{"gene":"MORF4L1","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":2001,"finding":"MRG15 forms a nuclear multiprotein complex with the retinoblastoma protein (Rb) and the novel protein PAM14; the helix-loop-helix and leucine zipper domains of MRG15 are required for these interactions. This complex activates the B-myb promoter by blocking Rb-induced repression.","method":"Co-immunoprecipitation, yeast two-hybrid, deletion mutagenesis, luciferase reporter assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and functional reporter assay in single lab with domain mapping","pmids":["11500496"],"is_preprint":false},{"year":2002,"finding":"MRG15 is present in two distinct nuclear protein complexes: MAF1 (containing Rb and PAM14, requiring the leucine zipper) and MAF2 (containing hMOF histone acetyltransferase, requiring the N-terminal chromodomain). Deletion of the chromodomain abolishes associated histone acetyltransferase activity and prevents B-myb promoter activation.","method":"Sucrose gradient fractionation, deletion mutant analysis, histone acetyltransferase activity assay, promoter activation assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical fractionation plus functional HAT assay, single lab, multiple orthogonal methods","pmids":["12397079"],"is_preprint":false},{"year":2002,"finding":"MRG15 (and MORF family members MORF4, MRGX) interact with the corepressors mSin3A and TLE to repress transcription. MRG15, but not MRGX or MORF4, additionally interacts with the PHD zinc finger protein Pf1, forming a distinct MRG15/Pf1/mSin3A complex. Dominant-negative TLE and mapping experiments showed repression by MORFs requires mSin3A and TLE associations.","method":"Gal4-fusion transcriptional repression assay, co-immunoprecipitation, domain mapping, dominant-negative TLE","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional reporter assay plus Co-IP with domain mapping, single lab","pmids":["12391155"],"is_preprint":false},{"year":2004,"finding":"Eaf3 (yeast ortholog of MRG15), a subunit of both NuA4 histone acetylase and Rpd3 histone deacetylase complexes, regulates the genomic profile of histone H3 and H4 acetylation such that loss of Eaf3 causes increased acetylation at coding sequences and decreased acetylation at promoters, without affecting overall H4 acetylation levels or NuA4 recruitment.","method":"Chromatin immunoprecipitation, genome-wide transcriptional profiling, histone acetylation profiling","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide ChIP plus transcriptional profiling in yeast, replicated by complementary studies","pmids":["14701747"],"is_preprint":false},{"year":2005,"finding":"Eaf3 chromodomain directly interacts with methylated H3-K36 peptides. This interaction links preferential Rpd3 complex-mediated histone deacetylation of 3' coding regions to H3-K36 methylation by Set2 and RNA Pol II CTD phosphorylation. Eaf3 also inhibits internal initiation within mRNA coding regions, similar to FACT and Spt6.","method":"Chromodomain-methylated peptide binding assay, genetic epistasis (eaf3Δ, set2Δ), chromatin immunoprecipitation","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct in vitro binding assay plus genetic epistasis plus ChIP, replicated across labs","pmids":["16364921"],"is_preprint":false},{"year":2005,"finding":"MRG15 knockout mice are embryonic lethal with developmental delay and reduced cell proliferation in multiple tissues; MRG15 is recruited to the alpha-globin promoter during erythroid differentiation. Mrg15-/- mouse embryonic fibroblasts exhibit cell proliferation defects.","method":"Knockout mouse generation, BrdU proliferation assay, chromatin immunoprecipitation, microarray","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo KO phenotype with ChIP validation, multiple tissue types analyzed","pmids":["15798182"],"is_preprint":false},{"year":2006,"finding":"Crystal structure of human MRG15 chromodomain at 2.2 Å resolution reveals a chromo barrel fold with a hydrophobic pocket formed by Tyr26, Tyr46, and Trp49. In vitro binding assays demonstrate selective binding to H3K36-methylated peptides but not H3K4me, H3K9me, or H3K27me.","method":"X-ray crystallography, in vitro peptide binding assay","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with functional binding validation, replicated by independent structural studies","pmids":["17135209"],"is_preprint":false},{"year":2006,"finding":"Crystal structure of the MRG15 MRG domain reveals an alpha-helical three-layer sandwich topology with a shallow hydrophobic pocket. Structure-based mutagenesis identified residues Ile160, Leu168, Val169, Trp172, Tyr235, Val268, and Arg269 as critical for PAM14 binding via primarily hydrophobic interactions.","method":"X-ray crystallography, yeast two-hybrid, in vitro binding assay, site-directed mutagenesis","journal":"Protein science","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus mutagenesis plus two independent binding assays","pmids":["17008723"],"is_preprint":false},{"year":2007,"finding":"MRG15 is predominantly localized to nuclear subdomains enriched for Ser2-phosphorylated RNA Pol II (active transcription sites). MRG15-containing complexes include the H3K4 demethylase RBP2; RBP2 overexpression reduces H3K4 methylation in vivo and in vitro, and RBP2 knockdown increases H3K4 methylation within transcribed regions of active genes.","method":"Immunofluorescence/nuclear fractionation, immunoprecipitation-mass spectrometry, H3K4 demethylase in vitro assay, RNAi knockdown with ChIP","journal":"Genes to cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — IP-MS identification, in vitro enzymatic assay, ChIP validation, single lab","pmids":["17573780"],"is_preprint":false},{"year":2007,"finding":"Mrg15 null and heterozygous mouse embryonic fibroblasts show impaired DNA damage response after gamma irradiation: defects in DNA repair, cell growth, and delayed recruitment of γH2AX and 53BP1 foci to sites of damage.","method":"Gamma irradiation, immunofluorescence for γH2AX and 53BP1 foci, cell growth assay","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO/heterozygous with defined DNA damage phenotype, single lab","pmids":["17961556"],"is_preprint":false},{"year":2008,"finding":"NMR structure of yeast Eaf3 (MRG15 ortholog) chromo barrel domain bound to methylated H3K36 reveals low-specificity, millimolar-range affinity binding to methylated peptides including H3K36 and H3K4. The structure was determined using an engineered linked Eaf3-H3K36 molecule with a chemically incorporated methyllysine analog.","method":"NMR structure determination, engineered linked protein with methyllysine analog, binding affinity measurements","journal":"Structure","confidence":"High","confidence_rationale":"Tier 1 / Strong — NMR structure with functional validation using novel chemical biology approach","pmids":["18818090"],"is_preprint":false},{"year":2009,"finding":"MRG15 directly binds PALB2 via an evolutionarily conserved region on PALB2. Loss of the PALB2-MRG15 interaction (via MRG15-binding-defective PALB2 mutants) results in elevated gene conversion rates and increased sister chromatid exchange frequencies, indicating MRG15 suppresses hyper-recombination.","method":"Co-immunoprecipitation, gene conversion assay, sister chromatid exchange assay, PALB2 mutant analysis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding mapping plus functional recombination assays, single lab","pmids":["19553677"],"is_preprint":false},{"year":2009,"finding":"MRG15 is required for proliferation and differentiation of neural precursor cells (NPCs). Mrg15-deficient NPCs have reduced proliferation (BrdU assay) and are defective in neuronal differentiation in vitro; neuroepithelia from Mrg15-deficient embryonic brains are thinner with increased apoptosis.","method":"Neurosphere culture from KO embryos, BrdU incorporation, differentiation assay","journal":"Journal of neuroscience research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO-based loss-of-function with defined cellular phenotype, single lab","pmids":["19115414"],"is_preprint":false},{"year":2010,"finding":"MRG15 directly binds PALB2 and mediates DNA-damage-response functions of the BRCA complex (BRCA1, PALB2, BRCA2, RAD51). MRG15 depletion reduces efficiency of homology-directed DNA repair, causes hypersensitivity to DNA interstrand crosslinking agents, and diminishes recruitment of PALB2, BRCA2, and RAD51 to sites of DNA damage.","method":"Purified protein complex analysis, Co-IP, siRNA knockdown, homology-directed repair assay, immunofluorescence for DNA damage foci","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (complex purification, Co-IP, functional repair assay, foci formation), replicated across labs","pmids":["20332121"],"is_preprint":false},{"year":2011,"finding":"MRG15 occupancy at the cdc2 promoter increases ~3-fold during S phase with concomitant increase in H4K12 acetylation (not H4K16). MRG15 cooperates with Tip60 HAT at the cdc2 promoter to activate transcription; HAT inhibition abolishes cdc2 mRNA expression.","method":"ChIP during cell cycle, luciferase reporter assay, siRNA knockdown, HAT inhibitor treatment, Tip60 co-transfection","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus functional reporter with pharmacological and genetic validation, single lab","pmids":["21324423"],"is_preprint":false},{"year":2011,"finding":"Loss of MRG15 in neural stem/progenitor cells specifically upregulates the CDK inhibitor p21 downstream of activated p53; p21 shRNA restores proliferation in Mrg15-deficient NSCs. DNA damage foci (γH2AX, 53BP1) are detectable in Mrg15-deficient NSCs under normal culture conditions.","method":"KO-derived NSCs, p21/p53 shRNA rescue, BrdU assay, immunostaining for γH2AX/53BP1","journal":"Stem cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic rescue experiment (shRNA) placing MRG15 upstream of p53/p21 axis, single lab","pmids":["21621175"],"is_preprint":false},{"year":2011,"finding":"NMR solution structure of mSin3A PAH2 bound to Pf1 SID1 reveals a Mad1/Mxd1-like interaction. Unexpectedly, MRG15 competes with Sin3 for the same Pf1 segment (encompassing SID1 and adjacent conserved motif), indicating competition between two subunits of the same Rpd3S/Sin3S complex for a third subunit.","method":"NMR structure determination, competition binding assay","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — NMR structure plus functional competition binding assay, single lab","pmids":["21440557"],"is_preprint":false},{"year":2012,"finding":"MRG15 chromodomain (CD) binds H3K36me2/3 and Pf1 PHD1 binds unmodified H3 N-terminus (H3K4me0) with >100 µM affinity each. Bivalent (not cooperative) engagement by both subunits is the operative mechanism for targeting the Rpd3S/Sin3S complex to chromatin. Pf1 PHD1 also contacts the MRG15 MRG domain in a Pf1 MBD-dependent manner.","method":"In vitro binding assays, fluorescence polarization/ITC affinity measurements, mutagenesis","journal":"Journal of molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — quantitative binding assays plus mutagenesis, single lab","pmids":["22728643"],"is_preprint":false},{"year":2013,"finding":"Drosophila Mrg15 physically interacts with the condensin Cap-H2 subunit (yeast two-hybrid). Mrg15 is required for Cap-H2-mediated unpairing of polytene chromosomes and homolog unpairing in diploid cells; chromatin-bound Cap-H2 levels are partially dependent on Mrg15, suggesting Mrg15 recruits Cap-H2 to chromatin for interphase chromosome compaction.","method":"Yeast two-hybrid, genetic interaction (transvection assay), RNAi depletion, chromatin fractionation","journal":"Genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid plus genetic epistasis plus RNAi phenotype, single lab","pmids":["23821596"],"is_preprint":false},{"year":2014,"finding":"HDAC2 interacts with MORF4L1 and maintains it in a deacetylated state at Lys-148. Deacetylation of Lys-148 is required for MORF4L1 homodimerization; acetylation-mimicking substitutions (K148L, K148Q) abolish self-assembly, while arginine substitution (K148R) augments it. HDAC2 knockdown reduces MORF4L1 homodimerization.","method":"Co-immunoprecipitation, site-directed mutagenesis, HDAC2 knockdown, self-assembly assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis plus Co-IP plus knockdown with consistent results, single lab","pmids":["24451372"],"is_preprint":false},{"year":2016,"finding":"Eaf3 (yeast MRG15 ortholog) is recruited to intron-containing genes and interacts with splicing factor Prp45. Eaf3 acts with Prp45 and Prp19 after precatalytic B complex formation (around splicing activation). H3K36 methylation by Set2 is required for proper cotranscriptional spliceosome assembly, mediated through Eaf3.","method":"High-throughput RNA sequencing (splicing analysis), ChIP, Co-IP of Eaf3 with splicing factors, genetic epistasis","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genome-wide splicing analysis plus Co-IP plus genetic epistasis, single lab","pmids":["31242410"],"is_preprint":false},{"year":2016,"finding":"Eaf3/5/7 subcomplex within NuA4 stimulates NuA4 binding to di- and trimethylated H3K36 in vitro, and is important for NuA4 occupancy in transcribed ORFs and RNA Pol II binding; mutations in Eaf3/5/7 reduce bulk H4 acetylation ~40% and cause transcription elongation processivity defects.","method":"In vitro nucleosome binding assay, H4 acetylation measurement, Pol II binding assay, transcription elongation assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro binding assay plus functional elongation assay, single lab","pmids":["27535225"],"is_preprint":false},{"year":2016,"finding":"Conditional knockout of MRG15 in the germline causes male sterility due to spermatogenic arrest at the round spermatid stage with specific mRNA sequence loss from 66 germ cell-expressed genes and intron retention in mRNAs of 4 genes (including transition proteins). MRG15 colocalizes with splicing factors PTBP1 and PTBP2 at H3K36me3 sites between exons and introns of Tnp2.","method":"Conditional KO mouse, RNA-seq, intron retention analysis, immunofluorescence co-localization with splicing factors","journal":"PNAS","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo conditional KO with genome-wide RNA-seq and molecular co-localization, multiple orthogonal approaches","pmids":["27573846"],"is_preprint":false},{"year":2017,"finding":"PALB2 associates with active genes through MRG15 binding to H3K36me3 deposited by SETD2 methyltransferase. PALB2 mutations ablating MRG15 binding confer elevated sensitivity to camptothecin, increased aberrant metaphase chromosomes and DNA stress in gene bodies, which is suppressed by preventing DNA replication.","method":"ChIP-seq, co-immunoprecipitation, camptothecin sensitivity assay, metaphase spread analysis, cell fractionation","journal":"PNAS","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP-seq plus functional genetic analysis with replication-suppression epistasis, multiple orthogonal methods","pmids":["28673974"],"is_preprint":false},{"year":2017,"finding":"Drosophila Mrg15 is a subunit of the Ash1 histone methyltransferase complex and stimulates Ash1 enzymatic activity in vitro. In vivo, Mrg15 is recruited by Ash1 to common targets, reinforces Ash1 chromatin association, and facilitates H3K36me2 deposition. An Ash1 point mutant (R1288A) with attenuated Mrg15 interaction shows homeotic transformation phenotypes partially rescued by Mrg15-Nurf55 fusion protein.","method":"In vitro HMT assay, ChIP, knock-in fly genetics, rescue experiment with Mrg15-Nurf55 fusion","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro enzymatic assay plus in vivo ChIP plus genetic rescue, multiple orthogonal methods","pmids":["29158494"],"is_preprint":false},{"year":2018,"finding":"C. elegans MRG-1 (MRG15 ortholog) safeguards germ cells against conversion into neurons; RNAi screening identified MRG-1 as a barrier for germ cell to neuron reprogramming. Protein-protein and genome interactions of MRG-1 were characterized.","method":"Automated solid-phase RNAi screen, germ cell reprogramming assay, protein interaction analysis","journal":"Genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genome-scale RNAi screen plus mechanistic follow-up in C. elegans, single lab","pmids":["30425042"],"is_preprint":false},{"year":2019,"finding":"Crystal structure of human Ash1L tandem MRG15-interacting and SET domains in complex with MRG15 MRG domain reveals that MRG15 binds a segment N-terminal to the Ash1L SET domain via an FxLP motif, displacing the autoinhibitory post-SET loop to permit substrate access to the catalytic pocket. SAM binding pocket changes are induced by MRG15 binding via conformational coupling.","method":"X-ray crystallography, in vitro HMT activity assay, mutagenesis","journal":"Structure","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus in vitro enzymatic assay plus mutagenesis, independently replicated by concurrent structural study","pmids":["30827843"],"is_preprint":false},{"year":2019,"finding":"Crystal structure of ASH1L SET domain with MRG15 MRG domain reveals that MRG15 binding to a conserved FxLP motif in ASH1L displaces the autoinhibitory loop from the post-SET region, permitting substrate access to the ASH1L SET domain catalytic pocket and activating H3K36me2 activity.","method":"X-ray crystallography, in vitro HMT activity assay","journal":"Structure","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with enzymatic validation, independently confirmed by concurrent study (PMID:30827843)","pmids":["30827841"],"is_preprint":false},{"year":2020,"finding":"MRG15 genomic recruitment displays a significant diurnal rhythm in the mouse liver and activates lipid synthesis genes. MRG15 interacts with the nuclear receptor LRH-1 (not core clock proteins), which recruits MRG15 to lipid gene loci. MRG15 depletion impairs rhythmic RNA Pol II recruitment and histone acetylation at these loci.","method":"ChIP-seq (rhythmic genomic binding), Co-IP (MRG15-LRH-1 interaction), CRISPR depletion, RNA-seq","journal":"Nature metabolism","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP-seq plus Co-IP plus CRISPR functional validation, multiple orthogonal methods","pmids":["32694659"],"is_preprint":false},{"year":2021,"finding":"Crystal structure of the MRG15 MRG domain bound to a PALB2 peptide reveals that PALB2 interacts with an extended surface of the MRG domain with nanomolar affinity. Breast cancer-related PALB2 mutations cause only minor attenuation of binding affinity. PALB2 binding to MRG15 is mutually exclusive with other MRG15 MRG domain partners.","method":"X-ray crystallography, binding affinity measurement (ITC/SPR), mutagenesis analysis of patient variants","journal":"Genes","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure plus quantitative affinity measurements with mutant analysis, single lab","pmids":["34946951"],"is_preprint":false},{"year":2022,"finding":"MRG15 associates with the outer mitochondrial membrane and interacts with and deacetylates TUFM at K82 and K91. Deacetylated TUFM undergoes accelerated degradation by the mitochondrial ClpXP protease. Reduced TUFM impairs mitophagy and activates the NLRP3 inflammasome pathway. Inflammatory cytokines in NASH livers stabilize MRG15 by increasing its acetylation.","method":"Immunoprecipitation-mass spectrometry, CRISPR depletion, site-directed mutagenesis (K82/K91), ClpXP protease assay, mitophagy assay, NLRP3 inflammasome measurement","journal":"Journal of hepatology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — IP-MS identification, mutagenesis of modification sites, functional protease and mitophagy assays, multiple orthogonal methods","pmids":["35985547"],"is_preprint":false},{"year":2023,"finding":"Full-length MRG15 (but not the isolated MRG domain alone) enhances ASH1L SET domain histone methyltransferase activity by recruiting it to nucleosome substrates via the MRG15 chromodomain. In solution, MRG15 binding has no detectable impact on the conformation of the ASH1L SET domain autoinhibitory loop or SAM cofactor binding site.","method":"In vitro HMT assay with nucleosomes, chromodomain deletion/mutagenesis, NMR/biophysical analysis of SET domain conformation","journal":"Structure","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with domain mutagenesis and structural analysis, challenges prior allosteric model","pmids":["37527654"],"is_preprint":false},{"year":2023,"finding":"Upon UV irradiation, the ASH1L-MRG15 complex adds H3K4me3 genome-wide and recruits the histone chaperone FACT to DNA lesions. In the absence of ASH1L or MRG15, XPC is misplaced and persists on damaged DNA without being able to deliver lesions to TFIIH, blocking nucleotide excision repair verification.","method":"Co-immunoprecipitation, ChIP-seq, siRNA knockdown of ASH1L/MRG15/FACT, XPC localization assay, NER functional assay","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus ChIP-seq plus siRNA functional assays, single lab","pmids":["37393406"],"is_preprint":false},{"year":2025,"finding":"MRG15 is identified as an endogenous substrate of the CRBN E3 ubiquitin ligase complex; CRBN promotes MORF4L1 degradation under physiological conditions, enhanced by the modulator CC-885.","method":"Proteomic analysis, co-immunoprecipitation, structural modeling, degradation assay with CC-885","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus proteomic identification plus functional degradation assay, single lab","pmids":["39827217"],"is_preprint":false},{"year":2025,"finding":"MORF4L1 acetylates PALB2 at lysine 628, inhibiting its ubiquitination and degradation. MORF4L1 also enhances histone H3 acetylation at lysine 4, facilitating DNA damage repair factor recruitment. MORF4L1 knockdown combined with radiotherapy activates cGAS-STING signaling.","method":"Immunoprecipitation-mass spectrometry, site-directed mutagenesis (K628), ubiquitination assay, ChIP for H3K4ac, cGAS-STING pathway assay","journal":"Cellular & molecular immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — IP-MS plus mutagenesis plus functional assays, single lab","pmids":["41188483"],"is_preprint":false},{"year":2025,"finding":"USP53 deubiquitinase binds MORF4L1 and prevents its ubiquitination and proteasomal degradation; K249 and K227 of MORF4L1 are the key ubiquitination sites. USP53 positively regulates MORF4L1 protein levels in colorectal cancer cells.","method":"IP-LC/MS, co-immunoprecipitation, ubiquitination assay, site-directed mutagenesis (K249, K227)","journal":"Biochimica et biophysica acta. Molecular basis of disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — IP-MS substrate identification plus mutagenesis of ubiquitination sites, single lab","pmids":["41061828"],"is_preprint":false},{"year":2025,"finding":"MRG15 forms phase-separated liquid condensates via its intrinsically disordered region (IDR) in human mesenchymal stem cells. IDR deletion and replacement assays showed MRG15 condensation is required to prevent cellular senescence; MRG15 depletion reduces binding at key senescence genes (p53, CDKN1A, LMNB1, CCNB1, NPM1, MYC, HMGB2).","method":"Phase separation assay, IDR deletion/replacement constructs, ChIP-seq, RNA-seq, hMSC senescence assay","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional IDR mutagenesis plus ChIP-seq, single lab","pmids":["40312521"],"is_preprint":false},{"year":2025,"finding":"MRG15 forms an activator complex with TIP60, p300, and RNA Pol II at the Ccnd1 enhancer in neonatal cardiomyocytes, facilitating histone acetylation and cardiomyocyte proliferation. Regulatory T cells induce transient MRG15 expression in neonatal cardiomyocytes via paracrine signaling, promoting heart regeneration.","method":"Cardiac-specific conditional KO mouse, ChIP for complex components and histone acetylation, adoptive transfer of Tregs, AAV9 overexpression rescue","journal":"Circulation","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple conditional KO models plus ChIP plus AAV rescue, multiple orthogonal methods","pmids":["41251000"],"is_preprint":false},{"year":2025,"finding":"MRG15L splice variant accumulates with advancing age, exhibits reduced affinity for histone H4 acetylation sites compared to MRG15S, weakens CDK1 regulation leading to G2/M arrest and cellular senescence. Targeted knockout of MRG15L in mice enhances cardiac repair after ischemia-reperfusion injury.","method":"Histone peptide binding assay, protein interaction analysis, MRG15L-specific KO mouse, cardiac ischemia-reperfusion model","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — splice variant-specific KO with binding assays, single lab","pmids":["40483328"],"is_preprint":false},{"year":2026,"finding":"MRG15 loss in muscle stem cells (MuSCs) severely compromises myogenic differentiation and muscle regeneration. ChIP-seq and RNA-seq reveal MRG15 modulates the chromatin landscape of myogenic genes through interaction with MyoD, facilitating transcriptional activation.","method":"MuSC-specific inducible KO mouse, RNA-seq, ChIP-seq of histone modifications, Co-IP of MRG15-MyoD","journal":"Cell regeneration","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with ChIP-seq and Co-IP, single lab","pmids":["41580578"],"is_preprint":false}],"current_model":"MORF4L1/MRG15 is a conserved chromodomain-MRG domain protein that acts as a multifunctional chromatin adaptor: its chromodomain selectively binds H3K36me2/3 to recruit histone-modifying complexes (NuA4/Tip60 HAT and Rpd3S/Sin3S HDAC) to actively transcribed gene bodies, thereby regulating histone acetylation patterns, cotranscriptional splicing, and DNA damage repair (notably by tethering PALB2/BRCA2/RAD51 to H3K36me3-marked chromatin); its MRG domain mediates protein-protein interactions with PALB2, Pf1, PAM14, Rb, LRH-1, and the Ash1L/ASH1L histone methyltransferase—directly activating Ash1L catalytic activity by displacing its autoinhibitory loop or by recruiting it to nucleosome substrates; additionally, MRG15 operates outside the nucleus at the outer mitochondrial membrane where it deacetylates TUFM to promote its ClpXP-mediated degradation, impairing mitophagy and driving NASH progression, and its homodimerization is regulated by HDAC2-dependent deacetylation at Lys-148."},"narrative":{"mechanistic_narrative":"MORF4L1 (MRG15) is a conserved chromodomain–MRG domain chromatin adaptor that reads methylated histone H3K36 and tethers histone-modifying machinery to actively transcribed gene bodies, coupling chromatin state to transcription, splicing, and genome maintenance [PMID:16364921, PMID:17135209]. Its N-terminal chromo barrel domain folds into a hydrophobic pocket (Tyr26, Tyr46, Trp49) that selectively engages H3K36me2/3 over H3K4/K9/K27 methylation, directing the protein to RNA Pol II–rich active transcription sites [PMID:17135209, PMID:17008723]. Through its MRG domain it nucleates distinct complexes: a Sin3/HDAC-containing corepressor module via the PHD protein Pf1 (where MRG15 and Sin3 compete for overlapping Pf1 segments and the MRG15 chromodomain plus Pf1 PHD1 achieve bivalent chromatin engagement) [PMID:12391155, PMID:21440557, PMID:22728643], NuA4/Tip60 and hMOF acetyltransferase complexes that govern H3/H4 acetylation across coding versus promoter regions [PMID:12397079, PMID:14701747, PMID:21324423, PMID:27535225], and an Ash1L/ASH1L histone methyltransferase complex in which the MRG domain binds a conserved FxLP motif to relieve the autoinhibitory post-SET loop while the chromodomain delivers the enzyme to nucleosomes, stimulating H3K36me2 deposition [PMID:29158494, PMID:30827843, PMID:37527654]. MORF4L1 supports homology-directed DNA repair by binding PALB2 through an extended high-affinity MRG-domain interface, anchoring the PALB2–BRCA2–RAD51 module to H3K36me3-marked, SETD2-modified gene bodies and suppressing replication-associated genomic instability [PMID:19553677, PMID:20332121, PMID:28673974, PMID:34946951]. The yeast ortholog Eaf3 additionally links H3K36 methylation by Set2 to Rpd3S-mediated deacetylation, suppression of cryptic internal transcription initiation, and cotranscriptional spliceosome assembly, a splicing role conserved in mouse spermatogenesis where MRG15 acts with PTBP1/PTBP2 at H3K36me3 sites [PMID:16364921, PMID:15798182, PMID:31242410, PMID:27573846]. Beyond the nucleus, MORF4L1 localizes to the outer mitochondrial membrane where it deacetylates TUFM at K82/K91 to promote its ClpXP-mediated degradation, impairing mitophagy and driving NLRP3 inflammasome activation and NASH progression [PMID:35985547]. MORF4L1 homodimerization requires HDAC2-dependent deacetylation at Lys-148, and its protein level is controlled by competing ubiquitin ligase (CRBN) and deubiquitinase (USP53) activities [PMID:24451372, PMID:39827217, PMID:41061828]. Loss of MRG15 is embryonic lethal and impairs proliferation and differentiation across neural, germline, muscle, and cardiac lineages [PMID:15798182, PMID:19115414, PMID:27573846, PMID:41251000, PMID:41580578].","teleology":[{"year":2002,"claim":"Establishing that MRG15 partitions into functionally opposite complexes defined its role as a bifunctional chromatin adaptor rather than a single-activity factor.","evidence":"Sucrose gradient fractionation and deletion analysis defining a chromodomain-dependent hMOF HAT complex (MAF2) and a leucine-zipper-dependent Rb/PAM14 complex (MAF1), plus Gal4-fusion repression assays linking MORFs to mSin3A/TLE corepressors","pmids":["12397079","12391155","11500496"],"confidence":"Medium","gaps":["Genomic targets of each complex not defined in mammals","Chromodomain ligand not yet identified"]},{"year":2005,"claim":"Identifying the chromodomain ligand as methylated H3K36 explained how MRG15/Eaf3 is targeted to gene bodies and linked it to Set2 and elongating Pol II.","evidence":"Chromodomain–methylated peptide binding, genetic epistasis (eaf3Δ, set2Δ) and ChIP in yeast showing Eaf3 couples H3K36 methylation to Rpd3S deacetylation and suppression of cryptic internal initiation","pmids":["16364921","14701747"],"confidence":"High","gaps":["Affinity and specificity quantification incomplete","Mechanism of acetylation redistribution across promoter vs ORF not fully resolved"]},{"year":2006,"claim":"Crystal structures of both functional modules defined the structural basis of H3K36me reading and MRG-domain protein recognition.","evidence":"X-ray structures of the human chromo barrel (Tyr26/Tyr46/Trp49 pocket, H3K36me-selective) and the MRG domain (hydrophobic pocket, mutagenesis identifying PAM14-contact residues)","pmids":["17135209","17008723"],"confidence":"High","gaps":["Structures of full-length protein on nucleosomes not solved","How a single MRG domain selects among competing partners unclear"]},{"year":2008,"claim":"NMR analysis of the Eaf3–H3K36me interaction revealed it is low-affinity and low-specificity, implying recognition requires additional avidity from partner subunits.","evidence":"NMR structure of yeast Eaf3 chromo barrel bound to a methyllysine-analog-linked H3K36 peptide with millimolar-range affinity","pmids":["18818090"],"confidence":"High","gaps":["Mechanism conferring in vivo specificity left unresolved until bivalent-engagement studies"]},{"year":2010,"claim":"Linking MRG15 to PALB2 placed it in the BRCA-dependent homologous recombination pathway, defining a direct role in genome maintenance.","evidence":"Complex purification, Co-IP, siRNA, HDR and crosslinker-sensitivity assays, and DNA-damage foci imaging showing MRG15 depletion impairs PALB2/BRCA2/RAD51 recruitment; earlier work mapped a direct PALB2-binding region","pmids":["20332121","19553677","17961556"],"confidence":"High","gaps":["Whether chromatin reading is required for repair role not yet tested","Structural basis of PALB2 binding unknown at this stage"]},{"year":2012,"claim":"Defining bivalent chromatin engagement by the MRG15 chromodomain and Pf1 PHD1 resolved how a low-affinity reader achieves stable, specific Rpd3S/Sin3S targeting.","evidence":"Quantitative in vitro binding (MRG15 CD–H3K36me2/3, Pf1 PHD1–H3K4me0) and competition NMR showing MRG15 and Sin3 vie for overlapping Pf1 segments","pmids":["22728643","21440557"],"confidence":"Medium","gaps":["In vivo verification of bivalency in mammals limited","Stoichiometry within the assembled complex not defined"]},{"year":2016,"claim":"Genetic and genome-wide work tied MRG15/Eaf3 to cotranscriptional splicing and NuA4 elongation function, extending its chromatin-reading role into RNA processing.","evidence":"RNA-seq, ChIP, Co-IP with splicing factors (Prp45) and Eaf3/5/7 in vitro nucleosome binding/elongation assays in yeast; conditional germline KO in mouse with intron-retention and PTBP1/PTBP2 colocalization at H3K36me3 sites","pmids":["31242410","27535225","27573846"],"confidence":"High","gaps":["Direct biochemical bridge between MRG15 and spliceosome in mammals incomplete","Which splicing events are chromodomain-dependent not fully mapped"]},{"year":2017,"claim":"Showing PALB2 is recruited to active genes via MRG15–H3K36me3 reading explained how HR factors are positioned to protect transcribed regions from replication stress.","evidence":"ChIP-seq, Co-IP, camptothecin sensitivity and metaphase analyses with replication-suppression epistasis; SETD2 establishes the mark read by MRG15","pmids":["28673974"],"confidence":"High","gaps":["Relative contribution of transcription-coupled vs canonical HR not quantified"]},{"year":2019,"claim":"Crystal structures of the Ash1L/ASH1L–MRG15 complex defined MRG15 as a direct allosteric activator of an H3K36 methyltransferase via FxLP-motif binding and autoinhibitory-loop displacement.","evidence":"X-ray structures with in vitro HMT activity assays and mutagenesis, building on Drosophila genetic and biochemical demonstration that Mrg15 stimulates Ash1 and is recruited to common targets","pmids":["30827843","30827841","29158494"],"confidence":"High","gaps":["Allosteric vs recruitment-based activation mechanism in conflict with later solution data"]},{"year":2021,"claim":"A high-resolution MRG–PALB2 structure quantified the interaction and showed it is mutually exclusive with other MRG-domain partners, defining competitive partner selection.","evidence":"X-ray crystallography with ITC/SPR affinity measurements and analysis of breast-cancer PALB2 variants","pmids":["34946951"],"confidence":"High","gaps":["Functional consequence of weak-affinity patient variants in cells unresolved","Regulation of partner switching in vivo unknown"]},{"year":2023,"claim":"Reconstitution with full-length MRG15 revised the Ash1L activation model toward chromodomain-mediated nucleosome recruitment rather than pure allostery, and extended the ASH1L–MRG15 axis to nucleotide excision repair.","evidence":"In vitro nucleosome HMT assays with chromodomain mutants plus NMR showing no SET-domain conformational change; separately Co-IP/ChIP-seq/siRNA showing ASH1L-MRG15 adds H3K4me3 and recruits FACT for XPC handover in NER","pmids":["37527654","37393406"],"confidence":"Medium","gaps":["Reconciliation of allosteric vs recruitment models incomplete","NER role rests on single-lab functional assays"]},{"year":2022,"claim":"Discovery of an outer-mitochondrial pool of MORF4L1 acting as a TUFM deacetylase established a non-chromatin function coupling it to mitophagy, inflammation, and NASH.","evidence":"IP-MS, CRISPR depletion, K82/K91 mutagenesis, ClpXP protease and mitophagy assays, NLRP3 readouts; cytokine-driven acetylation stabilizes MRG15","pmids":["35985547"],"confidence":"High","gaps":["Mechanism of MRG15 import/retention at the mitochondrial membrane unknown","Direct deacetylase catalytic basis not structurally defined"]},{"year":2025,"claim":"Multiple studies converged on post-translational control of MORF4L1 stability and on its functional roles in tissue regeneration, senescence, and DNA repair signaling.","evidence":"CRBN-mediated and USP53-counteracted ubiquitination (K249/K227) controlling protein levels; HDAC2-dependent K148 deacetylation gating homodimerization; IDR-driven phase separation preventing senescence; TIP60/p300/Pol II enhancer complexes in cardiomyocyte and muscle stem cell regeneration; MORF4L1 acetylation of PALB2 K628 and H3K4 acetylation modulating cGAS-STING after radiotherapy","pmids":["39827217","41061828","24451372","40312521","41251000","41580578","34946951","41188483","40483328"],"confidence":"Medium","gaps":["Several roles rest on single-lab Co-IP/KO data","How chromatin reader and PALB2-acetyltransferase activities are coordinated unclear","Tissue specificity of stability control not mapped"]},{"year":null,"claim":"How a single MRG15 molecule integrates competing MRG-domain partners (PALB2, Pf1, Ash1L, LRH-1) with chromodomain H3K36me reading at specific loci, and how its nuclear chromatin and mitochondrial deacetylase activities are partitioned, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure of full-length MORF4L1 engaging a nucleosome with a partner","Signals directing nuclear vs mitochondrial localization unknown","Whether reported acetyltransferase/deacetylase activities are intrinsic or complex-mediated undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[4,6,10,17]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[24,26,27,31]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[13,17,23,29]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[3,5,28]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[30,34]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,1,2,7]},{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[8]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[3,4,23]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[30]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[3,4,21,24]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[1,14,28,37]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[9,13,23,32]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[20,22]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[30]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[5,12,22,37]}],"complexes":["NuA4/Tip60 HAT complex","Rpd3S/Sin3S HDAC complex","ASH1L histone methyltransferase complex","PALB2-BRCA2-RAD51 DNA repair complex"],"partners":["PALB2","ASH1L","PF1","TIP60","LRH-1","HDAC2","TUFM","MYOD"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9UBU8","full_name":"Mortality factor 4-like protein 1","aliases":["MORF-related gene 15 protein","MRG15","Protein MSL3-1","Transcription factor-like protein MRG15"],"length_aa":362,"mass_kda":41.5,"function":"Component of the NuA4 histone acetyltransferase (HAT) complex which is involved in transcriptional activation of select genes principally by acetylation of nucleosomal histones H4 and H2A. This modification may both alter nucleosome - DNA interactions and promote interaction of the modified histones with other proteins which positively regulate transcription. This complex may be required for the activation of transcriptional programs associated with oncogene and proto-oncogene mediated growth induction, tumor suppressor mediated growth arrest and replicative senescence, apoptosis, and DNA repair. The NuA4 complex ATPase and helicase activities seem to be, at least in part, contributed by the association of RUVBL1 and RUVBL2 with EP400. NuA4 may also play a direct role in DNA repair when directly recruited to sites of DNA damage. As part of the SIN3B complex represses transcription and counteracts the histone acetyltransferase activity of EP300 through the recognition H3K27ac marks by PHF12 and the activity of the histone deacetylase HDAC2 (PubMed:12391155, PubMed:14966270, PubMed:37137925). SIN3B complex is recruited downstream of the constitutively active genes transcriptional start sites through interaction with histones and mitigates histone acetylation and RNA polymerase II progression within transcribed regions contributing to the regulation of transcription (PubMed:21041482). Required for homologous recombination repair (HRR) and resistance to mitomycin C (MMC). Involved in the localization of PALB2, BRCA2 and RAD51, but not BRCA1, to DNA-damage foci","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9UBU8/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MORF4L1","classification":"Not Classified","n_dependent_lines":99,"n_total_lines":1208,"dependency_fraction":0.08195364238410596},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"TRRAP","stoichiometry":10.0},{"gene":"H2AFZ","stoichiometry":0.2},{"gene":"HSPA4","stoichiometry":0.2},{"gene":"SNRPC","stoichiometry":0.2},{"gene":"SPTLC1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/MORF4L1","total_profiled":1310},"omim":[{"mim_id":"616905","title":"MORF4 FAMILY-ASSOCIATED PROTEIN 1; MRFAP1","url":"https://www.omim.org/entry/616905"},{"mim_id":"614041","title":"RB TRANSCRIPTIONAL COREPRESSOR 1; RB1","url":"https://www.omim.org/entry/614041"},{"mim_id":"611157","title":"MRG/MORF4L-BINDING PROTEIN; MRGBP","url":"https://www.omim.org/entry/611157"},{"mim_id":"607303","title":"MORTALITY FACTOR 4-LIKE PROTEIN 1; MORF4L1","url":"https://www.omim.org/entry/607303"},{"mim_id":"601409","title":"LYSINE ACETYLTRANSFERASE 5; KAT5","url":"https://www.omim.org/entry/601409"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nuclear speckles","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/MORF4L1"},"hgnc":{"alias_symbol":["MRG15","MORFRG15","HsT17725","Eaf3","MEAF3"],"prev_symbol":[]},"alphafold":{"accession":"Q9UBU8","domains":[{"cath_id":"2.30.30.140","chopping":"7-49_91-123","consensus_level":"medium","plddt":83.6849,"start":7,"end":123},{"cath_id":"1.10.274.30","chopping":"192-358","consensus_level":"high","plddt":90.2125,"start":192,"end":358}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UBU8","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UBU8-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UBU8-F1-predicted_aligned_error_v6.png","plddt_mean":73.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MORF4L1","jax_strain_url":"https://www.jax.org/strain/search?query=MORF4L1"},"sequence":{"accession":"Q9UBU8","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UBU8.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UBU8/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UBU8"}},"corpus_meta":[{"pmid":"16364921","id":"PMC_16364921","title":"Eaf3 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inactivation of MRG15 gene function limits survival during larval and adult stages of Drosophila melanogaster.","date":"2010","source":"Experimental gerontology","url":"https://pubmed.ncbi.nlm.nih.gov/20600782","citation_count":7,"is_preprint":false},{"pmid":"32808584","id":"PMC_32808584","title":"Development of a Microscale Thermophoresis-Based Method for Screening and Characterizing Inhibitors of the Methyl-Lysine Reader Protein MRG15.","date":"2020","source":"SLAS discovery : advancing life sciences R & D","url":"https://pubmed.ncbi.nlm.nih.gov/32808584","citation_count":7,"is_preprint":false},{"pmid":"23733253","id":"PMC_23733253","title":"Alternative splicing of the chromodomain protein Morf4l1 pre-mRNA has implications on cell differentiation in the developing chicken retina.","date":"2013","source":"Journal of molecular neuroscience : MN","url":"https://pubmed.ncbi.nlm.nih.gov/23733253","citation_count":6,"is_preprint":false},{"pmid":"35860629","id":"PMC_35860629","title":"ADSCs Promote Tenocyte Proliferation by Reducing the Methylation Level of lncRNA Morf4l1 in Tendon Injury.","date":"2022","source":"Frontiers in chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/35860629","citation_count":6,"is_preprint":false},{"pmid":"41251000","id":"PMC_41251000","title":"CD4+ Tregs Regulate Heart Growth and Regeneration Through MRG15/TIP60-Mediated Epigenomic Remodeling in Proliferating Cardiomyocytes.","date":"2025","source":"Circulation","url":"https://pubmed.ncbi.nlm.nih.gov/41251000","citation_count":5,"is_preprint":false},{"pmid":"37527654","id":"PMC_37527654","title":"MRG15 activates histone methyltransferase activity of ASH1L by recruiting it to the nucleosomes.","date":"2023","source":"Structure (London, England : 1993)","url":"https://pubmed.ncbi.nlm.nih.gov/37527654","citation_count":5,"is_preprint":false},{"pmid":"20844547","id":"PMC_20844547","title":"Mutation analysis of the gene encoding the PALB2-binding protein MRG15 in BRCA1/2-negative breast cancer 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and disease","url":"https://pubmed.ncbi.nlm.nih.gov/37504562","citation_count":4,"is_preprint":false},{"pmid":"41188483","id":"PMC_41188483","title":"Targeting MORF4L1-mediated DNA repair potentiates RT-induced antitumor immunity via cGAS-STING activation in hepatocellular carcinoma.","date":"2025","source":"Cellular & molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/41188483","citation_count":3,"is_preprint":false},{"pmid":"39757177","id":"PMC_39757177","title":"Predicting hepatocellular carcinoma outcomes and immune therapy response with ATP-dependent chromatin remodeling-related genes, highlighting MORF4L1 as a promising target.","date":"2025","source":"Cancer cell international","url":"https://pubmed.ncbi.nlm.nih.gov/39757177","citation_count":3,"is_preprint":false},{"pmid":"36478775","id":"PMC_36478775","title":"Targeting MRG15 for the treatment of nonalcoholic steatohepatitis.","date":"2022","source":"Metabolism 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and Cyclophosphamide Regulation of Circular RNA MORF4L1 and MicroRNA-29a-3p Targeting BRD4.","date":"2024","source":"Iranian journal of allergy, asthma, and immunology","url":"https://pubmed.ncbi.nlm.nih.gov/39549296","citation_count":0,"is_preprint":false},{"pmid":"41061828","id":"PMC_41061828","title":"Deubiquitinase USP53 suppressed tumorigenesis of colorectal cancer cells by mediating deubiquitination of MORF4L1.","date":"2025","source":"Biochimica et biophysica acta. Molecular basis of disease","url":"https://pubmed.ncbi.nlm.nih.gov/41061828","citation_count":0,"is_preprint":false},{"pmid":"41751172","id":"PMC_41751172","title":"Integrated Single-Cell and Spatial Transcriptomics Coupled with Machine Learning Uncovers MORF4L1 as a Critical Epigenetic Mediator of Radiotherapy Resistance in Colorectal Cancer Liver Metastasis.","date":"2026","source":"Biomedicines","url":"https://pubmed.ncbi.nlm.nih.gov/41751172","citation_count":0,"is_preprint":false},{"pmid":"41580578","id":"PMC_41580578","title":"MRG15 decline in aged/injured MuSCs hinders regeneration via differentiation defects.","date":"2026","source":"Cell regeneration (London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/41580578","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":30868,"output_tokens":9490,"usd":0.117477,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":19521,"output_tokens":5571,"usd":0.11844,"stage2_stop_reason":"end_turn"},"total_usd":0.235917,"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\": 2001,\n      \"finding\": \"MRG15 forms a nuclear multiprotein complex with the retinoblastoma protein (Rb) and the novel protein PAM14; the helix-loop-helix and leucine zipper domains of MRG15 are required for these interactions. This complex activates the B-myb promoter by blocking Rb-induced repression.\",\n      \"method\": \"Co-immunoprecipitation, yeast two-hybrid, deletion mutagenesis, luciferase reporter assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and functional reporter assay in single lab with domain mapping\",\n      \"pmids\": [\"11500496\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"MRG15 is present in two distinct nuclear protein complexes: MAF1 (containing Rb and PAM14, requiring the leucine zipper) and MAF2 (containing hMOF histone acetyltransferase, requiring the N-terminal chromodomain). Deletion of the chromodomain abolishes associated histone acetyltransferase activity and prevents B-myb promoter activation.\",\n      \"method\": \"Sucrose gradient fractionation, deletion mutant analysis, histone acetyltransferase activity assay, promoter activation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical fractionation plus functional HAT assay, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"12397079\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"MRG15 (and MORF family members MORF4, MRGX) interact with the corepressors mSin3A and TLE to repress transcription. MRG15, but not MRGX or MORF4, additionally interacts with the PHD zinc finger protein Pf1, forming a distinct MRG15/Pf1/mSin3A complex. Dominant-negative TLE and mapping experiments showed repression by MORFs requires mSin3A and TLE associations.\",\n      \"method\": \"Gal4-fusion transcriptional repression assay, co-immunoprecipitation, domain mapping, dominant-negative TLE\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional reporter assay plus Co-IP with domain mapping, single lab\",\n      \"pmids\": [\"12391155\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Eaf3 (yeast ortholog of MRG15), a subunit of both NuA4 histone acetylase and Rpd3 histone deacetylase complexes, regulates the genomic profile of histone H3 and H4 acetylation such that loss of Eaf3 causes increased acetylation at coding sequences and decreased acetylation at promoters, without affecting overall H4 acetylation levels or NuA4 recruitment.\",\n      \"method\": \"Chromatin immunoprecipitation, genome-wide transcriptional profiling, histone acetylation profiling\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide ChIP plus transcriptional profiling in yeast, replicated by complementary studies\",\n      \"pmids\": [\"14701747\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Eaf3 chromodomain directly interacts with methylated H3-K36 peptides. This interaction links preferential Rpd3 complex-mediated histone deacetylation of 3' coding regions to H3-K36 methylation by Set2 and RNA Pol II CTD phosphorylation. Eaf3 also inhibits internal initiation within mRNA coding regions, similar to FACT and Spt6.\",\n      \"method\": \"Chromodomain-methylated peptide binding assay, genetic epistasis (eaf3Δ, set2Δ), chromatin immunoprecipitation\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct in vitro binding assay plus genetic epistasis plus ChIP, replicated across labs\",\n      \"pmids\": [\"16364921\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"MRG15 knockout mice are embryonic lethal with developmental delay and reduced cell proliferation in multiple tissues; MRG15 is recruited to the alpha-globin promoter during erythroid differentiation. Mrg15-/- mouse embryonic fibroblasts exhibit cell proliferation defects.\",\n      \"method\": \"Knockout mouse generation, BrdU proliferation assay, chromatin immunoprecipitation, microarray\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo KO phenotype with ChIP validation, multiple tissue types analyzed\",\n      \"pmids\": [\"15798182\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Crystal structure of human MRG15 chromodomain at 2.2 Å resolution reveals a chromo barrel fold with a hydrophobic pocket formed by Tyr26, Tyr46, and Trp49. In vitro binding assays demonstrate selective binding to H3K36-methylated peptides but not H3K4me, H3K9me, or H3K27me.\",\n      \"method\": \"X-ray crystallography, in vitro peptide binding assay\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with functional binding validation, replicated by independent structural studies\",\n      \"pmids\": [\"17135209\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Crystal structure of the MRG15 MRG domain reveals an alpha-helical three-layer sandwich topology with a shallow hydrophobic pocket. Structure-based mutagenesis identified residues Ile160, Leu168, Val169, Trp172, Tyr235, Val268, and Arg269 as critical for PAM14 binding via primarily hydrophobic interactions.\",\n      \"method\": \"X-ray crystallography, yeast two-hybrid, in vitro binding assay, site-directed mutagenesis\",\n      \"journal\": \"Protein science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus mutagenesis plus two independent binding assays\",\n      \"pmids\": [\"17008723\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"MRG15 is predominantly localized to nuclear subdomains enriched for Ser2-phosphorylated RNA Pol II (active transcription sites). MRG15-containing complexes include the H3K4 demethylase RBP2; RBP2 overexpression reduces H3K4 methylation in vivo and in vitro, and RBP2 knockdown increases H3K4 methylation within transcribed regions of active genes.\",\n      \"method\": \"Immunofluorescence/nuclear fractionation, immunoprecipitation-mass spectrometry, H3K4 demethylase in vitro assay, RNAi knockdown with ChIP\",\n      \"journal\": \"Genes to cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — IP-MS identification, in vitro enzymatic assay, ChIP validation, single lab\",\n      \"pmids\": [\"17573780\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Mrg15 null and heterozygous mouse embryonic fibroblasts show impaired DNA damage response after gamma irradiation: defects in DNA repair, cell growth, and delayed recruitment of γH2AX and 53BP1 foci to sites of damage.\",\n      \"method\": \"Gamma irradiation, immunofluorescence for γH2AX and 53BP1 foci, cell growth assay\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO/heterozygous with defined DNA damage phenotype, single lab\",\n      \"pmids\": [\"17961556\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"NMR structure of yeast Eaf3 (MRG15 ortholog) chromo barrel domain bound to methylated H3K36 reveals low-specificity, millimolar-range affinity binding to methylated peptides including H3K36 and H3K4. The structure was determined using an engineered linked Eaf3-H3K36 molecule with a chemically incorporated methyllysine analog.\",\n      \"method\": \"NMR structure determination, engineered linked protein with methyllysine analog, binding affinity measurements\",\n      \"journal\": \"Structure\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — NMR structure with functional validation using novel chemical biology approach\",\n      \"pmids\": [\"18818090\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"MRG15 directly binds PALB2 via an evolutionarily conserved region on PALB2. Loss of the PALB2-MRG15 interaction (via MRG15-binding-defective PALB2 mutants) results in elevated gene conversion rates and increased sister chromatid exchange frequencies, indicating MRG15 suppresses hyper-recombination.\",\n      \"method\": \"Co-immunoprecipitation, gene conversion assay, sister chromatid exchange assay, PALB2 mutant analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding mapping plus functional recombination assays, single lab\",\n      \"pmids\": [\"19553677\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"MRG15 is required for proliferation and differentiation of neural precursor cells (NPCs). Mrg15-deficient NPCs have reduced proliferation (BrdU assay) and are defective in neuronal differentiation in vitro; neuroepithelia from Mrg15-deficient embryonic brains are thinner with increased apoptosis.\",\n      \"method\": \"Neurosphere culture from KO embryos, BrdU incorporation, differentiation assay\",\n      \"journal\": \"Journal of neuroscience research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO-based loss-of-function with defined cellular phenotype, single lab\",\n      \"pmids\": [\"19115414\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"MRG15 directly binds PALB2 and mediates DNA-damage-response functions of the BRCA complex (BRCA1, PALB2, BRCA2, RAD51). MRG15 depletion reduces efficiency of homology-directed DNA repair, causes hypersensitivity to DNA interstrand crosslinking agents, and diminishes recruitment of PALB2, BRCA2, and RAD51 to sites of DNA damage.\",\n      \"method\": \"Purified protein complex analysis, Co-IP, siRNA knockdown, homology-directed repair assay, immunofluorescence for DNA damage foci\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (complex purification, Co-IP, functional repair assay, foci formation), replicated across labs\",\n      \"pmids\": [\"20332121\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"MRG15 occupancy at the cdc2 promoter increases ~3-fold during S phase with concomitant increase in H4K12 acetylation (not H4K16). MRG15 cooperates with Tip60 HAT at the cdc2 promoter to activate transcription; HAT inhibition abolishes cdc2 mRNA expression.\",\n      \"method\": \"ChIP during cell cycle, luciferase reporter assay, siRNA knockdown, HAT inhibitor treatment, Tip60 co-transfection\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus functional reporter with pharmacological and genetic validation, single lab\",\n      \"pmids\": [\"21324423\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Loss of MRG15 in neural stem/progenitor cells specifically upregulates the CDK inhibitor p21 downstream of activated p53; p21 shRNA restores proliferation in Mrg15-deficient NSCs. DNA damage foci (γH2AX, 53BP1) are detectable in Mrg15-deficient NSCs under normal culture conditions.\",\n      \"method\": \"KO-derived NSCs, p21/p53 shRNA rescue, BrdU assay, immunostaining for γH2AX/53BP1\",\n      \"journal\": \"Stem cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic rescue experiment (shRNA) placing MRG15 upstream of p53/p21 axis, single lab\",\n      \"pmids\": [\"21621175\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"NMR solution structure of mSin3A PAH2 bound to Pf1 SID1 reveals a Mad1/Mxd1-like interaction. Unexpectedly, MRG15 competes with Sin3 for the same Pf1 segment (encompassing SID1 and adjacent conserved motif), indicating competition between two subunits of the same Rpd3S/Sin3S complex for a third subunit.\",\n      \"method\": \"NMR structure determination, competition binding assay\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR structure plus functional competition binding assay, single lab\",\n      \"pmids\": [\"21440557\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"MRG15 chromodomain (CD) binds H3K36me2/3 and Pf1 PHD1 binds unmodified H3 N-terminus (H3K4me0) with >100 µM affinity each. Bivalent (not cooperative) engagement by both subunits is the operative mechanism for targeting the Rpd3S/Sin3S complex to chromatin. Pf1 PHD1 also contacts the MRG15 MRG domain in a Pf1 MBD-dependent manner.\",\n      \"method\": \"In vitro binding assays, fluorescence polarization/ITC affinity measurements, mutagenesis\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — quantitative binding assays plus mutagenesis, single lab\",\n      \"pmids\": [\"22728643\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Drosophila Mrg15 physically interacts with the condensin Cap-H2 subunit (yeast two-hybrid). Mrg15 is required for Cap-H2-mediated unpairing of polytene chromosomes and homolog unpairing in diploid cells; chromatin-bound Cap-H2 levels are partially dependent on Mrg15, suggesting Mrg15 recruits Cap-H2 to chromatin for interphase chromosome compaction.\",\n      \"method\": \"Yeast two-hybrid, genetic interaction (transvection assay), RNAi depletion, chromatin fractionation\",\n      \"journal\": \"Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid plus genetic epistasis plus RNAi phenotype, single lab\",\n      \"pmids\": [\"23821596\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"HDAC2 interacts with MORF4L1 and maintains it in a deacetylated state at Lys-148. Deacetylation of Lys-148 is required for MORF4L1 homodimerization; acetylation-mimicking substitutions (K148L, K148Q) abolish self-assembly, while arginine substitution (K148R) augments it. HDAC2 knockdown reduces MORF4L1 homodimerization.\",\n      \"method\": \"Co-immunoprecipitation, site-directed mutagenesis, HDAC2 knockdown, self-assembly assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis plus Co-IP plus knockdown with consistent results, single lab\",\n      \"pmids\": [\"24451372\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Eaf3 (yeast MRG15 ortholog) is recruited to intron-containing genes and interacts with splicing factor Prp45. Eaf3 acts with Prp45 and Prp19 after precatalytic B complex formation (around splicing activation). H3K36 methylation by Set2 is required for proper cotranscriptional spliceosome assembly, mediated through Eaf3.\",\n      \"method\": \"High-throughput RNA sequencing (splicing analysis), ChIP, Co-IP of Eaf3 with splicing factors, genetic epistasis\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-wide splicing analysis plus Co-IP plus genetic epistasis, single lab\",\n      \"pmids\": [\"31242410\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Eaf3/5/7 subcomplex within NuA4 stimulates NuA4 binding to di- and trimethylated H3K36 in vitro, and is important for NuA4 occupancy in transcribed ORFs and RNA Pol II binding; mutations in Eaf3/5/7 reduce bulk H4 acetylation ~40% and cause transcription elongation processivity defects.\",\n      \"method\": \"In vitro nucleosome binding assay, H4 acetylation measurement, Pol II binding assay, transcription elongation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro binding assay plus functional elongation assay, single lab\",\n      \"pmids\": [\"27535225\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Conditional knockout of MRG15 in the germline causes male sterility due to spermatogenic arrest at the round spermatid stage with specific mRNA sequence loss from 66 germ cell-expressed genes and intron retention in mRNAs of 4 genes (including transition proteins). MRG15 colocalizes with splicing factors PTBP1 and PTBP2 at H3K36me3 sites between exons and introns of Tnp2.\",\n      \"method\": \"Conditional KO mouse, RNA-seq, intron retention analysis, immunofluorescence co-localization with splicing factors\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo conditional KO with genome-wide RNA-seq and molecular co-localization, multiple orthogonal approaches\",\n      \"pmids\": [\"27573846\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"PALB2 associates with active genes through MRG15 binding to H3K36me3 deposited by SETD2 methyltransferase. PALB2 mutations ablating MRG15 binding confer elevated sensitivity to camptothecin, increased aberrant metaphase chromosomes and DNA stress in gene bodies, which is suppressed by preventing DNA replication.\",\n      \"method\": \"ChIP-seq, co-immunoprecipitation, camptothecin sensitivity assay, metaphase spread analysis, cell fractionation\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP-seq plus functional genetic analysis with replication-suppression epistasis, multiple orthogonal methods\",\n      \"pmids\": [\"28673974\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Drosophila Mrg15 is a subunit of the Ash1 histone methyltransferase complex and stimulates Ash1 enzymatic activity in vitro. In vivo, Mrg15 is recruited by Ash1 to common targets, reinforces Ash1 chromatin association, and facilitates H3K36me2 deposition. An Ash1 point mutant (R1288A) with attenuated Mrg15 interaction shows homeotic transformation phenotypes partially rescued by Mrg15-Nurf55 fusion protein.\",\n      \"method\": \"In vitro HMT assay, ChIP, knock-in fly genetics, rescue experiment with Mrg15-Nurf55 fusion\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro enzymatic assay plus in vivo ChIP plus genetic rescue, multiple orthogonal methods\",\n      \"pmids\": [\"29158494\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"C. elegans MRG-1 (MRG15 ortholog) safeguards germ cells against conversion into neurons; RNAi screening identified MRG-1 as a barrier for germ cell to neuron reprogramming. Protein-protein and genome interactions of MRG-1 were characterized.\",\n      \"method\": \"Automated solid-phase RNAi screen, germ cell reprogramming assay, protein interaction analysis\",\n      \"journal\": \"Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-scale RNAi screen plus mechanistic follow-up in C. elegans, single lab\",\n      \"pmids\": [\"30425042\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Crystal structure of human Ash1L tandem MRG15-interacting and SET domains in complex with MRG15 MRG domain reveals that MRG15 binds a segment N-terminal to the Ash1L SET domain via an FxLP motif, displacing the autoinhibitory post-SET loop to permit substrate access to the catalytic pocket. SAM binding pocket changes are induced by MRG15 binding via conformational coupling.\",\n      \"method\": \"X-ray crystallography, in vitro HMT activity assay, mutagenesis\",\n      \"journal\": \"Structure\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus in vitro enzymatic assay plus mutagenesis, independently replicated by concurrent structural study\",\n      \"pmids\": [\"30827843\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Crystal structure of ASH1L SET domain with MRG15 MRG domain reveals that MRG15 binding to a conserved FxLP motif in ASH1L displaces the autoinhibitory loop from the post-SET region, permitting substrate access to the ASH1L SET domain catalytic pocket and activating H3K36me2 activity.\",\n      \"method\": \"X-ray crystallography, in vitro HMT activity assay\",\n      \"journal\": \"Structure\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with enzymatic validation, independently confirmed by concurrent study (PMID:30827843)\",\n      \"pmids\": [\"30827841\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"MRG15 genomic recruitment displays a significant diurnal rhythm in the mouse liver and activates lipid synthesis genes. MRG15 interacts with the nuclear receptor LRH-1 (not core clock proteins), which recruits MRG15 to lipid gene loci. MRG15 depletion impairs rhythmic RNA Pol II recruitment and histone acetylation at these loci.\",\n      \"method\": \"ChIP-seq (rhythmic genomic binding), Co-IP (MRG15-LRH-1 interaction), CRISPR depletion, RNA-seq\",\n      \"journal\": \"Nature metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP-seq plus Co-IP plus CRISPR functional validation, multiple orthogonal methods\",\n      \"pmids\": [\"32694659\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Crystal structure of the MRG15 MRG domain bound to a PALB2 peptide reveals that PALB2 interacts with an extended surface of the MRG domain with nanomolar affinity. Breast cancer-related PALB2 mutations cause only minor attenuation of binding affinity. PALB2 binding to MRG15 is mutually exclusive with other MRG15 MRG domain partners.\",\n      \"method\": \"X-ray crystallography, binding affinity measurement (ITC/SPR), mutagenesis analysis of patient variants\",\n      \"journal\": \"Genes\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure plus quantitative affinity measurements with mutant analysis, single lab\",\n      \"pmids\": [\"34946951\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"MRG15 associates with the outer mitochondrial membrane and interacts with and deacetylates TUFM at K82 and K91. Deacetylated TUFM undergoes accelerated degradation by the mitochondrial ClpXP protease. Reduced TUFM impairs mitophagy and activates the NLRP3 inflammasome pathway. Inflammatory cytokines in NASH livers stabilize MRG15 by increasing its acetylation.\",\n      \"method\": \"Immunoprecipitation-mass spectrometry, CRISPR depletion, site-directed mutagenesis (K82/K91), ClpXP protease assay, mitophagy assay, NLRP3 inflammasome measurement\",\n      \"journal\": \"Journal of hepatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — IP-MS identification, mutagenesis of modification sites, functional protease and mitophagy assays, multiple orthogonal methods\",\n      \"pmids\": [\"35985547\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Full-length MRG15 (but not the isolated MRG domain alone) enhances ASH1L SET domain histone methyltransferase activity by recruiting it to nucleosome substrates via the MRG15 chromodomain. In solution, MRG15 binding has no detectable impact on the conformation of the ASH1L SET domain autoinhibitory loop or SAM cofactor binding site.\",\n      \"method\": \"In vitro HMT assay with nucleosomes, chromodomain deletion/mutagenesis, NMR/biophysical analysis of SET domain conformation\",\n      \"journal\": \"Structure\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with domain mutagenesis and structural analysis, challenges prior allosteric model\",\n      \"pmids\": [\"37527654\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Upon UV irradiation, the ASH1L-MRG15 complex adds H3K4me3 genome-wide and recruits the histone chaperone FACT to DNA lesions. In the absence of ASH1L or MRG15, XPC is misplaced and persists on damaged DNA without being able to deliver lesions to TFIIH, blocking nucleotide excision repair verification.\",\n      \"method\": \"Co-immunoprecipitation, ChIP-seq, siRNA knockdown of ASH1L/MRG15/FACT, XPC localization assay, NER functional assay\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus ChIP-seq plus siRNA functional assays, single lab\",\n      \"pmids\": [\"37393406\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"MRG15 is identified as an endogenous substrate of the CRBN E3 ubiquitin ligase complex; CRBN promotes MORF4L1 degradation under physiological conditions, enhanced by the modulator CC-885.\",\n      \"method\": \"Proteomic analysis, co-immunoprecipitation, structural modeling, degradation assay with CC-885\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus proteomic identification plus functional degradation assay, single lab\",\n      \"pmids\": [\"39827217\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"MORF4L1 acetylates PALB2 at lysine 628, inhibiting its ubiquitination and degradation. MORF4L1 also enhances histone H3 acetylation at lysine 4, facilitating DNA damage repair factor recruitment. MORF4L1 knockdown combined with radiotherapy activates cGAS-STING signaling.\",\n      \"method\": \"Immunoprecipitation-mass spectrometry, site-directed mutagenesis (K628), ubiquitination assay, ChIP for H3K4ac, cGAS-STING pathway assay\",\n      \"journal\": \"Cellular & molecular immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — IP-MS plus mutagenesis plus functional assays, single lab\",\n      \"pmids\": [\"41188483\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"USP53 deubiquitinase binds MORF4L1 and prevents its ubiquitination and proteasomal degradation; K249 and K227 of MORF4L1 are the key ubiquitination sites. USP53 positively regulates MORF4L1 protein levels in colorectal cancer cells.\",\n      \"method\": \"IP-LC/MS, co-immunoprecipitation, ubiquitination assay, site-directed mutagenesis (K249, K227)\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular basis of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — IP-MS substrate identification plus mutagenesis of ubiquitination sites, single lab\",\n      \"pmids\": [\"41061828\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"MRG15 forms phase-separated liquid condensates via its intrinsically disordered region (IDR) in human mesenchymal stem cells. IDR deletion and replacement assays showed MRG15 condensation is required to prevent cellular senescence; MRG15 depletion reduces binding at key senescence genes (p53, CDKN1A, LMNB1, CCNB1, NPM1, MYC, HMGB2).\",\n      \"method\": \"Phase separation assay, IDR deletion/replacement constructs, ChIP-seq, RNA-seq, hMSC senescence assay\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional IDR mutagenesis plus ChIP-seq, single lab\",\n      \"pmids\": [\"40312521\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"MRG15 forms an activator complex with TIP60, p300, and RNA Pol II at the Ccnd1 enhancer in neonatal cardiomyocytes, facilitating histone acetylation and cardiomyocyte proliferation. Regulatory T cells induce transient MRG15 expression in neonatal cardiomyocytes via paracrine signaling, promoting heart regeneration.\",\n      \"method\": \"Cardiac-specific conditional KO mouse, ChIP for complex components and histone acetylation, adoptive transfer of Tregs, AAV9 overexpression rescue\",\n      \"journal\": \"Circulation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple conditional KO models plus ChIP plus AAV rescue, multiple orthogonal methods\",\n      \"pmids\": [\"41251000\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"MRG15L splice variant accumulates with advancing age, exhibits reduced affinity for histone H4 acetylation sites compared to MRG15S, weakens CDK1 regulation leading to G2/M arrest and cellular senescence. Targeted knockout of MRG15L in mice enhances cardiac repair after ischemia-reperfusion injury.\",\n      \"method\": \"Histone peptide binding assay, protein interaction analysis, MRG15L-specific KO mouse, cardiac ischemia-reperfusion model\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — splice variant-specific KO with binding assays, single lab\",\n      \"pmids\": [\"40483328\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"MRG15 loss in muscle stem cells (MuSCs) severely compromises myogenic differentiation and muscle regeneration. ChIP-seq and RNA-seq reveal MRG15 modulates the chromatin landscape of myogenic genes through interaction with MyoD, facilitating transcriptional activation.\",\n      \"method\": \"MuSC-specific inducible KO mouse, RNA-seq, ChIP-seq of histone modifications, Co-IP of MRG15-MyoD\",\n      \"journal\": \"Cell regeneration\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with ChIP-seq and Co-IP, single lab\",\n      \"pmids\": [\"41580578\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MORF4L1/MRG15 is a conserved chromodomain-MRG domain protein that acts as a multifunctional chromatin adaptor: its chromodomain selectively binds H3K36me2/3 to recruit histone-modifying complexes (NuA4/Tip60 HAT and Rpd3S/Sin3S HDAC) to actively transcribed gene bodies, thereby regulating histone acetylation patterns, cotranscriptional splicing, and DNA damage repair (notably by tethering PALB2/BRCA2/RAD51 to H3K36me3-marked chromatin); its MRG domain mediates protein-protein interactions with PALB2, Pf1, PAM14, Rb, LRH-1, and the Ash1L/ASH1L histone methyltransferase—directly activating Ash1L catalytic activity by displacing its autoinhibitory loop or by recruiting it to nucleosome substrates; additionally, MRG15 operates outside the nucleus at the outer mitochondrial membrane where it deacetylates TUFM to promote its ClpXP-mediated degradation, impairing mitophagy and driving NASH progression, and its homodimerization is regulated by HDAC2-dependent deacetylation at Lys-148.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"MORF4L1 (MRG15) is a conserved chromodomain–MRG domain chromatin adaptor that reads methylated histone H3K36 and tethers histone-modifying machinery to actively transcribed gene bodies, coupling chromatin state to transcription, splicing, and genome maintenance [#4, #6]. Its N-terminal chromo barrel domain folds into a hydrophobic pocket (Tyr26, Tyr46, Trp49) that selectively engages H3K36me2/3 over H3K4/K9/K27 methylation, directing the protein to RNA Pol II–rich active transcription sites [#6, #7]. Through its MRG domain it nucleates distinct complexes: a Sin3/HDAC-containing corepressor module via the PHD protein Pf1 (where MRG15 and Sin3 compete for overlapping Pf1 segments and the MRG15 chromodomain plus Pf1 PHD1 achieve bivalent chromatin engagement) [#2, #16, #17], NuA4/Tip60 and hMOF acetyltransferase complexes that govern H3/H4 acetylation across coding versus promoter regions [#1, #3, #14, #21], and an Ash1L/ASH1L histone methyltransferase complex in which the MRG domain binds a conserved FxLP motif to relieve the autoinhibitory post-SET loop while the chromodomain delivers the enzyme to nucleosomes, stimulating H3K36me2 deposition [#24, #26, #31]. MORF4L1 supports homology-directed DNA repair by binding PALB2 through an extended high-affinity MRG-domain interface, anchoring the PALB2–BRCA2–RAD51 module to H3K36me3-marked, SETD2-modified gene bodies and suppressing replication-associated genomic instability [#11, #13, #23, #29]. The yeast ortholog Eaf3 additionally links H3K36 methylation by Set2 to Rpd3S-mediated deacetylation, suppression of cryptic internal transcription initiation, and cotranscriptional spliceosome assembly, a splicing role conserved in mouse spermatogenesis where MRG15 acts with PTBP1/PTBP2 at H3K36me3 sites [#4, #5, #20, #22]. Beyond the nucleus, MORF4L1 localizes to the outer mitochondrial membrane where it deacetylates TUFM at K82/K91 to promote its ClpXP-mediated degradation, impairing mitophagy and driving NLRP3 inflammasome activation and NASH progression [#30]. MORF4L1 homodimerization requires HDAC2-dependent deacetylation at Lys-148, and its protein level is controlled by competing ubiquitin ligase (CRBN) and deubiquitinase (USP53) activities [#19, #33, #35]. Loss of MRG15 is embryonic lethal and impairs proliferation and differentiation across neural, germline, muscle, and cardiac lineages [#5, #12, #22, #37, #39].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Establishing that MRG15 partitions into functionally opposite complexes defined its role as a bifunctional chromatin adaptor rather than a single-activity factor.\",\n      \"evidence\": \"Sucrose gradient fractionation and deletion analysis defining a chromodomain-dependent hMOF HAT complex (MAF2) and a leucine-zipper-dependent Rb/PAM14 complex (MAF1), plus Gal4-fusion repression assays linking MORFs to mSin3A/TLE corepressors\",\n      \"pmids\": [\"12397079\", \"12391155\", \"11500496\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Genomic targets of each complex not defined in mammals\", \"Chromodomain ligand not yet identified\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Identifying the chromodomain ligand as methylated H3K36 explained how MRG15/Eaf3 is targeted to gene bodies and linked it to Set2 and elongating Pol II.\",\n      \"evidence\": \"Chromodomain–methylated peptide binding, genetic epistasis (eaf3Δ, set2Δ) and ChIP in yeast showing Eaf3 couples H3K36 methylation to Rpd3S deacetylation and suppression of cryptic internal initiation\",\n      \"pmids\": [\"16364921\", \"14701747\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Affinity and specificity quantification incomplete\", \"Mechanism of acetylation redistribution across promoter vs ORF not fully resolved\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Crystal structures of both functional modules defined the structural basis of H3K36me reading and MRG-domain protein recognition.\",\n      \"evidence\": \"X-ray structures of the human chromo barrel (Tyr26/Tyr46/Trp49 pocket, H3K36me-selective) and the MRG domain (hydrophobic pocket, mutagenesis identifying PAM14-contact residues)\",\n      \"pmids\": [\"17135209\", \"17008723\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structures of full-length protein on nucleosomes not solved\", \"How a single MRG domain selects among competing partners unclear\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"NMR analysis of the Eaf3–H3K36me interaction revealed it is low-affinity and low-specificity, implying recognition requires additional avidity from partner subunits.\",\n      \"evidence\": \"NMR structure of yeast Eaf3 chromo barrel bound to a methyllysine-analog-linked H3K36 peptide with millimolar-range affinity\",\n      \"pmids\": [\"18818090\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism conferring in vivo specificity left unresolved until bivalent-engagement studies\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Linking MRG15 to PALB2 placed it in the BRCA-dependent homologous recombination pathway, defining a direct role in genome maintenance.\",\n      \"evidence\": \"Complex purification, Co-IP, siRNA, HDR and crosslinker-sensitivity assays, and DNA-damage foci imaging showing MRG15 depletion impairs PALB2/BRCA2/RAD51 recruitment; earlier work mapped a direct PALB2-binding region\",\n      \"pmids\": [\"20332121\", \"19553677\", \"17961556\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether chromatin reading is required for repair role not yet tested\", \"Structural basis of PALB2 binding unknown at this stage\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Defining bivalent chromatin engagement by the MRG15 chromodomain and Pf1 PHD1 resolved how a low-affinity reader achieves stable, specific Rpd3S/Sin3S targeting.\",\n      \"evidence\": \"Quantitative in vitro binding (MRG15 CD–H3K36me2/3, Pf1 PHD1–H3K4me0) and competition NMR showing MRG15 and Sin3 vie for overlapping Pf1 segments\",\n      \"pmids\": [\"22728643\", \"21440557\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo verification of bivalency in mammals limited\", \"Stoichiometry within the assembled complex not defined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Genetic and genome-wide work tied MRG15/Eaf3 to cotranscriptional splicing and NuA4 elongation function, extending its chromatin-reading role into RNA processing.\",\n      \"evidence\": \"RNA-seq, ChIP, Co-IP with splicing factors (Prp45) and Eaf3/5/7 in vitro nucleosome binding/elongation assays in yeast; conditional germline KO in mouse with intron-retention and PTBP1/PTBP2 colocalization at H3K36me3 sites\",\n      \"pmids\": [\"31242410\", \"27535225\", \"27573846\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct biochemical bridge between MRG15 and spliceosome in mammals incomplete\", \"Which splicing events are chromodomain-dependent not fully mapped\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showing PALB2 is recruited to active genes via MRG15–H3K36me3 reading explained how HR factors are positioned to protect transcribed regions from replication stress.\",\n      \"evidence\": \"ChIP-seq, Co-IP, camptothecin sensitivity and metaphase analyses with replication-suppression epistasis; SETD2 establishes the mark read by MRG15\",\n      \"pmids\": [\"28673974\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of transcription-coupled vs canonical HR not quantified\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Crystal structures of the Ash1L/ASH1L–MRG15 complex defined MRG15 as a direct allosteric activator of an H3K36 methyltransferase via FxLP-motif binding and autoinhibitory-loop displacement.\",\n      \"evidence\": \"X-ray structures with in vitro HMT activity assays and mutagenesis, building on Drosophila genetic and biochemical demonstration that Mrg15 stimulates Ash1 and is recruited to common targets\",\n      \"pmids\": [\"30827843\", \"30827841\", \"29158494\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Allosteric vs recruitment-based activation mechanism in conflict with later solution data\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"A high-resolution MRG–PALB2 structure quantified the interaction and showed it is mutually exclusive with other MRG-domain partners, defining competitive partner selection.\",\n      \"evidence\": \"X-ray crystallography with ITC/SPR affinity measurements and analysis of breast-cancer PALB2 variants\",\n      \"pmids\": [\"34946951\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of weak-affinity patient variants in cells unresolved\", \"Regulation of partner switching in vivo unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Reconstitution with full-length MRG15 revised the Ash1L activation model toward chromodomain-mediated nucleosome recruitment rather than pure allostery, and extended the ASH1L–MRG15 axis to nucleotide excision repair.\",\n      \"evidence\": \"In vitro nucleosome HMT assays with chromodomain mutants plus NMR showing no SET-domain conformational change; separately Co-IP/ChIP-seq/siRNA showing ASH1L-MRG15 adds H3K4me3 and recruits FACT for XPC handover in NER\",\n      \"pmids\": [\"37527654\", \"37393406\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Reconciliation of allosteric vs recruitment models incomplete\", \"NER role rests on single-lab functional assays\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Discovery of an outer-mitochondrial pool of MORF4L1 acting as a TUFM deacetylase established a non-chromatin function coupling it to mitophagy, inflammation, and NASH.\",\n      \"evidence\": \"IP-MS, CRISPR depletion, K82/K91 mutagenesis, ClpXP protease and mitophagy assays, NLRP3 readouts; cytokine-driven acetylation stabilizes MRG15\",\n      \"pmids\": [\"35985547\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of MRG15 import/retention at the mitochondrial membrane unknown\", \"Direct deacetylase catalytic basis not structurally defined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Multiple studies converged on post-translational control of MORF4L1 stability and on its functional roles in tissue regeneration, senescence, and DNA repair signaling.\",\n      \"evidence\": \"CRBN-mediated and USP53-counteracted ubiquitination (K249/K227) controlling protein levels; HDAC2-dependent K148 deacetylation gating homodimerization; IDR-driven phase separation preventing senescence; TIP60/p300/Pol II enhancer complexes in cardiomyocyte and muscle stem cell regeneration; MORF4L1 acetylation of PALB2 K628 and H3K4 acetylation modulating cGAS-STING after radiotherapy\",\n      \"pmids\": [\"39827217\", \"41061828\", \"24451372\", \"40312521\", \"41251000\", \"41580578\", \"34946951\", \"41188483\", \"40483328\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Several roles rest on single-lab Co-IP/KO data\", \"How chromatin reader and PALB2-acetyltransferase activities are coordinated unclear\", \"Tissue specificity of stability control not mapped\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single MRG15 molecule integrates competing MRG-domain partners (PALB2, Pf1, Ash1L, LRH-1) with chromodomain H3K36me reading at specific loci, and how its nuclear chromatin and mitochondrial deacetylase activities are partitioned, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure of full-length MORF4L1 engaging a nucleosome with a partner\", \"Signals directing nuclear vs mitochondrial localization unknown\", \"Whether reported acetyltransferase/deacetylase activities are intrinsic or complex-mediated undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [4, 6, 10, 17]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [24, 26, 27, 31]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [13, 17, 23, 29]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [3, 5, 28]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [30, 34]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 1, 2, 7]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [8]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [3, 4, 23]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [30]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [3, 4, 21, 24]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [1, 14, 28, 37]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [9, 13, 23, 32]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [20, 22]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [30]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [5, 12, 22, 37]}\n    ],\n    \"complexes\": [\"NuA4/Tip60 HAT complex\", \"Rpd3S/Sin3S HDAC complex\", \"ASH1L histone methyltransferase complex\", \"PALB2-BRCA2-RAD51 DNA repair complex\"],\n    \"partners\": [\"PALB2\", \"ASH1L\", \"Pf1\", \"TIP60\", \"LRH-1\", \"HDAC2\", \"TUFM\", \"MyoD\"],\n    \"other_free_text\": []\n  }\n}\n```","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}