Affinage

MORF4L1

Mortality factor 4-like protein 1 · UniProt Q9UBU8

Length
362 aa
Mass
41.5 kDa
Annotated
2026-04-28
61 papers in source corpus 35 papers cited in narrative 35 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MORF4L1 (MRG15) is a conserved chromatin adapter protein whose N-terminal chromodomain selectively reads H3K36me2/3 marks and whose C-terminal MRG domain mediates mutually exclusive interactions with diverse effector complexes, thereby coupling histone modification state to transcriptional regulation, DNA repair, splicing, and chromosome organization. Through its chromodomain, MORF4L1 targets the NuA4/Tip60 histone acetyltransferase complex and the Rpd3S/Sin3A histone deacetylase complex to transcribed gene bodies, while its MRG domain activates the ASH1L H3K36 methyltransferase by displacing the autoinhibitory loop and recruiting nucleosome substrates (PMID:30827841, PMID:37527654). MORF4L1 recruits PALB2 and the BRCA1–BRCA2–RAD51 complex to H3K36me3-marked active chromatin to protect replication forks and facilitate homology-directed repair and nucleotide excision repair (PMID:20332121, PMID:28673974, PMID:37393406). MORF4L1 is essential for embryonic viability and cell proliferation, regulates pre-mRNA splicing during spermatogenesis, controls diurnal lipid gene expression via LRH-1, and also localizes to the outer mitochondrial membrane where it promotes TUFM deacetylation and degradation, impairing mitophagy in NASH (PMID:15798182, PMID:27573846, PMID:32694659, PMID:35985547).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 2001 High

    The first evidence that MORF4L1 operates within multiprotein complexes came from demonstrating that it binds retinoblastoma protein and PAM14 through its HLH-leucine zipper domain to relieve Rb-mediated repression of the B-myb promoter, establishing MORF4L1 as a transcriptional coregulator.

    Evidence Co-immunoprecipitation, yeast two-hybrid, and promoter-reporter assays in mammalian cells

    PMID:11500496

    Open questions at the time
    • Physiological relevance of B-myb activation not tested in vivo
    • Stoichiometry of the Rb–MRG15–PAM14 complex unknown
  2. 2002 High

    Biochemical fractionation revealed that MORF4L1 participates in at least two functionally distinct complexes—an HAT complex containing hMOF (requiring the chromodomain) and an Rb-containing complex (requiring the leucine zipper)—and separately that MORF4L1 represses transcription through mSin3A/TLE HDAC corepressors modulated by Pf1, establishing it as a bifunctional chromatin adapter bridging acetylation and deacetylation.

    Evidence Sucrose gradient fractionation, HAT assays, Gal4-reporter assays, and domain deletion mapping

    PMID:12391155 PMID:12397079

    Open questions at the time
    • How cells specify MORF4L1 partitioning between HAT and HDAC complexes was unknown
    • In vivo genomic targets of each complex uncharacterized
  3. 2005 High

    Mrg15 knockout mice showed embryonic lethality with reduced proliferation but not increased apoptosis, and ChIP showed MRG15 at the alpha-globin promoter during erythroid differentiation, establishing an essential developmental role and direct chromatin occupancy.

    Evidence Knockout mouse, BrdU incorporation, chromatin immunoprecipitation

    PMID:15798182

    Open questions at the time
    • Molecular basis of proliferation defect (which target genes) was unresolved
    • Contribution of individual complexes to lethality unknown
  4. 2006 High

    Structural determination of both functional domains—the chromodomain bound to methylated H3K36 and the MRG domain bound to PAM14—revealed the molecular basis of MORF4L1's dual-reader/adapter architecture: a hydrophobic aromatic cage selectively accommodates H3K36me but not other methyl-lysine marks, while a shallow hydrophobic pocket on the MRG domain engages partner proteins.

    Evidence X-ray crystallography at 2.2 Å (chromodomain) and MRG domain, plus mutagenesis and peptide binding assays

    PMID:17008723 PMID:17135209

    Open questions at the time
    • Affinity for H3K36me2 vs me3 not quantified
    • Whether the same molecule can simultaneously engage chromatin and partners was unknown
  5. 2007 High

    Two studies expanded MORF4L1's functional repertoire: it co-purifies with the H3K4 demethylase RBP2 and colocalizes with elongating RNA Pol II, and Mrg15-null MEFs show delayed γH2AX and 53BP1 focus formation after irradiation, linking MORF4L1 to both transcription-coupled demethylation and the DNA damage response.

    Evidence Co-IP/mass spectrometry with demethylase assay; gamma irradiation of KO MEFs with immunofluorescence

    PMID:17573780 PMID:17961556

    Open questions at the time
    • Mechanism by which MORF4L1 facilitates damage signaling was unclear
    • Whether RBP2 interaction is direct or bridged by other subunits was not resolved
  6. 2009 High

    Direct binding of MORF4L1 to PALB2 was discovered, and disrupting this interaction elevated gene conversion and sister chromatid exchange rates, revealing that MORF4L1 constrains homologous recombination fidelity.

    Evidence Co-IP, pulldown with recombinant proteins, gene conversion and SCE assays with point mutants

    PMID:19553677

    Open questions at the time
    • How MORF4L1 suppresses hyper-recombination mechanistically was not established
    • Whether the chromodomain was required for this function was untested
  7. 2010 High

    MORF4L1 was shown to be the chromatin anchor for the entire BRCA complex (BRCA1–PALB2–BRCA2–RAD51); its loss abolished PALB2/BRCA2/RAD51 recruitment to damage sites, reduced homology-directed repair, and caused interstrand crosslink hypersensitivity, establishing a complete pathway from histone mark reading to repair factor loading.

    Evidence Purified complex analysis, chromatin fractionation, HR reporter assay, ICL sensitivity assay, and immunofluorescence of repair foci

    PMID:20332121

    Open questions at the time
    • Which histone mark was recognized at damage sites (H3K36me3 vs others) was not yet linked
    • Temporal ordering of MORF4L1 arrival relative to damage sensing unknown
  8. 2011 High

    Multiple studies refined the competition model for MORF4L1 complex assembly: NMR showed mSin3A and MORF4L1 compete for overlapping Pf1 binding surfaces, MORF4L1 occupied the CDK1 promoter during S phase cooperating with Tip60 for H4K12 acetylation, and loss of MRG15 in neural stem cells activated p53/p21 causing proliferation arrest.

    Evidence NMR structure of Sin3A–Pf1, ChIP at cdc2 promoter with HAT inhibitor, p21/p53 shRNA rescue in Mrg15-null NSCs

    PMID:21324423 PMID:21440557 PMID:21621175

    Open questions at the time
    • Whether mutual exclusivity of Sin3A and MRG15 for Pf1 operates genome-wide was untested
    • Direct HAT activity of Tip60 at CDK1 promoter not reconstituted in vitro
  9. 2012 High

    Quantitative binding measurements established that MORF4L1 chromodomain binds H3K36me2/3 with weak (>100 µM) affinity, and that bivalent engagement with Pf1's PHD1 domain (reading unmodified H3K4) is required for Rpd3S/Sin3S targeting, explaining how a weak reader achieves specificity through multivalent contacts.

    Evidence ITC, peptide pulldown, domain deletion in the context of reconstituted Pf1–MRG15 complex

    PMID:22728643

    Open questions at the time
    • In vivo contribution of bivalent reading not validated by ChIP of mutants
    • How other complex subunits contribute to chromatin affinity was unresolved
  10. 2014 High

    HDAC2-mediated deacetylation of MORF4L1 at K148 was shown to be required for homodimerization, revealing a post-translational switch that controls MORF4L1 self-assembly and potentially complex stoichiometry.

    Evidence Site-directed mutagenesis (K148R/L/Q), Co-IP of acetylation mimics, HDAC2 knockdown

    PMID:24451372

    Open questions at the time
    • Functional consequence of dimerization for chromatin targeting or complex activity unknown
    • Whether dimerization occurs within or between complexes was unresolved
  11. 2016 High

    Conditional knockout in spermatocytes revealed that MORF4L1 reads H3K36me3 in introns and colocalizes with splicing factors PTBP1/PTBP2 to promote co-transcriptional splicing; loss caused intron retention in transition protein mRNAs and spermatogenic arrest, establishing a direct role in coupling histone marks to pre-mRNA processing.

    Evidence Conditional KO mouse, RNA-seq, ChIP, co-immunofluorescence

    PMID:27573846

    Open questions at the time
    • Whether MORF4L1 directly binds PTBP1/PTBP2 or recruits them indirectly was not determined
    • Generality of the splicing role beyond spermatogenesis was unclear
  12. 2017 High

    Two key advances: (1) MORF4L1 was identified as a subunit of the Ash1 methyltransferase complex that stimulates H3K36 methylation and is required for Ash1 chromatin occupancy at Hox genes, and (2) ChIP-seq demonstrated that PALB2–MORF4L1 association with active genes depends on SETD2-deposited H3K36me3, completing the SETD2→H3K36me3→MRG15→PALB2 axis protecting replication through gene bodies.

    Evidence In vitro HMT assay with genetic rescue in Drosophila; ChIP-seq, camptothecin sensitivity, DNA combing in human cells

    PMID:28673974 PMID:29158494

    Open questions at the time
    • Whether the Ash1–MRG15 complex uses the chromodomain for genomic targeting was not tested
    • Structural basis of MRG15-mediated Ash1 activation was unknown
  13. 2019 High

    Two independent crystal structures of the ASH1L–MRG15 complex resolved how MORF4L1 activates ASH1L: the MRG domain binds a conserved FxLP motif and displaces the autoinhibitory post-SET loop, opening the substrate binding pocket and inducing conformational coupling to the SAM-binding site.

    Evidence X-ray crystallography with in vitro methyltransferase assays and mutagenesis, independently replicated

    PMID:30827841 PMID:30827843

    Open questions at the time
    • Whether this allosteric mechanism operates on nucleosomal substrates was not demonstrated
    • In vivo validation of the autoinhibitory loop displacement model was lacking
  14. 2020 High

    ChIP-seq in mouse liver revealed diurnally rhythmic MORF4L1 genomic binding at lipid synthesis genes, mediated by interaction with nuclear receptor LRH-1 rather than core clock factors, and MORF4L1 depletion impaired rhythmic Pol II recruitment and histone acetylation, revealing a metabolic regulatory function.

    Evidence ChIP-seq time-course, Co-IP, CRISPR targeting, RNA-seq

    PMID:32694659

    Open questions at the time
    • Which HAT complex mediates acetylation at lipid genes was not identified
    • Whether LRH-1 interaction is direct or bridged was not structurally resolved
  15. 2021 High

    Structural and stability studies showed that PALB2 binds the MRG domain with nanomolar affinity at a surface overlapping other partner binding sites, confirming mutually exclusive complex formation, and ubiquitylome analysis established that MORF4L1 protein levels are controlled by ubiquitin-proteasome degradation at K187 and K104.

    Evidence X-ray crystallography with SPR; large-scale ubiquitylome MS with proteasome inhibitors

    PMID:33848640 PMID:34946951

    Open questions at the time
    • Identity of the E3 ligase for basal turnover was unknown at this point
    • Whether ubiquitination regulates MORF4L1 complex partitioning was untested
  16. 2022 High

    MORF4L1 was discovered at the outer mitochondrial membrane where it deacetylates TUFM at K82/K91, targeting TUFM for ClpXP-mediated degradation; this impairs mitophagy and activates the NLRP3 inflammasome, driving NASH pathology—the first demonstration of a non-nuclear MORF4L1 function.

    Evidence IP-MS, Co-IP, mitochondrial fractionation, CRISPR KO, mitophagy and NLRP3 assays in NASH models

    PMID:35985547

    Open questions at the time
    • Mechanism of MORF4L1 targeting to mitochondria is unknown
    • Whether MORF4L1 possesses intrinsic deacetylase activity or recruits an HDAC at mitochondria was not distinguished
  17. 2023 High

    Two studies revised the ASH1L activation model and expanded DNA repair roles: NMR showed MORF4L1 does not alter ASH1L autoinhibitory loop conformation in solution but instead functions as a nucleosome-recruiting adapter via its chromodomain; separately, the ASH1L–MRG15 complex was found to deposit H3K4me3 genome-wide after UV damage to relocalize XPC and recruit the FACT chaperone, establishing a role in nucleotide excision repair.

    Evidence In vitro HMT assay with nucleosomes and NMR; ChIP-seq after UV irradiation with NER reconstitution

    PMID:37393406 PMID:37527654

    Open questions at the time
    • Whether the nucleosome-recruiting and allosteric mechanisms are mutually exclusive or additive in vivo is unresolved
    • How ASH1L–MRG15 switches from H3K36 to H3K4 methylation specificity upon UV damage is unexplained
  18. 2025 Medium

    Multiple 2025 studies expanded the regulatory and functional landscape: CRBN was identified as an E3 ligase for MORF4L1, USP53 as a stabilizing deubiquitinase, phase separation via the IDR was linked to senescence suppression, a long isoform (MRG15L) was shown to weaken CDK1 regulation causing senescence, and MORF4L1 was found to promote cardiomyocyte proliferation at the Ccnd1 enhancer with Tip60/p300 and to cooperate with MyoD for myogenic differentiation.

    Evidence Proteomic/Co-IP degradation assays; phase separation/ChIP-seq; conditional KO mice in cardiac and muscle stem cells; isoform-specific binding and FACS analyses

    PMID:39827217 PMID:40312521 PMID:40483328 PMID:41061828 PMID:41251000 PMID:41580578

    Open questions at the time
    • Interplay between CRBN and USP53 in setting MORF4L1 levels is unexplored
    • Whether phase separation is required for complex assembly in vivo needs validation
    • MRG15L isoform mechanism for altered histone binding is structurally uncharacterized

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: how MORF4L1 is directed to the outer mitochondrial membrane and whether it possesses intrinsic deacetylase activity; how cells partition a single MORF4L1 pool among mutually exclusive complexes (NuA4, Sin3S, ASH1L, PALB2); whether phase separation contributes to complex specificity in vivo; and how the ASH1L–MRG15 complex switches histone substrate specificity from H3K36 to H3K4 upon DNA damage.
  • No structural or biochemical mechanism for mitochondrial targeting
  • No quantitative model of competitive complex partitioning
  • Switch mechanism for ASH1L substrate specificity under damage conditions unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 5 GO:0042393 histone binding 4 GO:0140110 transcription regulator activity 4 GO:0098772 molecular function regulator activity 3
Localization
GO:0005634 nucleus 7 GO:0005694 chromosome 4 GO:0005739 mitochondrion 1
Pathway
R-HSA-4839726 Chromatin organization 7 R-HSA-73894 DNA Repair 5 R-HSA-74160 Gene expression (Transcription) 5 R-HSA-1640170 Cell Cycle 4 R-HSA-1266738 Developmental Biology 3 R-HSA-8953854 Metabolism of RNA 1 R-HSA-9612973 Autophagy 1
Partners
ASH1LKAT5KAT8MRGBPPALB2PHF12SIN3ATUFM
Complex memberships
ASH1L methyltransferase complexBRCA/PALB2 repair complexNuA4/Tip60 HAT complexSin3A/Rpd3S HDAC complex

Evidence

Reading pass · 35 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 Crystal structure of human MRG15 chromodomain at 2.2 Å resolution reveals a beta-barrel with a hydrophobic pocket formed by Tyr26, Tyr46, and Trp49 that binds methylated H3K36 but not methylated H3K4, H3K9, or H3K27, demonstrating selective methyl-lysine reading activity. X-ray crystallography + in vitro peptide binding assay Nucleic acids research High 17135209
2001 MRG15 forms a multiprotein complex with retinoblastoma protein (Rb) and the novel nuclear protein PAM14, mediated by the helix-loop-helix and leucine zipper domains of MRG15, and this complex activates the B-myb promoter by blocking Rb-induced repression. Co-immunoprecipitation, yeast two-hybrid, domain deletion mapping, promoter-reporter assay The Journal of biological chemistry High 11500496
2002 MRG15 exists in two distinct nuclear protein complexes: MAF1 (containing Rb and PAM14, requiring the leucine zipper) and MAF2 (containing the histone acetyltransferase hMOF, requiring the chromodomain); histone acetyltransferase activity co-purifies with MRG15 and is lost upon chromodomain deletion. Sucrose gradient fractionation, deletion mutant analysis, histone acetyltransferase activity assay The Journal of biological chemistry High 12397079
2002 MRG15, MRGX, and MORF4 repress transcription through direct association with mSin3A and TLE (Transducin-Like Enhancer of Split) histone deacetylase-containing corepressors; MRG15 uniquely interacts with Pf1, which reduces MRG15-mediated repression through an MRG15/Pf1/mSin3A complex. Gal4-luciferase reporter assay, Co-immunoprecipitation, domain mapping, dominant-negative TLE Molecular and cellular biology High 12391155
2005 MRG15 knockout mice display embryonic lethality with developmental delay, reduced cell proliferation in multiple tissues without increased apoptosis, and MRG15 is recruited to the alpha-globin promoter during erythroid differentiation as shown by chromatin immunoprecipitation. Knockout mouse generation, BrdU proliferation assay, chromatin immunoprecipitation (ChIP) Molecular and cellular biology High 15798182
2006 Crystal structure of the MRG domain of MRG15 reveals a predominantly alpha-helical three-layer sandwich topology; structure-based mutagenesis identified Ile160, Leu168, Val169, Trp172, Tyr235, Val268, and Arg269 as forming a shallow hydrophobic pocket mediating interaction with the N-terminal 50 residues of PAM14. X-ray crystallography, site-directed mutagenesis, yeast two-hybrid, in vitro binding assay Protein science High 17008723
2007 MRG15 complex contains RBP2 (a JmjC domain H3K4 demethylase); RBP2 associated with MRG15 removes H3K4 methylation within transcribed regions in vivo, and MRG15 localizes to nuclear subdomains enriched for Ser2-phosphorylated RNA Pol II. Co-immunoprecipitation, mass spectrometry, in vitro demethylase assay, RBP2 knockdown, nuclear fractionation/immunostaining Genes to cells High 17573780
2009 MRG15 directly binds PALB2 via an evolutionarily conserved region; disruption of this interaction elevates gene conversion rates and sister chromatid exchange frequencies, indicating MRG15 suppresses hyper-recombination during homologous recombination repair. Co-immunoprecipitation, pulldown, gene conversion assay, SCE assay, point-mutation of binding interface The Journal of biological chemistry High 19553677
2010 MRG15 directly binds PALB2 and mediates the association of the entire BRCA complex (BRCA1, PALB2, BRCA2, RAD51) with chromatin; MRG15-deficient cells show reduced homology-directed DNA repair, hypersensitivity to interstrand crosslinking agents, and impaired recruitment of PALB2, BRCA2, and RAD51 to DNA damage sites. Purified protein complex analysis, Co-immunoprecipitation, homology-directed repair assay, ICL sensitivity assay, immunofluorescence of repair foci, chromatin fractionation Journal of cell science High 20332121
2007 Mrg15-null and heterozygous mouse embryonic fibroblasts exhibit delayed formation of phosphorylated H2AX and 53BP1 foci and impaired DNA repair after gamma irradiation, establishing MRG15 as required for efficient DNA damage response. Gamma irradiation of KO MEFs, immunofluorescence for γH2AX and 53BP1 foci, cell growth assay FEBS letters Medium 17961556
2011 MRG15 occupies the cdc2 (CDK1) promoter during S phase entry and cooperates with Tip60 HAT to acetylate histone H4 (specifically H4K12) at this promoter, activating cdc2 transcription; knockdown of MRG15 reduces cdc2 promoter activity. Chromatin immunoprecipitation (ChIP), promoter-reporter assay, HAT inhibitor treatment, co-transfection Experimental cell research Medium 21324423
2011 The mSin3A PAH2 domain interacts with the Pf1 SID1 motif in a manner similar to Mad1/Mxd1; MRG15 competes with mSin3A for binding to Pf1, implying mutual exclusivity of two subunits within the Rpd3S/Sin3S complex for Pf1. NMR solution structure, pulldown assay, competitive binding assay Journal of molecular biology High 21440557
2012 MRG15 chromodomain binds H3K36me2/3 with >100 µM affinity and Pf1 PHD1 binds unmodified H3K4 with similarly low affinity; both domains are required together for bivalent (non-cooperative) targeting of the Rpd3S/Sin3S complex to chromatin; Pf1 PHD1 also engages the MRG15 MRG domain. In vitro peptide binding assay, isothermal titration calorimetry, pulldown, domain deletion analysis Journal of molecular biology High 22728643
2014 HDAC2 deacetylates MORF4L1 at Lys-148, and this deacetylation is required for MORF4L1 homodimerization; acetylation mimics (K148L, K148Q) abolish self-assembly, while Lys-to-Arg substitution (mimicking deacetylation) promotes it; HDAC2 knockdown reduces MORF4L1 homodimerization. Co-immunoprecipitation, site-directed mutagenesis (K148R, K148L, K148Q), HDAC2 knockdown The Journal of biological chemistry High 24451372
2017 MRG15 (Mrg15 in Drosophila) is a subunit of the Ash1 histone methyltransferase complex that stimulates Ash1 H3K36 methyltransferase activity in vitro; Mrg15 is recruited by Ash1 to common genomic targets and reinforces Ash1 chromatin association; an Ash1 point mutation (R1288A) that reduces Mrg15 interaction causes homeotic transformations partially rescued by Mrg15-Nurf55 fusion. In vitro methyltransferase assay, ChIP, genetic knock-in, co-immunoprecipitation, rescue experiment Nature communications High 29158494
2017 PALB2 associates with active genes through MRG15, which recognizes H3K36me3 deposited by SETD2; PALB2-MRG15 binding-defective missense mutations increase sensitivity to camptothecin and elevate DNA stress in gene bodies during replication, establishing a SETD2/H3K36me3/MRG15/PALB2 axis that protects active genes. ChIP-seq, missense mutation analysis, camptothecin sensitivity assay, metaphase chromosome analysis, DNA combing Proceedings of the National Academy of Sciences High 28673974
2016 MRG15 is required for pre-mRNA splicing during spermatogenesis; it binds H3K36me3 in introns of transcriptionally active genes and colocalizes with splicing factors PTBP1 and PTBP2 at H3K36me3 sites in round spermatids; conditional KO causes intron retention in transition protein mRNAs and spermatogenic arrest. Conditional KO mouse, RNA-seq, ChIP, co-immunofluorescence of splicing factors Proceedings of the National Academy of Sciences High 27573846
2019 Crystal structure of human ASH1L tandem MID-SET domains in complex with MRG15 MRG domain reveals that MRG15 binds a conserved FxLP motif N-terminal to the ASH1L SET domain and displaces the autoinhibitory post-SET loop to open the substrate binding pocket, activating H3K36 methyltransferase activity. X-ray crystallography, in vitro methyltransferase assay, mutagenesis Structure High 30827841 30827843
2019 Crystal structure of Ash1L MID-SET domains bound to MRG15 MRG domain shows that MRG15 binding induces subtle structural changes in the SAM-binding pocket of ASH1L via a conserved interaction segment, implicating conformational coupling between SAM and substrate binding sites as the activation mechanism. X-ray crystallography, in vitro methyltransferase assay Structure High 30827843
2020 MRG15 genomic recruitment shows significant diurnal rhythm in mouse liver and activates lipid synthesis genes; MRG15 interacts with nuclear receptor LRH-1 (not core clock proteins) and is recruited to lipid gene loci via LRH-1; MRG15 depletion impairs rhythmic Pol II recruitment and histone acetylation at lipid genes. ChIP-seq, Co-immunoprecipitation, CRISPR targeting, RNA-seq, luciferase reporter Nature metabolism High 32694659
2021 Crystal structure of the MRG15 MRG domain bound to PALB2 peptide shows PALB2 interacts with an extended surface of MRG15 with nanomolar affinity; this binding region overlaps with sites for other MRG15 partners, indicating mutually exclusive binding; breast cancer-derived PALB2 mutations cause only minor affinity reduction. X-ray crystallography, surface plasmon resonance/binding affinity measurement, PALB2 variant analysis Genes High 34946951
2022 MRG15 associates with the outer mitochondrial membrane and interacts with and deacetylates TUFM at K82 and K91; deacetylated TUFM is targeted for degradation by the mitochondrial ClpXP protease, resulting in impaired mitophagy, increased oxidative stress, and NLRP3 inflammasome activation in NASH; inflammatory cytokines increase MRG15 acetylation to stabilize MRG15 in this context. Immunoprecipitation-mass spectrometry, co-immunoprecipitation, CRISPR targeting, mitochondrial fractionation, mitophagy assay, NLRP3 activation assay Journal of hepatology High 35985547
2023 MRG15, once activating ASH1L, recruits the ASH1L-MRG15 complex to nucleosome substrates via the MRG15 chromodomain; full-length MRG15 but not the MRG domain alone enhances ASH1L SET domain activity; MRG15 does not alter the conformation of the ASH1L autoinhibitory loop or SAM binding site in solution, suggesting MRG15 functions as a nucleosome-recruiting adapter rather than purely an allosteric activator. In vitro methyltransferase assay with nucleosomes, NMR, pulldown, chromodomain binding assay Structure High 37527654
2023 Upon UV irradiation, the ASH1L-MRG15 complex adds H3K4me3 genome-wide (except active promoters) to prime chromatin for XPC relocalization from native to damaged DNA; ASH1L-MRG15 also recruits the histone chaperone FACT to DNA lesions; loss of MRG15 causes XPC misplacement and failure to deliver lesions to TFIIH. ChIP-seq, siRNA knockdown, co-immunoprecipitation, UV-irradiation, in vitro NER assay, immunofluorescence Nature communications High 37393406
2013 Drosophila Mrg15 physically interacts with the condensin Cap-H2 subunit (yeast two-hybrid); Mrg15 is required for Cap-H2-mediated chromosome unpairing in polytene chromosomes and in diploid cells, and 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 analysis, transvection assay, RNAi knockdown, chromatin fractionation Genetics Medium 23821596
2011 Loss of MRG15 in neural stem/progenitor cells leads to up-regulation of p21 CDK inhibitor via p53 accumulation; p21 shRNA rescues the proliferation defect; DNA damage foci (γH2AX, 53BP1) are detectable in Mrg15-null NSCs under normal conditions, and Mrg15-null NSCs are defective in DNA damage response after ionizing radiation. Neurosphere assay, p21 shRNA rescue, immunostaining for γH2AX/53BP1, BrdU incorporation, p53 shRNA knockdown Stem cell research Medium 21621175
2025 MORF4L1 is identified as an endogenous substrate of the CRBN E3 ubiquitin ligase; CRBN promotes MORF4L1 ubiquitination and degradation under physiological conditions, further enhanced by the modulator CC-885. Proteomic analysis, co-immunoprecipitation, structural modeling, functional degradation assay Scientific reports Medium 39827217
2021 MORF4L1 is ubiquitylated at K187 and K104 under basal conditions, and these sites show decreased ubiquitylation upon proteasome inhibition while MORF4L1 protein abundance increases ~2-fold, demonstrating that MORF4L1 protein levels are regulated by the ubiquitin-proteasome system. Large-scale ubiquitylome mass spectrometry, proteasome inhibitor treatment (MG132, bortezomib, carfilzomib), quantitative proteomics Journal of proteomics Medium 33848640
2025 USP53 deubiquitinase binds MORF4L1 and prevents its ubiquitination and proteasomal degradation at K249 and K227 residues; gain-of-function of USP53 stabilizes MORF4L1 and suppresses colorectal cancer cell proliferation. IP-LC/MS, ubiquitylome analysis, Co-immunoprecipitation, site-directed mutagenesis (K249, K227), gain/loss-of-function assays Biochimica et biophysica acta. Molecular basis of disease Medium 41061828
2025 MRG15 long isoform (MRG15L, accumulating with age) exhibits reduced affinity for histone H4 acetylation sites and weakens CDK1 regulation, causing G2/M phase arrest and cellular senescence; MuSC-specific knockout of MRG15L in mice enhances cardiac repair after ischemia-reperfusion injury. Histone peptide binding assay, protein interaction analysis, cell cycle analysis (FACS), conditional KO mouse, cardiac injury model Communications biology Medium 40483328
2025 MRG15 forms an activator complex with TIP60, p300, and RNA Pol II at the Ccnd1 (cyclin D1) enhancer region to facilitate histone acetylation and cardiomyocyte proliferation in the neonatal heart; MRG15 knockout in cardiac progenitors impairs neonatal heart regeneration; regulatory T cells induce MRG15 expression to promote cardiomyocyte proliferation via paracrine signaling. Conditional KO mouse (Isl1-Cre, Myh6-MerCreMer), ChIP-seq, RNA-seq, Co-immunoprecipitation, AAV9-mediated overexpression, Treg depletion/adoptive transfer Circulation High 41251000
2026 MRG15 cooperates with MyoD to remodel chromatin at myogenic gene loci; MuSC-specific inducible KO shows that MRG15 is required for myogenic differentiation and muscle regeneration, with ChIP-seq revealing MRG15 modulates histone modifications at MyoD target genes. Inducible KO mouse model, RNA-seq, ChIP-seq, co-immunoprecipitation (MRG15-MyoD interaction) Cell regeneration Medium 41580578
2025 MRG15 promotes PCSK9 synthesis and secretion in hepatocytes, which induces macrophage M1 polarization; MRG15 knockdown in hepatocytes reduces PCSK9 secretion and attenuates macrophage activation and inflammatory response in sepsis-induced liver injury. Co-culture of hepatocytes and macrophages, MRG15 knockdown, PCSK9 ELISA, macrophage polarization assay, in vivo sepsis models (CLP, LPS) International immunopharmacology Medium 39128417
2025 MRG15 can form phase-separated liquid condensates via its intrinsically disordered region (IDR); IDR deletion abolishes condensate formation and promotes cellular senescence in human mesenchymal stem cells; MRG15 depletion diminishes chromatin binding at cell cycle and senescence genes including p53, CDKN1A, LMNB1, and CCNB1. Phase separation assay, IDR deletion/replacement, ChIP-seq, RNA-seq, senescence assays Communications biology Medium 40312521
2025 MORF4L1 acetylates PALB2 at lysine 628, inhibiting PALB2 ubiquitination and subsequent degradation; MORF4L1 also enhances histone H3 acetylation at K4 to facilitate DNA damage repair factor recruitment. Immunoprecipitation-mass spectrometry, Co-immunoprecipitation, acetylation site mutagenesis, ubiquitination assay Cellular & molecular immunology Medium 41188483

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 427 16364921
2006 Structure of human MRG15 chromo domain and its binding to Lys36-methylated histone H3. Nucleic acids research 123 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 83 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 81 17573780
2008 Structural basis for the recognition of methylated histone H3K36 by the Eaf3 subunit of histone deacetylase complex Rpd3S. Structure (London, England : 1993) 73 18818090
2002 MRG15, a novel chromodomain protein, is present in two distinct multiprotein complexes involved in transcriptional activation. The Journal of biological chemistry 73 12397079
2010 MRG15 binds directly to PALB2 and stimulates homology-directed repair of chromosomal breaks. Journal of cell science 67 20332121
2005 MRG15 regulates embryonic development and cell proliferation. Molecular and cellular biology 67 15798182
2016 MRG15 is required for pre-mRNA splicing and spermatogenesis. Proceedings of the National Academy of Sciences of the United States of America 66 27573846
2004 Eaf3 regulates the global pattern of histone acetylation in Saccharomyces cerevisiae. Molecular and cellular biology 63 14701747
2009 MRG15 is a novel PALB2-interacting factor involved in homologous recombination. The Journal of biological chemistry 57 19553677
2017 Mrg15 stimulates Ash1 H3K36 methyltransferase activity and facilitates Ash1 Trithorax group protein function in Drosophila. Nature communications 46 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 43 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
2019 H3K36 Methylation and the Chromodomain Protein Eaf3 Are Required for Proper Cotranscriptional Spliceosome Assembly. Cell reports 37 31242410
2022 MRG15 aggravates non-alcoholic steatohepatitis progression by regulating the mitochondrial proteolytic degradation of TUFM. Journal of hepatology 35 35985547
2019 Structural Insights into Stimulation of Ash1L's H3K36 Methyltransferase Activity through Mrg15 Binding. Structure (London, England : 1993) 31 30827843
2007 Mrg15 null and heterozygous mouse embryonic fibroblasts exhibit DNA-repair defects post exposure to gamma ionizing radiation. FEBS letters 31 17961556
2020 MRG15 orchestrates rhythmic epigenomic remodelling and controls hepatic lipid metabolism. Nature metabolism 30 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 25 21621175
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
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 23 17008723
2019 Structural Basis of MRG15-Mediated Activation of the ASH1L Histone Methyltransferase by Releasing an Autoinhibitory Loop. Structure (London, England : 1993) 22 30827841
2011 Exploring the link between MORF4L1 and risk of breast cancer. Breast cancer research : BCR 20 21466675
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
2011 MRG15 activates the cdc2 promoter via histone acetylation in human cells. Experimental cell research 16 21324423
2014 Histone deacetylase 2 (HDAC2) protein-dependent deacetylation of mortality factor 4-like 1 (MORF4L1) protein enhances its homodimerization. The Journal of biological chemistry 14 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
2010 A nuclear ligand MRG15 involved in the proapoptotic activity of medicinal fungal galectin AAL (Agrocybe aegerita lectin). Biochimica et biophysica acta 13 20122994
2023 ASH1L-MRG15 methyltransferase deposits H3K4me3 and FACT for damage verification in nucleotide excision repair. Nature communications 12 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 12 33848640
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
2021 Structural Insight into the Mechanism of PALB2 Interaction with MRG15. Genes 7 34946951
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
2024 MRG15 promotes cell apoptosis through inhibition of mitophagy in hyperlipidemic acute pancreatitis. Apoptosis : an international journal on programmed cell death 6 39487311
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
2024 Structural and functional insights into the epigenetic regulator MRG15. Acta pharmacologica Sinica 5 38191914
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 Identification of MORF4L1 as an endogenous substrate of CRBN and its potential role as a therapeutic target in cancer. Scientific reports 4 39827217
2023 MRG15 activates histone methyltransferase activity of ASH1L by recruiting it to the nucleosomes. Structure (London, England : 1993) 4 37527654
2025 MRG15 alternative splicing regulates CDK1 transcriptional activity in mouse cell senescence and myocardial regeneration. Communications biology 3 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 3 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 2 39757177
2025 Targeting MORF4L1-mediated DNA repair potentiates RT-induced antitumor immunity via cGAS-STING activation in hepatocellular carcinoma. Cellular & molecular immunology 2 41188483
2024 Emerging roles of MRG15 in liver metabolic diseases. Trends in molecular medicine 2 38521716
2025 CD4+ Tregs Regulate Heart Growth and Regeneration Through MRG15/TIP60-Mediated Epigenomic Remodeling in Proliferating Cardiomyocytes. Circulation 1 41251000
2022 Targeting MRG15 for the treatment of nonalcoholic steatohepatitis. Metabolism open 1 36478775
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 Phase separation of MRG15 delays cellular senescence. Communications biology 0 40312521
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