blocks myrf-dependent neuronal rewiring.","method":"Co-immunoprecipitation, live imaging of localization, genetic epistasis in C. elegans loss-of-function","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP plus direct localization imaging with clear functional consequence (rewiring arrest), multiple orthogonal methods in C. elegans","pmids":["33950834"],"is_preprint":false},{"year":2019,"finding":"MYRF physically interacts with TMEM98 (confirmed by Co-immunoprecipitation); Myrf conditional knockout mice develop retinal pigment epithelium depigmentation and retinal degeneration, and show reduced expression of Tmem98, indicating MYRF regulates Tmem98 expression.","method":"Co-immunoprecipitation, conditional knockout mouse model (Myrf CKO), histological and molecular phenotyping","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP for physical interaction plus conditional KO phenotype, single lab, interaction with TMEM98 also replicated in PMID 32236127","pmids":["31048900"],"is_preprint":false},{"year":2022,"finding":"MYRF physically interacts with DNMT3A (demonstrated by Co-immunoprecipitation); in Myrf mutant mouse retinas, Dnmt3a is downregulated and DNA methylation patterns at glaucoma-related loci are altered, linking the MYRF–DNMT3A interaction to primary angle-closure glaucoma pathogenesis.","method":"Co-immunoprecipitation, transcriptome sequencing of Myrf mutant retinas, DNA methylation sequencing","journal":"Human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — single Co-IP plus transcriptomic/epigenomic correlation; physical interaction established but downstream mechanistic details are correlative","pmids":["36129575"],"is_preprint":false},{"year":2020,"finding":"In pancreatic ductal adenocarcinoma cells, MYRF expression is controlled by the transcription factor HNF1B; MYRF acts to regulate expression of highly glycosylated, cysteine-rich secretory proteins, preventing ER overload. MYRF-deficient PDAC cells show ER stress and impaired proliferation.","method":"Conditional MYRF knockout in PDAC cells, RNA-seq, spheroid formation assay, in vivo tumor models","journal":"Developmental cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with specific ER stress phenotype, upstream regulator identified, multiple readouts; single lab","pmids":["32997974"],"is_preprint":false},{"year":2024,"finding":"In C. elegans, MYRF-1 is necessary for activation of the microRNA lin-4; increased MYRF-1 cleavage and nuclear accumulation coincides with lin-4 expression timing, and hyperactive MYRF-1 can prematurely drive lin-4 expression; MYRF-1 directly binds to the lin-4 promoter as shown by nuclear GFP focus formation at the tandem lin-4 promoter.","method":"C. elegans genetics (loss-of-function and gain-of-function), live imaging of MYRF-1::GFP nuclear foci at lin-4 promoter loci, cleavage/translocation timing assays","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct promoter binding demonstrated by nuclear focus formation, genetic epistasis, and gain-of-function timing experiments; single lab","pmids":["38963411"],"is_preprint":false},{"year":2016,"finding":"Sox10 and Myrf cooperatively activate Dusp15 expression through the Dusp15 promoter, which contains both a functional Sox10-binding site and a functional Myrf-binding site; Sox10 binds as a monomer while Myrf binds as a trimer; cooperative activation occurs at a step after binding rather than through facilitated binding.","method":"ChIP, EMSA, reporter/promoter assays, shRNA knockdown of Dusp15 in oligodendroglial cells","journal":"Glia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and EMSA establish binding modes; functional synergy confirmed by reporter assays; knockdown establishes downstream role; single lab","pmids":["27532821"],"is_preprint":false},{"year":2031,"finding":"In C. elegans, MYRF-1 cleavage is dually inhibited by (1) a juxtamembrane (JM) region of MYRF-1 that acts as a cis self-inhibitor of cleavage, and (2) the cytoplasmic tail (CCT) of PAN-1 which acts as a trans-inhibitor; deletion of either leads to premature MYRF-1 nuclear entry, early lin-4 activation, and larval lethality, establishing these as key regulators of developmental timing.","method":"Endogenous gene editing (CRISPR), C. elegans genetics (deletion mutants), live imaging of nuclear accumulation, lin-4 reporter assays","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — endogenous CRISPR editing with clean functional readouts; preprint, not yet peer-reviewed","pmids":["41542402"],"is_preprint":true},{"year":2025,"finding":"In C. elegans, MYRF-1 directly activates key heterochronic microRNAs (lin-4, mir-48/241/84, let-7) and amplifies oscillatory gene networks including nhr-23; MYRF-1 nuclear accumulation oscillates across larval stages; lin-42/Period feeds back to repress myrf; loss of MYRF causes developmental arrest during late intermolt phase.","method":"C. elegans genetics, ChIP or direct binding assays for heterochronic miRNA promoters, loss-of-function with stage-arrest readout, oscillation imaging","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function, direct binding evidence for miRNA promoters, oscillation imaging; preprint, not yet peer-reviewed","pmids":["41659655"],"is_preprint":true},{"year":2025,"finding":"In C. elegans, MYRF-1 directly binds the promoter of pqn-41 (a polyglutamine protein gene required for linker cell death); MYRF-1 nuclear translocation in the linker cell primes linker-cell-type death early during migration; deleting a bona fide MYRF-1 binding site within pqn-41 promotes linker cell survival.","method":"Single-cell mRNA sequencing, auxin-inducible degradation of MYRF-1, promoter binding/deletion assays in C. elegans","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct promoter binding confirmed by deletion of binding site with survival readout; auxin-degradation system for temporal control; preprint, not yet peer-reviewed","pmids":["41427293"],"is_preprint":true},{"year":2025,"finding":"MYRF is most highly expressed in epicardial cells among cardiac cell types; conditional deletion of Myrf in epicardial cells (EPCs) causes severely degenerated epicardium, dramatically reduced epicardial-derived cells, and thin myocardial wall; deletion in cardiomyocytes produces no overt phenotype, establishing epicardial MYRF as the cell-type-specific requirement for cardiac development.","method":"Cell-type-specific conditional KO (epicardial Cre vs cardiomyocyte Cre), histological analysis, cell fate tracing","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell-type-specific genetic epistasis with clear phenotypic readout; preprint, not yet peer-reviewed","pmids":["bio_10.1101_2025.10.17.682841"],"is_preprint":true},{"year":2026,"finding":"Myrf inactivation early in embryogenesis causes CDH and defective mesothelium specification in mice; later inactivation leads to enhanced mesothelial differentiation into mesenchymal cell types including elastin-expressing smooth muscle/myofibroblasts encasing the lung; MYRF functions synergistically with YAP/TAZ in mesothelium differentiation, as shown by compound mutants.","method":"Conditional Myrf knockout mice with temporally controlled Cre, compound Myrf/YAP-TAZ mutants (genetic epistasis), histological and cell fate analysis","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 / Moderate — conditional KO with temporal control, genetic epistasis with YAP/TAZ, specific cellular phenotypes; peer-reviewed publication","pmids":["41558485"],"is_preprint":false},{"year":2031,"finding":"In C. elegans, MYRF-1 must traffic to the cell membrane before cleavage occurs; the timing of N-MYRF release from the membrane coincides with the onset of synaptic rewiring; PAN-1 and MYRF interact via their extracellular regions on the cell membrane, and loss of PAN-1 abolishes MYRF membrane localization and blocks myrf-dependent neuronal rewiring.","method":"Live imaging of subcellular localization, Co-IP of extracellular domain interactions, C. elegans genetics","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization imaging tied to functional genetic consequence; single lab; builds on PMID 28441531","pmids":["33950834"],"is_preprint":false}],"current_model":"MYRF is an ER/membrane-anchored transcription factor that trimerizes via a bacteriophage tailspike-related intramolecular chaperone (ICA) domain, which catalyzes autoproteolytic self-cleavage through a serine-lysine dyad active only in the trimeric state; the released N-terminal homo-trimer translocates to the nucleus where its Ig-fold DNA-binding domain recognizes a trimeric DNA motif to activate myelin genes and other targets, with transcriptional activity residing in an N-terminal transactivation domain subject to SUMO repression; cleavage is negatively regulated by TMEM98 (binding the C-terminus) and, in C. elegans, by a juxtamembrane cis-inhibitory region and the PAN-1 cytoplasmic tail, while the N-terminal fragment is degraded by GSK-3-primed, SCF-FBXW7-mediated ubiquitylation; MYRF cooperates with and is induced by Sox10 during oligodendrocyte differentiation, and its activity governs myelination, synaptic rewiring, mesothelial specification, eye size, and multiple organ developmental programs."},"narrative":{"mechanistic_narrative":"MYRF is a membrane-anchored transcription factor that governs terminal differentiation programs across multiple tissues by coupling regulated proteolysis to gene activation [PMID:23966833, PMID:23966832, PMID:28441531]. Synthesized as an ER/membrane-associated protein, MYRF undergoes constitutive, cell-type-independent autoproteolytic self-cleavage that liberates a nuclear-targeted N-terminal fragment from its transmembrane C-terminal region [PMID:23966833, PMID:23966832]. Cleavage is catalyzed by a bacteriophage tailspike-related intramolecular chaperone (ICA) domain whose triple-helical coiled-coil drives trimerization, and self-cleavage proceeds through a serine-lysine catalytic dyad that is active only when ICA domains are organized as trimers [PMID:23966832, PMID:34345217]. The released N-terminal fragments themselves assemble into stable homo-trimers, and this homo-trimerization both is essential for function and defines DNA-binding specificity, enabling recognition of a homo-trimeric DNA motif at enhancers of oligodendrocyte and myelin genes [PMID:23966833, PMID:23966832, PMID:28160598]. Transcriptional activity resides in an N-terminal-most transactivation domain that is repressed by SUMOylation at K276 without affecting stability or nuclear localization [PMID:30166609]. In the myelinating lineage, Sox10 induces Myrf and the two factors physically interact to co-activate differentiation genes while MYRF also restrains Sox10-dependent OPC-stage genes, producing a bimodal switch into maturation [PMID:24204311, PMID:31828317, PMID:27532821]. MYRF activation is held in check at the membrane: the ER transmembrane protein TMEM98 binds the MYRF C-terminus to inhibit self-cleavage and nuclear translocation, controlling outcomes such as RPE integrity and eye size [PMID:30249802, PMID:32236127], while the released N-terminal fragment is targeted for degradation by GSK-3-primed, SCF-FBXW7-mediated ubiquitylation to balance myelin growth and homeostasis [PMID:29472293, PMID:40841354]. Beyond myelination, MYRF directs mesothelial specification synergistically with YAP/TAZ, with early loss causing congenital diaphragmatic hernia [PMID:41558485], and is required for epicardial development [PMID:bio_10.1101_2025.10.17.682841]. Disease-associated DNA-binding-domain missense mutations abolish transcriptional activity by disrupting homo-trimerization, acting through haploinsufficiency or dominant-negative mechanisms [PMID:33798553].","teleology":[{"year":2013,"claim":"Established the core paradigm that MYRF is a membrane-tethered transcription factor activated by autoproteolytic release of a nuclear DNA-binding fragment, answering how an ER-associated protein controls myelin gene transcription.","evidence":"Biochemical fractionation, ChIP-Seq, domain mutagenesis and reporter assays in two simultaneous studies","pmids":["23966833","23966832"],"confidence":"High","gaps":["Did not resolve the structural basis of cleavage","Trigger/regulation of cleavage timing unknown"]},{"year":2013,"claim":"Identified the bacteriophage tailspike-related ICA chaperone domain as the trimerization and self-cleavage module, explaining the catalytic mechanism behind activation and showing it is constitutive and tissue-independent.","evidence":"Bioinformatics and reconstitution in E. coli and yeast plus functional transcriptional assays","pmids":["23966832"],"confidence":"High","gaps":["Catalytic residues not yet defined structurally","How cleavage is regulated in vivo if constitutive in heterologous systems"]},{"year":2013,"claim":"Placed MYRF downstream of and in physical partnership with Sox10, defining the transcriptional circuit that drives oligodendrocyte differentiation.","evidence":"Enhancer/reporter mapping, Co-IP, and luciferase synergy assays with in vivo genetics","pmids":["24204311"],"confidence":"High","gaps":["Direct vs indirect mechanism of synergy not resolved here","Stoichiometry of MYRF-Sox10 complex unknown"]},{"year":2016,"claim":"Clarified that MYRF binds DNA as a trimer while Sox10 binds as a monomer and that cooperation occurs after binding, refining the biochemical logic of co-activation.","evidence":"ChIP, EMSA, promoter reporter assays and shRNA knockdown in oligodendroglial cells","pmids":["27532821"],"confidence":"Medium","gaps":["Post-binding cooperative step molecularly undefined","Single target gene (Dusp15) analyzed"]},{"year":2017,"claim":"Showed the N-terminal fragment functions as a homo-trimer that itself dictates DNA-binding specificity, converting the trimerization requirement into a sequence-recognition mechanism via a homo-trimeric DNA motif.","evidence":"Gel filtration, mutagenesis, C. elegans rescue and DNA motif analysis","pmids":["28160598"],"confidence":"High","gaps":["Structure of fragment-DNA complex not determined","Region driving N-fragment trimerization mapped only approximately"]},{"year":2017,"claim":"Demonstrated conservation of the membrane-cleavage-nuclear translocation mechanism in C. elegans and extended MYRF function beyond myelination to synaptic rewiring.","evidence":"Live imaging of GFP fusions, cleavage assays, loss- and gain-of-function in C. elegans","pmids":["28441531"],"confidence":"High","gaps":["Direct target genes for rewiring not identified here","What triggers stage-specific cleavage unknown"]},{"year":2018,"claim":"Identified TMEM98 as a C-terminus-binding inhibitor of MYRF self-cleavage, providing a negative feedback brake on activation during oligodendrocyte differentiation.","evidence":"Reciprocal Co-IP, overexpression in chicken spinal cord, cleavage and nuclear translocation assays","pmids":["30249802"],"confidence":"High","gaps":["Structural basis of inhibition unknown","Whether TMEM98 release is signal-regulated unresolved"]},{"year":2018,"claim":"Established a degradation arm of MYRF control whereby GSK-3 phosphorylation of a phosphodegron licenses SCF-FBXW7 to ubiquitylate MYRF, adding post-cleavage turnover regulation.","evidence":"Co-IP, in vitro ubiquitylation with recombinant SCF-FBXW7, phosphodegron mutagenesis, GSK-3 inhibition","pmids":["29472293"],"confidence":"High","gaps":["In vivo significance not yet shown at this stage","Which MYRF fragment is the primary substrate not fully resolved"]},{"year":2018,"claim":"Localized transcriptional activity to an N-terminal transactivation domain and showed SUMOylation at K276 represses it independently of stability/localization, identifying a tunable activity setpoint.","evidence":"Gal4 fusion reporter assays and site-directed sumoylation-site mutagenesis","pmids":["30166609"],"confidence":"Medium","gaps":["SUMO ligase/conditions in vivo not identified","No structural validation"]},{"year":2019,"claim":"Linked MYRF to retinal pigment epithelium maintenance and showed a regulatory relationship with TMEM98 (physical interaction plus MYRF control of Tmem98 expression).","evidence":"Co-IP and conditional Myrf knockout mouse with histological/molecular phenotyping","pmids":["31048900"],"confidence":"Medium","gaps":["Direct vs indirect regulation of Tmem98 unresolved","Mechanism of RPE degeneration not dissected"]},{"year":2020,"claim":"Confirmed in vivo that TMEM98 restrains MYRF activation, with loss causing ectopic MYRF nuclear localization and altered eye size, validating the membrane brake physiologically.","evidence":"BioID proximity labeling and RPE-specific Tmem98 conditional knockout mice with localization and cleavage assays","pmids":["32236127"],"confidence":"High","gaps":["Downstream MYRF targets controlling eye size unidentified","Signal that relieves inhibition unknown"]},{"year":2020,"claim":"Defined a bimodal regulatory logic in which MYRF co-activates differentiation genes with Sox10 yet sequesters Sox10 to repress OPC-stage genes, explaining the differentiation switch.","evidence":"ChIP, EMSA, reporter assays, Co-IP and loss-of-function analysis","pmids":["31828317"],"confidence":"High","gaps":["Quantitative thresholds for switch behavior undefined","Generality across all Sox10 targets untested"]},{"year":2020,"claim":"Extended MYRF function to non-neural epithelia, showing HNF1B-driven MYRF regulates secretory protein expression to prevent ER overload in pancreatic ductal adenocarcinoma.","evidence":"Conditional MYRF knockout in PDAC cells, RNA-seq, spheroid and in vivo tumor models","pmids":["32997974"],"confidence":"Medium","gaps":["Direct MYRF target genes in PDAC not enumerated","Whether the proteolytic mechanism operates identically here untested"]},{"year":2021,"claim":"Provided the crystal structure of the ICA domain plus stalk, showing the C-terminal coiled-coil drives trimerization and that the serine-lysine dyad self-cleaves only in the trimeric state, giving an atomic basis for activation control.","evidence":"X-ray crystallography at 2.4 Angstrom with catalytic-residue mutagenesis","pmids":["34345217"],"confidence":"High","gaps":["Structure of full-length membrane-anchored MYRF lacking","Conformational change driving cleavage not captured"]},{"year":2021,"claim":"Showed disease-associated DBD missense mutations abolish activity by disrupting homo-trimerization, defining distinct haploinsufficient versus dominant-negative allele classes for MYRF disorders.","evidence":"Mutagenesis with transcriptional and trimerization biochemical assays and structural perturbation analysis","pmids":["33798553"],"confidence":"Medium","gaps":["No patient-tissue validation in this study","Structural basis of dominant-negative G435R not directly visualized"]},{"year":2021,"claim":"Identified the LRR-TM protein PAN-1 as required for MYRF membrane localization in C. elegans, revealing that proper membrane targeting is a prerequisite for rewiring-controlling cleavage.","evidence":"Co-IP, live imaging and genetic epistasis in C. elegans","pmids":["33950834"],"confidence":"High","gaps":["Whether a PAN-1 ortholog functions in vertebrates unknown","How PAN-1 binding influences cleavage timing not fully resolved"]},{"year":2022,"claim":"Connected MYRF to epigenetic regulation through physical interaction with DNMT3A, linking MYRF to DNA methylation at glaucoma-related loci.","evidence":"Co-IP, transcriptome sequencing and DNA methylation sequencing of Myrf mutant retinas","pmids":["36129575"],"confidence":"Medium","gaps":["Single Co-IP without reciprocal validation in vivo","Causal link between methylation changes and glaucoma correlative"]},{"year":2024,"claim":"Demonstrated MYRF-1 directly activates the heterochronic microRNA lin-4 in C. elegans with cleavage/nuclear timing matching expression onset, positioning MYRF as a developmental timing driver.","evidence":"C. elegans loss- and gain-of-function plus live imaging of MYRF-1::GFP foci at the lin-4 promoter","pmids":["38963411"],"confidence":"Medium","gaps":["Upstream signal setting cleavage timing not defined","Whether vertebrate MYRF has analogous miRNA targets unknown"]},{"year":2025,"claim":"Showed FBXW7 degrades the N-terminal MYRF fragment in vivo to balance myelin growth and homeostasis, establishing the physiological importance of the degradation arm in myelinating oligodendrocytes.","evidence":"Zebrafish and conditional mouse oligodendrocyte knockouts, primary OL cultures, Co-IP and degradation assays","pmids":["40841354"],"confidence":"High","gaps":["Whether GSK-3 priming operates identically in OLs not retested here","Signals controlling FBXW7 access to N-MYRF unknown"]},{"year":2025,"claim":"Expanded MYRF developmental roles to epicardium, showing epicardial but not cardiomyocyte MYRF is required for cardiac development.","evidence":"Cell-type-specific conditional knockouts with histology and fate tracing (preprint)","pmids":["bio_10.1101_2025.10.17.682841"],"confidence":"Medium","gaps":["Peer review pending","Direct epicardial target genes not identified"]},{"year":2025,"claim":"Broadened the heterochronic role to a network of microRNAs and oscillatory genes with lin-42/Period feedback, framing MYRF as a node in a developmental timing oscillator.","evidence":"C. elegans genetics, direct binding assays at miRNA promoters and oscillation imaging (preprint)","pmids":["41659655"],"confidence":"Medium","gaps":["Peer review pending","Molecular mechanism of oscillation generation unresolved"]},{"year":2025,"claim":"Showed MYRF-1 directly primes linker cell death by binding the pqn-41 promoter, extending MYRF function to programmed cell death timing.","evidence":"Single-cell RNA-seq, auxin-inducible MYRF-1 degradation, promoter binding-site deletion in C. elegans (preprint)","pmids":["41427293"],"confidence":"Medium","gaps":["Peer review pending","Conservation of cell-death role in vertebrates untested"]},{"year":2026,"claim":"Established MYRF as a driver of mesothelial specification acting synergistically with YAP/TAZ, with early loss causing congenital diaphragmatic hernia.","evidence":"Temporally controlled conditional Myrf knockouts and compound Myrf/YAP-TAZ mutants with fate analysis","pmids":["41558485"],"confidence":"High","gaps":["Mechanism of MYRF-YAP/TAZ synergy molecularly undefined","Direct mesothelial target genes not enumerated"]},{"year":2031,"claim":"Resolved dual cis/trans inhibition of cleavage via the MYRF-1 juxtamembrane region and the PAN-1 cytoplasmic tail, defining the molecular brakes that set developmental timing of activation.","evidence":"Endogenous CRISPR editing, deletion mutants, live imaging and lin-4 reporters in C. elegans (preprint)","pmids":["41542402"],"confidence":"Medium","gaps":["Peer review pending","Whether equivalent cis-inhibition exists in vertebrate MYRF unknown"]},{"year":null,"claim":"The signals that trigger MYRF self-cleavage and relieve membrane inhibition in vertebrate tissues, and the full structure of the membrane-anchored holoprotein, remain undefined.","evidence":"Not addressed by current timeline","pmids":[],"confidence":"Medium","gaps":["No activating signal for cleavage identified in mammals","No full-length membrane-anchored structure","Direct vertebrate target gene catalog incomplete"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,3,8,9]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[0,3,17,21]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[1,11]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[1,11]},{"term_id":"GO:0044183","term_label":"protein folding chaperone","supporting_discovery_ids":[1,11]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0,4,12]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,3,5,12]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[13,24]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression 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DNA-binding consensus sequence to activate their transcription.\",\n      \"method\": \"Biochemical fractionation, ChIP-Seq, domain mutagenesis, reporter assays\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — two independent labs (PMID 23966833 and 23966832) published simultaneously with multiple orthogonal methods including ChIP-Seq, mutagenesis, and functional assays; findings replicated across both papers\",\n      \"pmids\": [\"23966833\", \"23966832\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"MYRF contains a protein domain related to bacteriophage tailspike intramolecular chaperone (ICA) domains that facilitates MYRF trimerization and autoproteolytic self-cleavage; this chaperone domain-mediated autoproteolysis is essential for MYRF transcriptional activity and its ability to promote oligodendrocyte maturation. The proteolysis occurs constitutively and independent of cell- or tissue-type, as demonstrated by reconstitution in E. coli and yeast.\",\n      \"method\": \"Bioinformatics, biochemical reconstitution in E. coli and yeast, functional transcriptional assays, domain mutagenesis\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution in heterologous systems plus mutagenesis plus functional validation in a single rigorous study, replicated in parallel by PMID 23966833\",\n      \"pmids\": [\"23966832\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Sox10 induces Myrf expression through a Sox10-responsive enhancer in intron 1 of the Myrf gene; once induced, Myrf physically interacts with Sox10 and they synergistically activate several myelin-specific genes.\",\n      \"method\": \"Reporter/enhancer assays, Co-immunoprecipitation (physical interaction), luciferase synergy assays, in vivo genetics\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal interaction confirmed by Co-IP, multiple functional assays including enhancer mapping and synergy, single lab but ≥2 orthogonal methods\",\n      \"pmids\": [\"24204311\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"MYRF N-terminal fragments assemble into stable homo-trimers before ER release; homo-trimerization is essential for the biological function of the N-terminal fragment, and the region adjacent to the DNA-binding domain is pivotal for homo-trimerization. Homo-trimerization defines the DNA-binding specificity of Myrf N-terminal fragments, enabling binding to a novel homo-trimeric DNA motif.\",\n      \"method\": \"Biochemical fractionation, gel filtration, mutagenesis, C. elegans genetic rescue, computational DNA motif analysis\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — multiple orthogonal biochemical and genetic methods in a single study; mutagenesis tied to in vivo functional readout in C. elegans\",\n      \"pmids\": [\"28160598\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TMEM98, an ER-associated transmembrane protein, physically binds to the C-terminal region of MYRF and inhibits its self-cleavage and N-fragment nuclear translocation, thereby acting as a negative feedback regulator of MYRF activity during oligodendrocyte differentiation.\",\n      \"method\": \"Co-immunoprecipitation, overexpression in embryonic chicken spinal cord, Western blot for cleavage products, nuclear translocation assays\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP for physical interaction, in vivo functional assay (chicken spinal cord), and cleavage assay in a single study with multiple orthogonal methods\",\n      \"pmids\": [\"30249802\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TMEM98 inhibits the autoproteolytic self-cleavage of MYRF; in retinal pigment epithelium lacking TMEM98, MYRF is ectopically activated and abnormally localised to nuclei, demonstrating that TMEM98–MYRF interaction controls MYRF activation state and eye size.\",\n      \"method\": \"Proximity labeling (BioID) to identify interacting partners, conditional Tmem98 knockout mice (RPE-specific), immunofluorescence for MYRF nuclear localization, cleavage assays\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proximity labeling plus conditional KO with localization readout, independent replication of TMEM98–MYRF interaction from PMID 30249802\",\n      \"pmids\": [\"32236127\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The SCF-FBXW7 E3 ubiquitin ligase complex directly binds the NH2-terminal cytoplasmic domain of MYRF and polyubiquitylates it in an in vitro ubiquitylation assay; GSK-3 kinase phosphorylates a putative phosphodegron in MYRF, and this phosphorylation is required for FBXW7-mediated degradation of MYRF.\",\n      \"method\": \"Co-immunoprecipitation, in vitro ubiquitylation assay with recombinant SCF-FBXW7, phosphodegron mutagenesis, GSK-3 inhibitor treatment\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstituted ubiquitylation with purified components, Co-IP, and mutagenesis in a single study\",\n      \"pmids\": [\"29472293\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FBXW7 directly binds and degrades the N-terminal fragment of MYRF (N-MYRF) to control the balance between oligodendrocyte myelin growth and homeostasis; loss of Fbxw7 in myelinating oligodendrocytes increases myelin sheath lengths and causes progressive myelin abnormalities including outfolds and ectopic ensheathment.\",\n      \"method\": \"Zebrafish genetics, conditional mouse KO in oligodendrocytes, primary OL cultures, biochemical Co-IP and degradation assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP plus in vivo conditional KO in two vertebrate models (zebrafish and mouse) with specific cellular phenotype readout; replicates and extends PMID 29472293\",\n      \"pmids\": [\"40841354\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Myrf cooperates with Sox10 in a bimodal manner: it co-activates differentiation genes by joint binding with Sox10 to the same regulatory regions, and it inhibits Sox10-dependent activation of OPC-stage genes by physical interaction with Sox10 leading to Sox10 sequestration on genes lacking Myrf binding sites.\",\n      \"method\": \"ChIP, EMSA, reporter assays, Co-immunoprecipitation, loss-of-function analysis\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (ChIP, EMSA, Co-IP, reporter assays) in a single study establishing two mechanistically distinct modes of cooperation/inhibition\",\n      \"pmids\": [\"31828317\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The N-terminal-most (NTM) domain of Myrf functions as its transactivation domain; when fused to Gal4 it activates transcription independently of trimerization. This NTM domain can be sumoylated at three lysine residues (K123, K208, K276), with K276 as the main acceptor; K276 sumoylation represses the transactivation function without affecting Myrf stability or nuclear localization.\",\n      \"method\": \"Gal4 fusion reporter assays, site-directed mutagenesis of sumoylation sites, Western blot, nuclear localization assays\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional reporter plus mutagenesis, single lab, no orthogonal structural validation\",\n      \"pmids\": [\"30166609\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Four disease-associated MYRF DNA-binding domain missense mutations (F387S, Q403H, G435R, L479V) abolish transcriptional activity by disrupting homo-trimerization through perturbation of DBD structure. Three mutations (F387S, Q403H, L479V) are tolerated as single copies within a homo-trimer (haploinsufficiency mechanism), while G435R acts as a dominant negative.\",\n      \"method\": \"Mutagenesis, transcriptional activity assays, trimerization biochemical assays, structural perturbation analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis linked to functional transcriptional and biochemical trimerization assays, single lab, clear mechanistic distinction between allele classes\",\n      \"pmids\": [\"33798553\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Crystal structure of the MyRF ICA domain with its upstream β-helical stalk (at 2.4 Å) reveals that a triple α-helical coiled-coil at the ICA domain C-terminus is the main driving force for trimerization; self-cleavage occurs via a conserved serine-lysine catalytic dyad and is activated only when ICA domains are organized as trimers.\",\n      \"method\": \"X-ray crystallography, structural analysis, mutagenesis of catalytic residues\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure determination with functional validation of catalytic mechanism by mutagenesis, single lab\",\n      \"pmids\": [\"34345217\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"In C. elegans, the MYRF family members MYRF-1 and MYRF-2 localize to the ER membrane, undergo proteolytic cleavage to release active N-terminal fragments that translocate to the nucleus, and cooperatively regulate synaptic rewiring; overexpression of active forms of MYRF is sufficient to accelerate synaptic rewiring.\",\n      \"method\": \"Live imaging of GFP fusions, cleavage assays, genetic loss-of-function, overexpression rescue in C. elegans\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization by live imaging tied to functional genetic evidence; cleavage-to-nuclear-translocation mechanism confirmed in vivo in C. elegans\",\n      \"pmids\": [\"28441531\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In C. elegans, the LRR-TM protein PAN-1 localizes on the cell membrane, physically interacts with MYRF via extracellular domains, and is required for MYRF cell membrane localization; loss of PAN-1 abolishes MYRF membrane localization and consequently blocks myrf-dependent neuronal rewiring.\",\n      \"method\": \"Co-immunoprecipitation, live imaging of localization, genetic epistasis in C. elegans loss-of-function\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP plus direct localization imaging with clear functional consequence (rewiring arrest), multiple orthogonal methods in C. elegans\",\n      \"pmids\": [\"33950834\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"MYRF physically interacts with TMEM98 (confirmed by Co-immunoprecipitation); Myrf conditional knockout mice develop retinal pigment epithelium depigmentation and retinal degeneration, and show reduced expression of Tmem98, indicating MYRF regulates Tmem98 expression.\",\n      \"method\": \"Co-immunoprecipitation, conditional knockout mouse model (Myrf CKO), histological and molecular phenotyping\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for physical interaction plus conditional KO phenotype, single lab, interaction with TMEM98 also replicated in PMID 32236127\",\n      \"pmids\": [\"31048900\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"MYRF physically interacts with DNMT3A (demonstrated by Co-immunoprecipitation); in Myrf mutant mouse retinas, Dnmt3a is downregulated and DNA methylation patterns at glaucoma-related loci are altered, linking the MYRF–DNMT3A interaction to primary angle-closure glaucoma pathogenesis.\",\n      \"method\": \"Co-immunoprecipitation, transcriptome sequencing of Myrf mutant retinas, DNA methylation sequencing\",\n      \"journal\": \"Human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — single Co-IP plus transcriptomic/epigenomic correlation; physical interaction established but downstream mechanistic details are correlative\",\n      \"pmids\": [\"36129575\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In pancreatic ductal adenocarcinoma cells, MYRF expression is controlled by the transcription factor HNF1B; MYRF acts to regulate expression of highly glycosylated, cysteine-rich secretory proteins, preventing ER overload. MYRF-deficient PDAC cells show ER stress and impaired proliferation.\",\n      \"method\": \"Conditional MYRF knockout in PDAC cells, RNA-seq, spheroid formation assay, in vivo tumor models\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with specific ER stress phenotype, upstream regulator identified, multiple readouts; single lab\",\n      \"pmids\": [\"32997974\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In C. elegans, MYRF-1 is necessary for activation of the microRNA lin-4; increased MYRF-1 cleavage and nuclear accumulation coincides with lin-4 expression timing, and hyperactive MYRF-1 can prematurely drive lin-4 expression; MYRF-1 directly binds to the lin-4 promoter as shown by nuclear GFP focus formation at the tandem lin-4 promoter.\",\n      \"method\": \"C. elegans genetics (loss-of-function and gain-of-function), live imaging of MYRF-1::GFP nuclear foci at lin-4 promoter loci, cleavage/translocation timing assays\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct promoter binding demonstrated by nuclear focus formation, genetic epistasis, and gain-of-function timing experiments; single lab\",\n      \"pmids\": [\"38963411\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Sox10 and Myrf cooperatively activate Dusp15 expression through the Dusp15 promoter, which contains both a functional Sox10-binding site and a functional Myrf-binding site; Sox10 binds as a monomer while Myrf binds as a trimer; cooperative activation occurs at a step after binding rather than through facilitated binding.\",\n      \"method\": \"ChIP, EMSA, reporter/promoter assays, shRNA knockdown of Dusp15 in oligodendroglial cells\",\n      \"journal\": \"Glia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and EMSA establish binding modes; functional synergy confirmed by reporter assays; knockdown establishes downstream role; single lab\",\n      \"pmids\": [\"27532821\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2031,\n      \"finding\": \"In C. elegans, MYRF-1 cleavage is dually inhibited by (1) a juxtamembrane (JM) region of MYRF-1 that acts as a cis self-inhibitor of cleavage, and (2) the cytoplasmic tail (CCT) of PAN-1 which acts as a trans-inhibitor; deletion of either leads to premature MYRF-1 nuclear entry, early lin-4 activation, and larval lethality, establishing these as key regulators of developmental timing.\",\n      \"method\": \"Endogenous gene editing (CRISPR), C. elegans genetics (deletion mutants), live imaging of nuclear accumulation, lin-4 reporter assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — endogenous CRISPR editing with clean functional readouts; preprint, not yet peer-reviewed\",\n      \"pmids\": [\"41542402\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In C. elegans, MYRF-1 directly activates key heterochronic microRNAs (lin-4, mir-48/241/84, let-7) and amplifies oscillatory gene networks including nhr-23; MYRF-1 nuclear accumulation oscillates across larval stages; lin-42/Period feeds back to repress myrf; loss of MYRF causes developmental arrest during late intermolt phase.\",\n      \"method\": \"C. elegans genetics, ChIP or direct binding assays for heterochronic miRNA promoters, loss-of-function with stage-arrest readout, oscillation imaging\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function, direct binding evidence for miRNA promoters, oscillation imaging; preprint, not yet peer-reviewed\",\n      \"pmids\": [\"41659655\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In C. elegans, MYRF-1 directly binds the promoter of pqn-41 (a polyglutamine protein gene required for linker cell death); MYRF-1 nuclear translocation in the linker cell primes linker-cell-type death early during migration; deleting a bona fide MYRF-1 binding site within pqn-41 promotes linker cell survival.\",\n      \"method\": \"Single-cell mRNA sequencing, auxin-inducible degradation of MYRF-1, promoter binding/deletion assays in C. elegans\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct promoter binding confirmed by deletion of binding site with survival readout; auxin-degradation system for temporal control; preprint, not yet peer-reviewed\",\n      \"pmids\": [\"41427293\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"MYRF is most highly expressed in epicardial cells among cardiac cell types; conditional deletion of Myrf in epicardial cells (EPCs) causes severely degenerated epicardium, dramatically reduced epicardial-derived cells, and thin myocardial wall; deletion in cardiomyocytes produces no overt phenotype, establishing epicardial MYRF as the cell-type-specific requirement for cardiac development.\",\n      \"method\": \"Cell-type-specific conditional KO (epicardial Cre vs cardiomyocyte Cre), histological analysis, cell fate tracing\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-type-specific genetic epistasis with clear phenotypic readout; preprint, not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.10.17.682841\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Myrf inactivation early in embryogenesis causes CDH and defective mesothelium specification in mice; later inactivation leads to enhanced mesothelial differentiation into mesenchymal cell types including elastin-expressing smooth muscle/myofibroblasts encasing the lung; MYRF functions synergistically with YAP/TAZ in mesothelium differentiation, as shown by compound mutants.\",\n      \"method\": \"Conditional Myrf knockout mice with temporally controlled Cre, compound Myrf/YAP-TAZ mutants (genetic epistasis), histological and cell fate analysis\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with temporal control, genetic epistasis with YAP/TAZ, specific cellular phenotypes; peer-reviewed publication\",\n      \"pmids\": [\"41558485\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2031,\n      \"finding\": \"In C. elegans, MYRF-1 must traffic to the cell membrane before cleavage occurs; the timing of N-MYRF release from the membrane coincides with the onset of synaptic rewiring; PAN-1 and MYRF interact via their extracellular regions on the cell membrane, and loss of PAN-1 abolishes MYRF membrane localization and blocks myrf-dependent neuronal rewiring.\",\n      \"method\": \"Live imaging of subcellular localization, Co-IP of extracellular domain interactions, C. elegans genetics\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization imaging tied to functional genetic consequence; single lab; builds on PMID 28441531\",\n      \"pmids\": [\"33950834\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MYRF is an ER/membrane-anchored transcription factor that trimerizes via a bacteriophage tailspike-related intramolecular chaperone (ICA) domain, which catalyzes autoproteolytic self-cleavage through a serine-lysine dyad active only in the trimeric state; the released N-terminal homo-trimer translocates to the nucleus where its Ig-fold DNA-binding domain recognizes a trimeric DNA motif to activate myelin genes and other targets, with transcriptional activity residing in an N-terminal transactivation domain subject to SUMO repression; cleavage is negatively regulated by TMEM98 (binding the C-terminus) and, in C. elegans, by a juxtamembrane cis-inhibitory region and the PAN-1 cytoplasmic tail, while the N-terminal fragment is degraded by GSK-3-primed, SCF-FBXW7-mediated ubiquitylation; MYRF cooperates with and is induced by Sox10 during oligodendrocyte differentiation, and its activity governs myelination, synaptic rewiring, mesothelial specification, eye size, and multiple organ developmental programs.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MYRF is a membrane-anchored transcription factor that governs terminal differentiation programs across multiple tissues by coupling regulated proteolysis to gene activation [#0, #12]. Synthesized as an ER/membrane-associated protein, MYRF undergoes constitutive, cell-type-independent autoproteolytic self-cleavage that liberates a nuclear-targeted N-terminal fragment from its transmembrane C-terminal region [#0, #1]. Cleavage is catalyzed by a bacteriophage tailspike-related intramolecular chaperone (ICA) domain whose triple-helical coiled-coil drives trimerization, and self-cleavage proceeds through a serine-lysine catalytic dyad that is active only when ICA domains are organized as trimers [#1, #11]. The released N-terminal fragments themselves assemble into stable homo-trimers, and this homo-trimerization both is essential for function and defines DNA-binding specificity, enabling recognition of a homo-trimeric DNA motif at enhancers of oligodendrocyte and myelin genes [#0, #3]. Transcriptional activity resides in an N-terminal-most transactivation domain that is repressed by SUMOylation at K276 without affecting stability or nuclear localization [#9]. In the myelinating lineage, Sox10 induces Myrf and the two factors physically interact to co-activate differentiation genes while MYRF also restrains Sox10-dependent OPC-stage genes, producing a bimodal switch into maturation [#2, #8, #18]. MYRF activation is held in check at the membrane: the ER transmembrane protein TMEM98 binds the MYRF C-terminus to inhibit self-cleavage and nuclear translocation, controlling outcomes such as RPE integrity and eye size [#4, #5], while the released N-terminal fragment is targeted for degradation by GSK-3-primed, SCF-FBXW7-mediated ubiquitylation to balance myelin growth and homeostasis [#6, #7]. Beyond myelination, MYRF directs mesothelial specification synergistically with YAP/TAZ, with early loss causing congenital diaphragmatic hernia [#23], and is required for epicardial development [#22]. Disease-associated DNA-binding-domain missense mutations abolish transcriptional activity by disrupting homo-trimerization, acting through haploinsufficiency or dominant-negative mechanisms [#10].\",\n  \"teleology\": [\n    {\n      \"year\": 2013,\n      \"claim\": \"Established the core paradigm that MYRF is a membrane-tethered transcription factor activated by autoproteolytic release of a nuclear DNA-binding fragment, answering how an ER-associated protein controls myelin gene transcription.\",\n      \"evidence\": \"Biochemical fractionation, ChIP-Seq, domain mutagenesis and reporter assays in two simultaneous studies\",\n      \"pmids\": [\"23966833\", \"23966832\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the structural basis of cleavage\", \"Trigger/regulation of cleavage timing unknown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified the bacteriophage tailspike-related ICA chaperone domain as the trimerization and self-cleavage module, explaining the catalytic mechanism behind activation and showing it is constitutive and tissue-independent.\",\n      \"evidence\": \"Bioinformatics and reconstitution in E. coli and yeast plus functional transcriptional assays\",\n      \"pmids\": [\"23966832\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Catalytic residues not yet defined structurally\", \"How cleavage is regulated in vivo if constitutive in heterologous systems\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Placed MYRF downstream of and in physical partnership with Sox10, defining the transcriptional circuit that drives oligodendrocyte differentiation.\",\n      \"evidence\": \"Enhancer/reporter mapping, Co-IP, and luciferase synergy assays with in vivo genetics\",\n      \"pmids\": [\"24204311\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct vs indirect mechanism of synergy not resolved here\", \"Stoichiometry of MYRF-Sox10 complex unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Clarified that MYRF binds DNA as a trimer while Sox10 binds as a monomer and that cooperation occurs after binding, refining the biochemical logic of co-activation.\",\n      \"evidence\": \"ChIP, EMSA, promoter reporter assays and shRNA knockdown in oligodendroglial cells\",\n      \"pmids\": [\"27532821\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Post-binding cooperative step molecularly undefined\", \"Single target gene (Dusp15) analyzed\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showed the N-terminal fragment functions as a homo-trimer that itself dictates DNA-binding specificity, converting the trimerization requirement into a sequence-recognition mechanism via a homo-trimeric DNA motif.\",\n      \"evidence\": \"Gel filtration, mutagenesis, C. elegans rescue and DNA motif analysis\",\n      \"pmids\": [\"28160598\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of fragment-DNA complex not determined\", \"Region driving N-fragment trimerization mapped only approximately\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrated conservation of the membrane-cleavage-nuclear translocation mechanism in C. elegans and extended MYRF function beyond myelination to synaptic rewiring.\",\n      \"evidence\": \"Live imaging of GFP fusions, cleavage assays, loss- and gain-of-function in C. elegans\",\n      \"pmids\": [\"28441531\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct target genes for rewiring not identified here\", \"What triggers stage-specific cleavage unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified TMEM98 as a C-terminus-binding inhibitor of MYRF self-cleavage, providing a negative feedback brake on activation during oligodendrocyte differentiation.\",\n      \"evidence\": \"Reciprocal Co-IP, overexpression in chicken spinal cord, cleavage and nuclear translocation assays\",\n      \"pmids\": [\"30249802\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of inhibition unknown\", \"Whether TMEM98 release is signal-regulated unresolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Established a degradation arm of MYRF control whereby GSK-3 phosphorylation of a phosphodegron licenses SCF-FBXW7 to ubiquitylate MYRF, adding post-cleavage turnover regulation.\",\n      \"evidence\": \"Co-IP, in vitro ubiquitylation with recombinant SCF-FBXW7, phosphodegron mutagenesis, GSK-3 inhibition\",\n      \"pmids\": [\"29472293\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo significance not yet shown at this stage\", \"Which MYRF fragment is the primary substrate not fully resolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Localized transcriptional activity to an N-terminal transactivation domain and showed SUMOylation at K276 represses it independently of stability/localization, identifying a tunable activity setpoint.\",\n      \"evidence\": \"Gal4 fusion reporter assays and site-directed sumoylation-site mutagenesis\",\n      \"pmids\": [\"30166609\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"SUMO ligase/conditions in vivo not identified\", \"No structural validation\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Linked MYRF to retinal pigment epithelium maintenance and showed a regulatory relationship with TMEM98 (physical interaction plus MYRF control of Tmem98 expression).\",\n      \"evidence\": \"Co-IP and conditional Myrf knockout mouse with histological/molecular phenotyping\",\n      \"pmids\": [\"31048900\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect regulation of Tmem98 unresolved\", \"Mechanism of RPE degeneration not dissected\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Confirmed in vivo that TMEM98 restrains MYRF activation, with loss causing ectopic MYRF nuclear localization and altered eye size, validating the membrane brake physiologically.\",\n      \"evidence\": \"BioID proximity labeling and RPE-specific Tmem98 conditional knockout mice with localization and cleavage assays\",\n      \"pmids\": [\"32236127\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream MYRF targets controlling eye size unidentified\", \"Signal that relieves inhibition unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined a bimodal regulatory logic in which MYRF co-activates differentiation genes with Sox10 yet sequesters Sox10 to repress OPC-stage genes, explaining the differentiation switch.\",\n      \"evidence\": \"ChIP, EMSA, reporter assays, Co-IP and loss-of-function analysis\",\n      \"pmids\": [\"31828317\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative thresholds for switch behavior undefined\", \"Generality across all Sox10 targets untested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Extended MYRF function to non-neural epithelia, showing HNF1B-driven MYRF regulates secretory protein expression to prevent ER overload in pancreatic ductal adenocarcinoma.\",\n      \"evidence\": \"Conditional MYRF knockout in PDAC cells, RNA-seq, spheroid and in vivo tumor models\",\n      \"pmids\": [\"32997974\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct MYRF target genes in PDAC not enumerated\", \"Whether the proteolytic mechanism operates identically here untested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Provided the crystal structure of the ICA domain plus stalk, showing the C-terminal coiled-coil drives trimerization and that the serine-lysine dyad self-cleaves only in the trimeric state, giving an atomic basis for activation control.\",\n      \"evidence\": \"X-ray crystallography at 2.4 Angstrom with catalytic-residue mutagenesis\",\n      \"pmids\": [\"34345217\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of full-length membrane-anchored MYRF lacking\", \"Conformational change driving cleavage not captured\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed disease-associated DBD missense mutations abolish activity by disrupting homo-trimerization, defining distinct haploinsufficient versus dominant-negative allele classes for MYRF disorders.\",\n      \"evidence\": \"Mutagenesis with transcriptional and trimerization biochemical assays and structural perturbation analysis\",\n      \"pmids\": [\"33798553\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No patient-tissue validation in this study\", \"Structural basis of dominant-negative G435R not directly visualized\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified the LRR-TM protein PAN-1 as required for MYRF membrane localization in C. elegans, revealing that proper membrane targeting is a prerequisite for rewiring-controlling cleavage.\",\n      \"evidence\": \"Co-IP, live imaging and genetic epistasis in C. elegans\",\n      \"pmids\": [\"33950834\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether a PAN-1 ortholog functions in vertebrates unknown\", \"How PAN-1 binding influences cleavage timing not fully resolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Connected MYRF to epigenetic regulation through physical interaction with DNMT3A, linking MYRF to DNA methylation at glaucoma-related loci.\",\n      \"evidence\": \"Co-IP, transcriptome sequencing and DNA methylation sequencing of Myrf mutant retinas\",\n      \"pmids\": [\"36129575\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single Co-IP without reciprocal validation in vivo\", \"Causal link between methylation changes and glaucoma correlative\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrated MYRF-1 directly activates the heterochronic microRNA lin-4 in C. elegans with cleavage/nuclear timing matching expression onset, positioning MYRF as a developmental timing driver.\",\n      \"evidence\": \"C. elegans loss- and gain-of-function plus live imaging of MYRF-1::GFP foci at the lin-4 promoter\",\n      \"pmids\": [\"38963411\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Upstream signal setting cleavage timing not defined\", \"Whether vertebrate MYRF has analogous miRNA targets unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed FBXW7 degrades the N-terminal MYRF fragment in vivo to balance myelin growth and homeostasis, establishing the physiological importance of the degradation arm in myelinating oligodendrocytes.\",\n      \"evidence\": \"Zebrafish and conditional mouse oligodendrocyte knockouts, primary OL cultures, Co-IP and degradation assays\",\n      \"pmids\": [\"40841354\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether GSK-3 priming operates identically in OLs not retested here\", \"Signals controlling FBXW7 access to N-MYRF unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Expanded MYRF developmental roles to epicardium, showing epicardial but not cardiomyocyte MYRF is required for cardiac development.\",\n      \"evidence\": \"Cell-type-specific conditional knockouts with histology and fate tracing (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.10.17.682841\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Peer review pending\", \"Direct epicardial target genes not identified\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Broadened the heterochronic role to a network of microRNAs and oscillatory genes with lin-42/Period feedback, framing MYRF as a node in a developmental timing oscillator.\",\n      \"evidence\": \"C. elegans genetics, direct binding assays at miRNA promoters and oscillation imaging (preprint)\",\n      \"pmids\": [\"41659655\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Peer review pending\", \"Molecular mechanism of oscillation generation unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed MYRF-1 directly primes linker cell death by binding the pqn-41 promoter, extending MYRF function to programmed cell death timing.\",\n      \"evidence\": \"Single-cell RNA-seq, auxin-inducible MYRF-1 degradation, promoter binding-site deletion in C. elegans (preprint)\",\n      \"pmids\": [\"41427293\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Peer review pending\", \"Conservation of cell-death role in vertebrates untested\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Established MYRF as a driver of mesothelial specification acting synergistically with YAP/TAZ, with early loss causing congenital diaphragmatic hernia.\",\n      \"evidence\": \"Temporally controlled conditional Myrf knockouts and compound Myrf/YAP-TAZ mutants with fate analysis\",\n      \"pmids\": [\"41558485\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of MYRF-YAP/TAZ synergy molecularly undefined\", \"Direct mesothelial target genes not enumerated\"]\n    },\n    {\n      \"year\": 2031,\n      \"claim\": \"Resolved dual cis/trans inhibition of cleavage via the MYRF-1 juxtamembrane region and the PAN-1 cytoplasmic tail, defining the molecular brakes that set developmental timing of activation.\",\n      \"evidence\": \"Endogenous CRISPR editing, deletion mutants, live imaging and lin-4 reporters in C. elegans (preprint)\",\n      \"pmids\": [\"41542402\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Peer review pending\", \"Whether equivalent cis-inhibition exists in vertebrate MYRF unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The signals that trigger MYRF self-cleavage and relieve membrane inhibition in vertebrate tissues, and the full structure of the membrane-anchored holoprotein, remain undefined.\",\n      \"evidence\": \"Not addressed by current timeline\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No activating signal for cleavage identified in mammals\", \"No full-length membrane-anchored structure\", \"Direct vertebrate target gene catalog incomplete\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 3, 8, 9]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0, 3, 17, 21]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [1, 11]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [1, 11]},\n      {\"term_id\": \"GO:0044183\", \"supporting_discovery_ids\": [1, 11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0, 4, 12]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 3, 5, 12]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [13, 24]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 2, 8]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [12, 22, 23]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [6, 7]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [21]}\n    ],\n    \"complexes\": [\"SCF-FBXW7 (substrate of)\", \"MYRF homo-trimer\"],\n    \"partners\": [\"SOX10\", \"TMEM98\", \"FBXW7\", \"GSK-3\", \"PAN-1\", \"DNMT3A\", \"HNF1B\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":9,"faith_total":9,"faith_pct":100.0}}