Affinage

Showing MORF4L1 — MRG15 is a alias.

MORF4L1

Mortality factor 4-like protein 1 · UniProt Q9UBU8

Length
362 aa
Mass
41.5 kDa
Annotated
2026-06-10
61 papers in source corpus 40 papers cited in narrative 40 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2002 Medium

    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

    PMID:11500496 PMID:12391155 PMID:12397079

    Open questions at the time
    • Genomic targets of each complex not defined in mammals
    • Chromodomain ligand not yet identified
  2. 2005 High

    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

    PMID:14701747 PMID:16364921

    Open questions at the time
    • Affinity and specificity quantification incomplete
    • Mechanism of acetylation redistribution across promoter vs ORF not fully resolved
  3. 2006 High

    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)

    PMID:17008723 PMID:17135209

    Open questions at the time
    • Structures of full-length protein on nucleosomes not solved
    • How a single MRG domain selects among competing partners unclear
  4. 2008 High

    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

    PMID:18818090

    Open questions at the time
    • Mechanism conferring in vivo specificity left unresolved until bivalent-engagement studies
  5. 2010 High

    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

    PMID:17961556 PMID:19553677 PMID:20332121

    Open questions at the time
    • Whether chromatin reading is required for repair role not yet tested
    • Structural basis of PALB2 binding unknown at this stage
  6. 2012 Medium

    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

    PMID:21440557 PMID:22728643

    Open questions at the time
    • In vivo verification of bivalency in mammals limited
    • Stoichiometry within the assembled complex not defined
  7. 2016 High

    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

    PMID:27535225 PMID:27573846 PMID:31242410

    Open questions at the time
    • Direct biochemical bridge between MRG15 and spliceosome in mammals incomplete
    • Which splicing events are chromodomain-dependent not fully mapped
  8. 2017 High

    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

    PMID:28673974

    Open questions at the time
    • Relative contribution of transcription-coupled vs canonical HR not quantified
  9. 2019 High

    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

    PMID:29158494 PMID:30827841 PMID:30827843

    Open questions at the time
    • Allosteric vs recruitment-based activation mechanism in conflict with later solution data
  10. 2021 High

    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

    PMID:34946951

    Open questions at the time
    • Functional consequence of weak-affinity patient variants in cells unresolved
    • Regulation of partner switching in vivo unknown
  11. 2023 Medium

    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

    PMID:37393406 PMID:37527654

    Open questions at the time
    • Reconciliation of allosteric vs recruitment models incomplete
    • NER role rests on single-lab functional assays
  12. 2022 High

    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

    PMID:35985547

    Open questions at the time
    • Mechanism of MRG15 import/retention at the mitochondrial membrane unknown
    • Direct deacetylase catalytic basis not structurally defined
  13. 2025 Medium

    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

    PMID:24451372 PMID:34946951 PMID:39827217 PMID:40312521 PMID:40483328 PMID:41061828 PMID:41188483 PMID:41251000 PMID:41580578

    Open questions at the time
    • 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

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0042393 histone binding 4 GO:0060090 molecular adaptor activity 4 GO:0098772 molecular function regulator activity 4 GO:0003677 DNA binding 3 GO:0140096 catalytic activity, acting on a protein 2
Localization
GO:0005634 nucleus 4 GO:0000228 nuclear chromosome 3 GO:0005654 nucleoplasm 1 GO:0005739 mitochondrion 1
Pathway
R-HSA-1266738 Developmental Biology 4 R-HSA-4839726 Chromatin organization 4 R-HSA-73894 DNA Repair 4 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-8953854 Metabolism of RNA 2 R-HSA-9612973 Autophagy 1
Partners
ASH1LHDAC2LRH-1MYODPALB2PF1TIP60TUFM
Complex memberships
ASH1L histone methyltransferase complexNuA4/Tip60 HAT complexPALB2-BRCA2-RAD51 DNA repair complexRpd3S/Sin3S HDAC complex

Evidence

Reading pass · 40 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 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. Co-immunoprecipitation, yeast two-hybrid, deletion mutagenesis, luciferase reporter assay The Journal of biological chemistry Medium 11500496
2002 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. Sucrose gradient fractionation, deletion mutant analysis, histone acetyltransferase activity assay, promoter activation assay The Journal of biological chemistry Medium 12397079
2002 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. Gal4-fusion transcriptional repression assay, co-immunoprecipitation, domain mapping, dominant-negative TLE Molecular and cellular biology Medium 12391155
2004 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. Chromatin immunoprecipitation, genome-wide transcriptional profiling, histone acetylation profiling Molecular and cellular biology High 14701747
2005 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. Chromodomain-methylated peptide binding assay, genetic epistasis (eaf3Δ, set2Δ), chromatin immunoprecipitation Molecular cell High 16364921
2005 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. Knockout mouse generation, BrdU proliferation assay, chromatin immunoprecipitation, microarray Molecular and cellular biology High 15798182
2006 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. X-ray crystallography, in vitro peptide binding assay Nucleic acids research High 17135209
2006 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. X-ray crystallography, yeast two-hybrid, in vitro binding assay, site-directed mutagenesis Protein science High 17008723
2007 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. Immunofluorescence/nuclear fractionation, immunoprecipitation-mass spectrometry, H3K4 demethylase in vitro assay, RNAi knockdown with ChIP Genes to cells Medium 17573780
2007 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. Gamma irradiation, immunofluorescence for γH2AX and 53BP1 foci, cell growth assay FEBS letters Medium 17961556
2008 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. NMR structure determination, engineered linked protein with methyllysine analog, binding affinity measurements Structure High 18818090
2009 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. Co-immunoprecipitation, gene conversion assay, sister chromatid exchange assay, PALB2 mutant analysis The Journal of biological chemistry Medium 19553677
2009 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. Neurosphere culture from KO embryos, BrdU incorporation, differentiation assay Journal of neuroscience research Medium 19115414
2010 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. Purified protein complex analysis, Co-IP, siRNA knockdown, homology-directed repair assay, immunofluorescence for DNA damage foci Journal of cell science High 20332121
2011 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. ChIP during cell cycle, luciferase reporter assay, siRNA knockdown, HAT inhibitor treatment, Tip60 co-transfection Experimental cell research Medium 21324423
2011 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. KO-derived NSCs, p21/p53 shRNA rescue, BrdU assay, immunostaining for γH2AX/53BP1 Stem cell research Medium 21621175
2011 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. NMR structure determination, competition binding assay Journal of molecular biology High 21440557
2012 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. In vitro binding assays, fluorescence polarization/ITC affinity measurements, mutagenesis Journal of molecular biology Medium 22728643
2013 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. Yeast two-hybrid, genetic interaction (transvection assay), RNAi depletion, chromatin fractionation Genetics Medium 23821596
2014 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. Co-immunoprecipitation, site-directed mutagenesis, HDAC2 knockdown, self-assembly assays The Journal of biological chemistry Medium 24451372
2016 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. High-throughput RNA sequencing (splicing analysis), ChIP, Co-IP of Eaf3 with splicing factors, genetic epistasis Cell reports Medium 31242410
2016 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. In vitro nucleosome binding assay, H4 acetylation measurement, Pol II binding assay, transcription elongation assay The Journal of biological chemistry Medium 27535225
2016 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. Conditional KO mouse, RNA-seq, intron retention analysis, immunofluorescence co-localization with splicing factors PNAS High 27573846
2017 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. ChIP-seq, co-immunoprecipitation, camptothecin sensitivity assay, metaphase spread analysis, cell fractionation PNAS High 28673974
2017 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. In vitro HMT assay, ChIP, knock-in fly genetics, rescue experiment with Mrg15-Nurf55 fusion Nature communications High 29158494
2018 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. Automated solid-phase RNAi screen, germ cell reprogramming assay, protein interaction analysis Genetics Medium 30425042
2019 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. X-ray crystallography, in vitro HMT activity assay, mutagenesis Structure High 30827843
2019 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. X-ray crystallography, in vitro HMT activity assay Structure High 30827841
2020 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. ChIP-seq (rhythmic genomic binding), Co-IP (MRG15-LRH-1 interaction), CRISPR depletion, RNA-seq Nature metabolism High 32694659
2021 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. X-ray crystallography, binding affinity measurement (ITC/SPR), mutagenesis analysis of patient variants Genes High 34946951
2022 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. Immunoprecipitation-mass spectrometry, CRISPR depletion, site-directed mutagenesis (K82/K91), ClpXP protease assay, mitophagy assay, NLRP3 inflammasome measurement Journal of hepatology High 35985547
2023 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. In vitro HMT assay with nucleosomes, chromodomain deletion/mutagenesis, NMR/biophysical analysis of SET domain conformation Structure High 37527654
2023 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. Co-immunoprecipitation, ChIP-seq, siRNA knockdown of ASH1L/MRG15/FACT, XPC localization assay, NER functional assay Nature communications Medium 37393406
2025 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. Proteomic analysis, co-immunoprecipitation, structural modeling, degradation assay with CC-885 Scientific reports Medium 39827217
2025 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. Immunoprecipitation-mass spectrometry, site-directed mutagenesis (K628), ubiquitination assay, ChIP for H3K4ac, cGAS-STING pathway assay Cellular & molecular immunology Medium 41188483
2025 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. IP-LC/MS, co-immunoprecipitation, ubiquitination assay, site-directed mutagenesis (K249, K227) Biochimica et biophysica acta. Molecular basis of disease Medium 41061828
2025 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). Phase separation assay, IDR deletion/replacement constructs, ChIP-seq, RNA-seq, hMSC senescence assay Communications biology Medium 40312521
2025 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. Cardiac-specific conditional KO mouse, ChIP for complex components and histone acetylation, adoptive transfer of Tregs, AAV9 overexpression rescue Circulation High 41251000
2025 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. Histone peptide binding assay, protein interaction analysis, MRG15L-specific KO mouse, cardiac ischemia-reperfusion model Communications biology Medium 40483328
2026 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. MuSC-specific inducible KO mouse, RNA-seq, ChIP-seq of histone modifications, Co-IP of MRG15-MyoD Cell regeneration Medium 41580578

Source papers

Stage 0 corpus · 61 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 Eaf3 chromodomain interaction with methylated H3-K36 links histone deacetylation to Pol II elongation. Molecular cell 428 16364921
2006 Structure of human MRG15 chromo domain and its binding to Lys36-methylated histone H3. Nucleic acids research 124 17135209
2002 Role for the mortality factors MORF4, MRGX, and MRG15 in transcriptional repression via associations with Pf1, mSin3A, and Transducin-Like Enhancer of Split. Molecular and cellular biology 84 12391155
2007 RBP2 is an MRG15 complex component and down-regulates intragenic histone H3 lysine 4 methylation. Genes to cells : devoted to molecular & cellular mechanisms 82 17573780
2008 Structural basis for the recognition of methylated histone H3K36 by the Eaf3 subunit of histone deacetylase complex Rpd3S. Structure (London, England : 1993) 74 18818090
2002 MRG15, a novel chromodomain protein, is present in two distinct multiprotein complexes involved in transcriptional activation. The Journal of biological chemistry 74 12397079
2010 MRG15 binds directly to PALB2 and stimulates homology-directed repair of chromosomal breaks. Journal of cell science 68 20332121
2005 MRG15 regulates embryonic development and cell proliferation. Molecular and cellular biology 68 15798182
2016 MRG15 is required for pre-mRNA splicing and spermatogenesis. Proceedings of the National Academy of Sciences of the United States of America 67 27573846
2004 Eaf3 regulates the global pattern of histone acetylation in Saccharomyces cerevisiae. Molecular and cellular biology 64 14701747
2009 MRG15 is a novel PALB2-interacting factor involved in homologous recombination. The Journal of biological chemistry 58 19553677
2017 Mrg15 stimulates Ash1 H3K36 methyltransferase activity and facilitates Ash1 Trithorax group protein function in Drosophila. Nature communications 48 29158494
2001 MRG15 activates the B-myb promoter through formation of a nuclear complex with the retinoblastoma protein and the novel protein PAM14. The Journal of biological chemistry 46 11500496
2017 MRG15-mediated tethering of PALB2 to unperturbed chromatin protects active genes from genotoxic stress. Proceedings of the National Academy of Sciences of the United States of America 44 28673974
2009 MRG15, a component of HAT and HDAC complexes, is essential for proliferation and differentiation of neural precursor cells. Journal of neuroscience research 42 19115414
2022 MRG15 aggravates non-alcoholic steatohepatitis progression by regulating the mitochondrial proteolytic degradation of TUFM. Journal of hepatology 38 35985547
2019 H3K36 Methylation and the Chromodomain Protein Eaf3 Are Required for Proper Cotranscriptional Spliceosome Assembly. Cell reports 37 31242410
2019 Structural Insights into Stimulation of Ash1L's H3K36 Methyltransferase Activity through Mrg15 Binding. Structure (London, England : 1993) 32 30827843
2007 Mrg15 null and heterozygous mouse embryonic fibroblasts exhibit DNA-repair defects post exposure to gamma ionizing radiation. FEBS letters 32 17961556
2020 MRG15 orchestrates rhythmic epigenomic remodelling and controls hepatic lipid metabolism. Nature metabolism 31 32694659
2013 Maintenance of interphase chromosome compaction and homolog pairing in Drosophila is regulated by the condensin cap-h2 and its partner Mrg15. Genetics 30 23821596
2018 MRG-1/MRG15 Is a Barrier for Germ Cell to Neuron Reprogramming in Caenorhabditis elegans. Genetics 29 30425042
2011 Solution structure of the mSin3A PAH2-Pf1 SID1 complex: a Mad1/Mxd1-like interaction disrupted by MRG15 in the Rpd3S/Sin3S complex. Journal of molecular biology 28 21440557
2011 Loss of the chromatin regulator MRG15 limits neural stem/progenitor cell proliferation via increased expression of the p21 Cdk inhibitor. Stem cell research 26 21621175
2006 The MRG domain of human MRG15 uses a shallow hydrophobic pocket to interact with the N-terminal region of PAM14. Protein science : a publication of the Protein Society 24 17008723
2019 Structural Basis of MRG15-Mediated Activation of the ASH1L Histone Methyltransferase by Releasing an Autoinhibitory Loop. Structure (London, England : 1993) 23 30827841
2012 Sequence requirements for combinatorial recognition of histone H3 by the MRG15 and Pf1 subunits of the Rpd3S/Sin3S corepressor complex. Journal of molecular biology 23 22728643
2011 Exploring the link between MORF4L1 and risk of breast cancer. Breast cancer research : BCR 20 21466675
2011 MRG15 activates the cdc2 promoter via histone acetylation in human cells. Experimental cell research 17 21324423
2016 The Eaf3/5/7 Subcomplex Stimulates NuA4 Interaction with Methylated Histone H3 Lys-36 and RNA Polymerase II. The Journal of biological chemistry 16 27535225
2014 Histone deacetylase 2 (HDAC2) protein-dependent deacetylation of mortality factor 4-like 1 (MORF4L1) protein enhances its homodimerization. The Journal of biological chemistry 15 24451372
2005 Functional analysis of MRG-1: the ortholog of human MRG15 in Caenorhabditis elegans. The journals of gerontology. Series A, Biological sciences and medical sciences 14 15972600
2023 ASH1L-MRG15 methyltransferase deposits H3K4me3 and FACT for damage verification in nucleotide excision repair. Nature communications 13 37393406
2021 In-depth proteomic analysis of proteasome inhibitors bortezomib, carfilzomib and MG132 reveals that mortality factor 4-like 1 (MORF4L1) protein ubiquitylation is negatively impacted. Journal of proteomics 13 33848640
2010 A nuclear ligand MRG15 involved in the proapoptotic activity of medicinal fungal galectin AAL (Agrocybe aegerita lectin). Biochimica et biophysica acta 13 20122994
2018 MORF4L1 suppresses cell proliferation, migration and invasion by increasing p21 and E-cadherin expression in nasopharyngeal carcinoma. Oncology letters 12 30655767
2002 A chromodomain-containing nuclear protein, MRG15 is expressed as a novel type of dendritic mRNA in neurons. Neuroscience research 11 11985882
2024 MRG15 aggravates sepsis-related liver injury by promoting PCSK9 synthesis and secretion. International immunopharmacology 9 39128417
2024 MRG15 promotes cell apoptosis through inhibition of mitophagy in hyperlipidemic acute pancreatitis. Apoptosis : an international journal on programmed cell death 8 39487311
2021 Structural Insight into the Mechanism of PALB2 Interaction with MRG15. Genes 8 34946951
2024 Structural and functional insights into the epigenetic regulator MRG15. Acta pharmacologica Sinica 7 38191914
2020 Development of a Microscale Thermophoresis-Based Method for Screening and Characterizing Inhibitors of the Methyl-Lysine Reader Protein MRG15. SLAS discovery : advancing life sciences R & D 7 32808584
2010 Conditional inactivation of MRG15 gene function limits survival during larval and adult stages of Drosophila melanogaster. Experimental gerontology 7 20600782
2022 ADSCs Promote Tenocyte Proliferation by Reducing the Methylation Level of lncRNA Morf4l1 in Tendon Injury. Frontiers in chemistry 6 35860629
2013 Alternative splicing of the chromodomain protein Morf4l1 pre-mRNA has implications on cell differentiation in the developing chicken retina. Journal of molecular neuroscience : MN 6 23733253
2025 Identification of MORF4L1 as an endogenous substrate of CRBN and its potential role as a therapeutic target in cancer. Scientific reports 5 39827217
2025 CD4+ Tregs Regulate Heart Growth and Regeneration Through MRG15/TIP60-Mediated Epigenomic Remodeling in Proliferating Cardiomyocytes. Circulation 5 41251000
2023 MRG15 activates histone methyltransferase activity of ASH1L by recruiting it to the nucleosomes. Structure (London, England : 1993) 5 37527654
2010 Mutation analysis of the gene encoding the PALB2-binding protein MRG15 in BRCA1/2-negative breast cancer families. Journal of human genetics 5 20844547
2025 MRG15 alternative splicing regulates CDK1 transcriptional activity in mouse cell senescence and myocardial regeneration. Communications biology 4 40483328
2023 H3K36 Di-Methylation Marks, Mediated by Ash1 in Complex with Caf1-55 and MRG15, Are Required during Drosophila Heart Development. Journal of cardiovascular development and disease 4 37504562
2025 Predicting hepatocellular carcinoma outcomes and immune therapy response with ATP-dependent chromatin remodeling-related genes, highlighting MORF4L1 as a promising target. Cancer cell international 3 39757177
2025 Targeting MORF4L1-mediated DNA repair potentiates RT-induced antitumor immunity via cGAS-STING activation in hepatocellular carcinoma. Cellular & molecular immunology 3 41188483
2024 Emerging roles of MRG15 in liver metabolic diseases. Trends in molecular medicine 2 38521716
2022 Targeting MRG15 for the treatment of nonalcoholic steatohepatitis. Metabolism open 2 36478775
2025 Phase separation of MRG15 delays cellular senescence. Communications biology 1 40312521
2026 MRG15 decline in aged/injured MuSCs hinders regeneration via differentiation defects. Cell regeneration (London, England) 0 41580578
2026 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. Biomedicines 0 41751172
2026 MORF4L1 regulation and its role in chromatin remodeling, DNA damage, cellular senescence, and cardiometabolic disease. Vascular pharmacology 0 41819434
2025 Deubiquitinase USP53 suppressed tumorigenesis of colorectal cancer cells by mediating deubiquitination of MORF4L1. Biochimica et biophysica acta. Molecular basis of disease 0 41061828
2024 Synergistic Treatment Approach for Pulmonary Fibrosis: Prednisone and Cyclophosphamide Regulation of Circular RNA MORF4L1 and MicroRNA-29a-3p Targeting BRD4. Iranian journal of allergy, asthma, and immunology 0 39549296

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