{"gene":"YTHDC1","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":2014,"finding":"Crystal structure of the YTHDC1 YTH domain in complex with m6A-containing RNA revealed the specific mode of m6A binding; YTHDC1 preferentially recognizes GG(m6A)C sequences through an aromatic cage, with a distinctly selective binding pocket for the nucleotide preceding m6A that is absent in other YTH family members.","method":"X-ray crystallography, biochemical binding assays, transcriptome-wide PAR-CLIP-seq","journal":"Nature chemical biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with functional validation, replicated and extended by multiple structural studies","pmids":["25242552"],"is_preprint":false},{"year":2015,"finding":"Structural comparison of YTH domain proteins revealed that only YTHDC1 harbors a distinctly selective binding pocket for the nucleotide preceding the m6A modification; all YTH domains use a conserved aromatic cage to recognize m6A, but YTHDC1's selectivity for 5'-GGm6AC is unique.","method":"X-ray crystallography of YTHDF1 and yeast Pho92 YTH domains in complex with m6A RNA, isothermal titration calorimetry binding assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structures plus binding assays, independently confirms YTHDC1 selectivity","pmids":["26318451"],"is_preprint":false},{"year":1999,"finding":"YTHDC1 (YT521-B) interacts with Sam68 and scaffold attachment factor B in nuclear dots; the C-terminal glutamic acid/arginine-rich region mediates protein-protein interactions; Src family kinase p59(fyn)-mediated tyrosine phosphorylation of Sam68 negatively regulates its association with YT521-B and dissolves nuclear dots; overexpression of YT521-B modulates alternative splice site selection in a concentration-dependent manner in vivo.","method":"Co-immunoprecipitation, yeast two-hybrid, in vivo splicing assays, immunofluorescence, kinase overexpression","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal protein interactions, functional splicing assay, signaling pathway placement, multiple orthogonal methods","pmids":["10564280"],"is_preprint":false},{"year":2000,"finding":"YTHDC1 (YT521-B) localizes to a novel subnuclear structure (YT bodies) that first appears at the beginning of S-phase and disperses during mitosis; YT bodies contain transcriptionally active sites and are in close contact with speckles and coiled bodies; actinomycin D disperses YT bodies; the N-terminal glutamic acid-rich domain and C-terminal glutamic acid/arginine-rich region are required for YT body formation.","method":"Fluorescence microscopy, cell cycle synchronization, deletion analysis, transcriptional inhibitor treatment","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct localization experiment with functional consequence, multiple orthogonal approaches, deletion mapping","pmids":["10973987"],"is_preprint":false},{"year":2003,"finding":"YTHDC1 (YT521-B) interacts directly with emerin (a nuclear membrane protein) via a bipartite binding site in emerin; this interaction inhibits YT521-B-dependent splice site selection in vivo, suggesting emerin regulates splicing through YTHDC1.","method":"Yeast two-hybrid, pull-down assay, BIAcore biomolecular interaction analysis, in vivo splicing assay, alanine substitution mutagenesis","journal":"European journal of biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro binding confirmed by multiple methods, functional splicing consequence shown, single lab","pmids":["12755701"],"is_preprint":false},{"year":2004,"finding":"YTHDC1 (YT521-B) is tyrosine-phosphorylated by c-Abl in the nucleus and by c-Src or p59(fyn) in the cytoplasm; tyrosine phosphorylation disperses YT521-B from YT bodies to an insoluble nucleoplasmic form; phosphorylation by c-Abl abolishes the concentration-dependent effect of YT521-B on alternative splice site selection of IL-4 receptor, CD44, and SRp20.","method":"Kinase assay, phosphorylation site mapping, subcellular fractionation, in vivo splicing assay, immunofluorescence","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct kinase assay identifies writer, multiple substrates tested, functional splicing consequence, localization link","pmids":["15175272"],"is_preprint":false},{"year":1998,"finding":"YTHDC1 (YT521) was identified as an RA301-binding protein via yeast two-hybrid; Far Western blot showed YT521 protein interacts with splicing factors SC35 and SF2, suggesting a role in RNA splicing.","method":"Yeast two-hybrid, Far Western blot","journal":"Brain research. Molecular brain research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, initial identification by yeast two-hybrid and Far Western only","pmids":["9473574"],"is_preprint":false},{"year":2016,"finding":"Nuclear m6A reader YTHDC1 promotes exon inclusion by recruiting splicing factor SRSF3 while blocking SRSF10 binding to target mRNAs; YTHDC1 facilitates SRSF3 and represses SRSF10 in nuclear speckle localization and RNA-binding affinity; these effects require m6A-binding ability of YTHDC1 as shown by reconstitution with wild-type but not m6A-binding-defective YTHDC1.","method":"PAR-CLIP-seq, in vitro pull-down assay showing competitive SRSF3/SRSF10 binding, RNA-seq transcriptome analysis, knockdown/reconstitution with wild-type vs. m6A-binding-defective YTHDC1","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods, m6A-binding mutant rescue, transcriptome-wide and biochemical validation, broadly replicated","pmids":["26876937"],"is_preprint":false},{"year":2017,"finding":"YTHDC1 mediates nuclear export of m6A-methylated mRNAs in HeLa cells; knockdown of YTHDC1 causes nuclear accumulation and cytoplasmic depletion of m6A-containing transcripts; YTHDC1 interacts with SRSF3 and NXF1 and facilitates RNA binding to both.","method":"YTHDC1 knockdown with nuclear/cytoplasmic fractionation, m6A-seq, co-immunoprecipitation with SRSF3 and NXF1, RNA binding assays","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal interactions, fractionation with functional consequence, multiple orthogonal methods, independently replicated concept","pmids":["28984244"],"is_preprint":false},{"year":2017,"finding":"YTHDC1 reads m6A marks deposited by METTL16 in the 3' UTR of MAT2A mRNA; in response to SAM depletion, YTHDC1 and METTL16 together mediate SAM-responsive regulation of MAT2A mRNA stability; knockdown of YTHDC1 abolishes this regulation.","method":"In vitro methylation assay with recombinant METTL16, YTHDC1 knockdown, mutagenesis of METTL16 target adenines in 3' UTR, mRNA stability assay","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro reconstitution with recombinant METTL16, multiple mutagenesis experiments, functional mRNA stability assay","pmids":["29262316"],"is_preprint":false},{"year":2018,"finding":"YTHDC1 is essential for spermatogonial development and oocyte growth/maturation in mice; loss of YTHDC1 causes extensive alternative polyadenylation (altering 3' UTR length) and massive alternative splicing defects in oocytes; YTHDC1 associates with 3' end processing factors CPSF6, SRSF3, and SRSF7; splicing defects are rescued by wild-type but not m6A-binding-deficient YTHDC1.","method":"Conditional knockout mouse model, RNA-seq, m6A sequencing, co-immunoprecipitation with CPSF6/SRSF3/SRSF7, rescue with wild-type vs. m6A-binding-deficient YTHDC1","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo knockout with multiple cellular phenotypes, m6A-binding mutant rescue, co-IP partners identified","pmids":["29799838"],"is_preprint":false},{"year":2019,"finding":"Atomistic simulations, X-ray crystallography, and isothermal titration calorimetry showed that m6A is captured by an aromatic cage of YTHDC1; 3' terminus nucleotides are stabilized by cation-π-π interactions; the 5' terminus remains flexible; the methyl group of m6A shifts conformational preferences of the oligoribonucleotide to a bound-like conformation facilitating association.","method":"Atomistic molecular dynamics simulations, X-ray crystallography, isothermal titration calorimetry","journal":"Journal of chemical theory and computation","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure combined with ITC and MD simulations, single lab but multiple orthogonal methods","pmids":["31670957"],"is_preprint":false},{"year":2019,"finding":"Metadherin interacts with YTHDC1, Sam68, and T-STAR in nuclear speckles and influences splice site selection in a dose-dependent manner in CD44v5-luc minigene reporter assays.","method":"Yeast two-hybrid, co-immunoprecipitation, minigene splicing reporter assay","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — yeast two-hybrid plus IP plus functional splicing assay, single lab","pmids":["31450747"],"is_preprint":false},{"year":2020,"finding":"The YTH domain of YTHDC1 binds N6-methyladenine in single-stranded DNA with ~10 nM Kd, stronger than its affinity for N6-methyladenosine RNA; crystal structures of YTHDC1 YTH domain bound to N6mA-containing ssDNA show methylated adenine binding in a single-stranded region flanked by duplexed DNA.","method":"X-ray crystallography (two structures), fluorescence polarization/ITC binding assays","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — two crystal structures with quantitative binding measurements, single lab but rigorous structural validation","pmids":["32663306"],"is_preprint":false},{"year":2021,"finding":"YTHDC1 is required for maintenance of mouse ES cell identity in an m6A-dependent manner; depletion initiates reprogramming to a 2C-like state; YTHDC1 binds transcripts of retrotransposons (IAPs, ERVK, LINE1) and its depletion causes reactivation of silenced retrotransposons accompanied by global decrease in SETDB1-mediated H3K9me3; YTHDC1 and its target m6A RNAs act upstream of SETDB1 to repress retrotransposons and Dux.","method":"Conditional knockout in mouse ESCs, RNA-seq, ChIP-seq (H3K9me3), RIP-seq, epistasis analysis with SETDB1","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO with defined molecular phenotype, epistasis to SETDB1, multiple orthogonal sequencing approaches","pmids":["33658714"],"is_preprint":false},{"year":2021,"finding":"YTHDC1 recognizes m6A on LINE1 RNAs in the nucleus and regulates formation of the LINE1-nucleolin (NCL) partnership and chromatin recruitment of KAP1; Ythdc1 depletion interrupts H3K9me3 establishment on 2C-related retrotransposons in ESCs and inner cell mass cells, increasing transcriptional activity of the 2C program.","method":"Conditional knockout in ESCs, LACE-seq, ChIP-seq, RIP, Co-IP (YTHDC1-NCL, YTHDC1-KAP1)","journal":"Protein & cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO with chromatin phenotype, protein complex identification by Co-IP, epistasis, multiple sequencing modalities","pmids":["33886094"],"is_preprint":false},{"year":2021,"finding":"YTHDC1 regulates leukemogenesis through MCM4, a critical regulator of DNA replication; YTHDC1 is required for proliferation and survival of AML cells and self-renewal of leukemia stem cells in vivo; Ythdc1 haploinsufficiency reduces LSC but not HSC self-renewal.","method":"Genetic deletion of Ythdc1 in mouse AML models, YTHDC1 knockdown in primary AML cells, RNA-seq, m6A-MeRIP-seq identifying MCM4 as target","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic deletion, identification of downstream target MCM4, multiple AML models","pmids":["34255814"],"is_preprint":false},{"year":2021,"finding":"YTHDC1 binds SQSTM1 mRNA in the nucleus and cooperates with ELAVL1/HuR to modulate its stability; knockdown of YTHDC1 drives SQSTM1 mRNA degradation in the nucleus, causing blockade of autophagic flux in keratinocytes.","method":"RIP assay (YTHDC1 binding to SQSTM1 mRNA), co-immunoprecipitation (YTHDC1-ELAVL1), YTHDC1 knockdown/overexpression, autophagic flux assays","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — RIP, Co-IP, functional autophagic flux readout, single lab","pmids":["34657574"],"is_preprint":false},{"year":2021,"finding":"YTHDC1 facilitated the biogenesis of mature miR-30d via m6A-mediated regulation of mRNA stability in pancreatic cancer cells.","method":"RIP, MeRIP, RNA stability assay, YTHDC1 knockdown","journal":"Cell death and differentiation","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single RIP/stability approach without mechanistic dissection","pmids":["34021267"],"is_preprint":false},{"year":2021,"finding":"YTHDC1 regulates splicing of Titin mRNA via m6A modification; cardiac-specific Ythdc1 knockout leads to aberrant Titin splicing, disordered sarcomere arrangement, and dilated cardiomyopathy in mice.","method":"Cardiac-specific conditional Ythdc1 knockout, m6A-MeRIP-seq, RIP-seq, mRNA-seq, integrated target identification","journal":"Journal of cellular and molecular medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo KO with defined molecular target (Titin splicing), multiple sequencing modalities","pmids":["34716659"],"is_preprint":false},{"year":2021,"finding":"In HIV-1 producer cells, YTHDC1 binds HIV-1 transcripts in a METTL3-dependent manner and controls unspliced/incompletely spliced HIV-1 RNA levels; YTHDC1 knockdown reduces Env and Vpu expression and leads to incorporation of unprocessed Env gp160 into viral particles, decreasing infectivity.","method":"YTHDC1 knockdown, RIP assay, RT-qPCR for HIV-1 RNA species, Western blot for viral proteins","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP confirms binding, functional splicing and protein expression consequences shown, single lab","pmids":["33883220"],"is_preprint":false},{"year":2021,"finding":"Site-directed mutagenesis and atomistic simulations identified four residues (Trp428, Met438, Ser378, Thr379) regulating m6A binding; Trp428 switches between two states to build/dismantle the aromatic cage; a structural water molecule synergistically binds YTHDC1 with m6A as a hydrogen-bond hub; Thr379Val significantly impairs binding and thermal stability.","method":"Site-directed mutagenesis, isothermal titration calorimetry, molecular dynamics simulations, free energy calculations","journal":"Journal of chemical theory and computation","confidence":"High","confidence_rationale":"Tier 1 / Moderate — mutagenesis combined with ITC and MD simulations, mechanistic detail of aromatic cage dynamics","pmids":["33472367"],"is_preprint":false},{"year":2021,"finding":"NMR and MD simulations showed that structured water molecules surrounding the bound RNA and the methylated substrate's ability to exclude bulk water contribute to YTHDC1's preference for m6A; the D479A mutant disrupts a water network and destabilizes m6A binding; YTHDC1's 5'-Gm6A-3' motif preference is partially facilitated by water-mediated interactions with the guanosine 2-amino group.","method":"Molecular dynamics simulations, NMR spectroscopy, isothermal titration calorimetry, site-directed mutagenesis (D479A)","journal":"The journal of physical chemistry. B","confidence":"High","confidence_rationale":"Tier 1 / Moderate — NMR, ITC, MD simulations with mutagenesis, multiple orthogonal methods in single study","pmids":["34258996"],"is_preprint":false},{"year":2022,"finding":"NMR solution structure of the (m6A)UCG hairpin and crystal structure of YTHDC1 bound to it revealed that YTHDC1 recognizes the (m6A)UC nucleotides in a single-stranded conformation by inserting m6A into the aromatic cage; recognition requires local unfolding of the upper stem region of the hairpin, shown by NMR and fluorescence quenching.","method":"NMR spectroscopy (solution structure), X-ray crystallography, fluorescence quenching binding assay","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure combined with NMR structure and binding assay, mechanistic model of hairpin unfolding validated","pmids":["35166835"],"is_preprint":false},{"year":2022,"finding":"Nuclear AURKA disrupts the binding of SRSF3 to YTHDC1 and recruits hnRNP K to YTHDC1 in a kinase-independent manner, switching from m6A-YTHDC1-SRSF3-mediated exon inclusion of RBM4-FL to m6A-YTHDC1-hnRNPK-dependent exon skipping to produce the short RBM4-S isoform that promotes lung cancer progression.","method":"Co-immunoprecipitation, RIP, RNA-seq, AURKA nuclear translocation experiments, minigene splicing assay","journal":"Signal transduction and targeted therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP for complex switching, functional splicing outcome, single lab","pmids":["35361747"],"is_preprint":false},{"year":2022,"finding":"YTHDC1 suppresses proximal alternative polyadenylation (APA) sites by binding upstream m6A sites; YTHDC1 directly interacts with 3' end processing factor FIP1L1 and interferes with FIP1L1's ability to recruit CPSF4; m6A binding promotes liquid-liquid phase separation of YTHDC1 and FIP1L1.","method":"m6A-seq, APA analysis, co-immunoprecipitation (YTHDC1-FIP1L1), FRAP/phase separation assay, YTHDC1 knockdown","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct protein interaction, functional APA consequence, phase separation characterization, multiple orthogonal methods","pmids":["36094741"],"is_preprint":false},{"year":2022,"finding":"YTHDC1 promotes nuclear export of SMAD3 mRNA in an m6A-dependent manner; YTHDC1 depletion causes nuclear retention of SMAD3 mRNA and reduced SMAD3 protein, impairing TGF-β-induced EMT and TNBC cell migration/invasion; m6A-binding defective YTHDC1 mutant cannot rescue the phenotype.","method":"RNA-seq, m6A-seq, RIP-seq, nuclear/cytoplasmic fractionation of SMAD3 mRNA, YTHDC1 KO with SMAD3 overexpression rescue, m6A-binding mutant","journal":"Theranostics","confidence":"High","confidence_rationale":"Tier 2 / Strong — fractionation with functional rescue, m6A-binding mutant validation, multiple sequencing modalities","pmids":["35966596"],"is_preprint":false},{"year":2023,"finding":"YTHDC1 is an essential regulator of skeletal muscle satellite cell (SC) activation and proliferation; transcriptome-wide LACE-seq identified m6A-mediated binding targets; YTHDC1 regulates splicing and nuclear export of target mRNAs; hnRNPG was identified as a bona fide interacting partner of YTHDC1 in myoblasts.","method":"Inducible YTHDC1 depletion in satellite cells, LACE-seq, splicing analysis, nuclear export analysis, interactome mapping, co-IP (hnRNPG)","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo KO with regeneration phenotype, transcriptome-wide binding and splicing analysis, interaction partner co-IP","pmids":["36892464"],"is_preprint":false},{"year":2023,"finding":"The m6A reader YTHDC1 interacts with DDX5 RNA helicase; YTHDC1 and DDX5 together promote production of a common subset of circRNAs via back-splicing in rhabdomyosarcoma, and their depletion reduces RMS cell proliferation.","method":"Co-immunoprecipitation (YTHDC1-DDX5), circRNA-seq, YTHDC1/DDX5 knockdown, proliferation assays","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP interaction identified, functional circRNA and proliferation consequence, single lab","pmids":["37019933"],"is_preprint":false},{"year":2023,"finding":"YTHDC1 promotes muscle stem cell proliferation via PI4K-Akt-mTOR signalling; Ythdc1 binds m6A-modified Pi4k2a and Pi4kb mRNAs and regulates their alternative splicing, thus controlling PI4K-Akt-mTOR signalling; Ythdc1-null muscle stem cells show deficiency in PIP3, phospho-Akt, and phospho-S6.","method":"Inducible Ythdc1 knockout in muscle stem cells, RIP (Pi4k2a, Pi4kb binding), splicing analysis, phospho-signaling Western blot","journal":"Cell proliferation","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo KO, direct mRNA targets identified by RIP, pathway placement via signaling measurements","pmids":["36722312"],"is_preprint":false},{"year":2023,"finding":"YTHDC1 binding to m6A sites in the FSP1 3'-UTR recruits alternative polyadenylation regulator CSTF3 to generate a less stable shorter 3'-UTR FSP1 mRNA; YTHDC1 downregulation generates longer 3'-UTR FSP1 mRNA stabilized by HuR, increasing FSP1 protein and ferroptosis resistance in lung cancer.","method":"RIP (YTHDC1-FSP1 mRNA), Co-IP (YTHDC1-CSTF3, FSP1-HuR), APA analysis, RNA stability assay, YTHDC1 knockdown","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple Co-IP interactions, functional APA and mRNA stability consequences, single lab","pmids":["37903990"],"is_preprint":false},{"year":2023,"finding":"YTHDC1 promotes IAV replication by binding to influenza A virus NS segment m6A sites at the NS 3' splicing site and inhibiting NS mRNA splicing, thereby promoting viral replication and pathogenicity in vitro and in vivo.","method":"YTHDC1 knockdown/overexpression, m6A mapping on NS RNA, RIP assay, splicing assay, in vivo infection model","journal":"PLoS pathogens","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP confirms binding at 3' splice site, functional splicing consequence, in vivo validation, single lab","pmids":["37053288"],"is_preprint":false},{"year":2023,"finding":"YTHDC1 delays stress-induced pulmonary senescence and fibrosis in an m6A-independent manner by promoting interaction between TopBP1 and MRE11, thereby activating ATR and facilitating DNA damage repair; m6A-binding-defective YTHDC1 retains this function.","method":"Ythdc1 conditional KO mice, YTHDC1 overexpression with m6A-binding mutant, co-immunoprecipitation (TopBP1-MRE11 interaction), ATR activation assay","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo KO, m6A-binding mutant distinguishes mechanism, direct protein complex identified by Co-IP","pmids":["38177310"],"is_preprint":false},{"year":2023,"finding":"YTHDC1 positively regulates PTEN expression by stabilizing PTEN mRNA in an m6A-dependent manner; YTHDC1 knockdown destabilizes PTEN mRNA and activates PI3K/AKT signaling, promoting cisplatin resistance in bladder cancer.","method":"RIP assay (YTHDC1-PTEN mRNA), RNA stability assay, YTHDC1 knockdown/overexpression, qPCR, Western blot","journal":"Cell proliferation","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — RIP confirms binding, stability assay, functional signaling consequence, single lab","pmids":["37070134"],"is_preprint":false},{"year":2024,"finding":"YTHDC1 cooperates with the THO complex (THOC) to prevent RNA-damage-induced DNA breaks (RDIBs); YTHDC1 binds to chemically induced N1-methyladenosine (m1A) in addition to m6A; without YTHDC1, alkylation-damaged RNA forms R-loops that are converted to DNA breaks by XPG nuclease; a nuclear RNA m1A methyltransferase is sufficient to induce DNA breaks in the absence of YTHDC1 or THOC.","method":"CRISPR-KO of YTHDC1 and THOC, comet assay, DNA break quantification, RNA dealkylase rescue experiment, R-loop detection, XPG nuclease epistasis","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple KO epistasis experiments, RNA-specific dealkylase rescue, XPG nuclease pathway placement, multiple orthogonal methods","pmids":["40037355"],"is_preprint":false},{"year":2024,"finding":"YTHDC1 m6A-binding activity promotes transcriptional elongation at the TP53 locus and other DNA damage response genes, and prevents intron retention in key DDR factors; TP53 transcriptional pause-release by YTHDC1 is independent of m6A; YTHDC1 deficiency causes genomic instability and aberrant cancer cell proliferation.","method":"CRISPR-KO screen identifying YTHDC1 in p53 response, m6A binding mutant analysis, intron retention analysis, ChIP (YTHDC1 at transcription start sites), RNA-seq","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — CRISPR screen plus orthogonal mechanistic validation, m6A-independent function distinguished by mutant analysis, transcription-level mechanism shown by ChIP","pmids":["38951610"],"is_preprint":false},{"year":2024,"finding":"DDX41 promotes the recruitment of YTHDC1 to R-loops by promoting binding between METTL3 and YTHDC1; DDX41 KO/KI cells show impaired METTL3-YTHDC1 interaction and increased m6A-methylated R-loops, leading to genomic instability.","method":"DDX41 KO and knock-in cell lines, Co-IP (DDX41-METTL3, METTL3-YTHDC1), m6A quantification, R-loop detection, primary patient samples","journal":"Leukemia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP in multiple cell lines, patient samples, single lab","pmids":["38514771"],"is_preprint":false},{"year":2024,"finding":"YTHDC1 is O-GlcNAcylated at Ser396 upon DNA damage, which is required for YTHDC1 chromatin binding, IRIF formation, and m6A RNA binding at DNA damage sites; O-GlcNAcylation promotes YTHDC1 condensate formation and HR-mediated DNA repair and Rad51 recruitment.","method":"Site-directed mutagenesis (Ser396), RIP showing O-GlcNAc-dependent m6A binding, FRAP analysis of condensate formation, Rad51 foci quantification, HR assay","journal":"Fundamental research","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — mutagenesis of modification site, RIP, FRAP, HR functional assay, MD simulations, multiple methods in one study","pmids":["40242544"],"is_preprint":false},{"year":2024,"finding":"YTHDC1 binds to and stabilizes m6A-modified KMT2C mRNA; KMT2C catalyzes H3K4 methylation required for DDR gene expression; YTHDC1 knockdown increases DNA damage in B-ALL cells; EPZ-5676 was identified as a YTHDC1 inhibitor by molecular docking and biochemical experiments.","method":"RIP (YTHDC1-KMT2C mRNA), ChIP-seq (H3K4me1/me3), RNA stability assay, molecular docking, biochemical YTHDC1 inhibitor assay, B-ALL xenograft","journal":"Leukemia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP confirms binding, ChIP shows downstream histone consequence, small molecule target engagement, single lab","pmids":["39501105"],"is_preprint":false},{"year":2024,"finding":"Structure-based design produced YTHDC1 inhibitor compound 40 (Kd = 49 nM); crystal structure at 1.6 Å validated the binding mode; compound 40 is selective against cytoplasmic YTH readers and shows antiproliferative activity in AML cell lines; cellular thermal shift assay confirmed target engagement.","method":"X-ray crystallography (1.6 Å), biochemical binding assay, selectivity panel, cellular thermal shift assay, AML cell antiproliferative assay","journal":"Journal of medicinal chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure validates design, cellular target engagement confirmed by CETSA, antiproliferative correlation with affinity","pmids":["38787793"],"is_preprint":false},{"year":2025,"finding":"YTHDC1 is lactylated at K82 by p300 under hypoxia; K82 lactylation (YTHDC1K82la) increases YTHDC1 phase separation and nuclear condensate expansion, protecting oncogenic transcripts BCL2 and E2F2 from degradation by the PAXT-exosome complex in renal cell carcinoma cells.","method":"Lactylome analysis, site-directed mutagenesis (K82), p300 inhibition/overexpression, FRAP phase separation assay, RNA stability assay, PAXT-exosome interaction","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — lactylome-identified modification, mutagenesis validates K82, phase separation mechanistically linked to mRNA protection, multiple orthogonal methods","pmids":["40680722"],"is_preprint":false},{"year":2025,"finding":"YTHDC1 directly interacts with PPARγ through its intrinsically disordered region (IDR) and protects PPARγ from ARIH2 E3 ubiquitin ligase-mediated proteasomal degradation, in an m6A-independent manner; deletion of Ythdc1 in brown adipose tissue increases PPARγ degradation, impairing interscapular BAT development and thermogenesis.","method":"Conditional Ythdc1 KO in BAT, co-immunoprecipitation (YTHDC1-PPARγ, ARIH2-PPARγ), domain mapping (YTHDC1 IDR, PPARγ A/B domain), proteasomal degradation assay, energy expenditure measurements","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo KO, direct protein-protein interaction mapped to domains, proteasome pathway placed, m6A-independent function validated","pmids":["40355558"],"is_preprint":false},{"year":2024,"finding":"YTHDC1 interacts with HP1BP3 (a nuclear RNA-binding protein); YTHDC1 deficiency causes significant alterations in microRNA levels and HSC apoptosis; overexpression of mir-125b, mir-99b, and let-7e partially rescues functional defects of YTHDC1-null HSCs, indicating YTHDC1 regulates HSC maintenance via HP1BP3-dependent microRNA maturation.","method":"Conditional Ythdc1 KO and Ythdc1/Mettl3 double KO mice, co-IP (YTHDC1-HP1BP3), small RNA-seq, miRNA rescue experiments","journal":"Cell death discovery","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo double KO, direct interaction identified, miRNA rescue epistatically places pathway","pmids":["39414764"],"is_preprint":false}],"current_model":"YTHDC1 is a nuclear m6A reader protein that uses an aromatic cage to selectively recognize N6-methyladenosine (and N1-methyladenosine) in RNA and DNA; it regulates pre-mRNA splicing by recruiting SRSF3 and blocking SRSF10, promotes nuclear export of m6A-modified mRNAs through SRSF3-NXF1, controls alternative polyadenylation by interacting with FIP1L1/CPSF6, silences retrotransposons by facilitating SETDB1-mediated H3K9me3 via LINE1 RNA scaffolds, and protects genomic integrity through cooperation with the THO complex against RNA-damage-induced R-loops, while also performing m6A-independent functions including promoting TopBP1-MRE11-ATR-mediated DNA damage repair, driving TP53 transcriptional elongation, and protecting PPARγ from ubiquitin-mediated degradation via its intrinsically disordered region; its activity is modulated by tyrosine phosphorylation (c-Abl, c-Src, p59(fyn)), O-GlcNAcylation at Ser396, and lysine lactylation at K82, the latter enhancing phase separation and nuclear condensate formation."},"narrative":{"mechanistic_narrative":"YTHDC1 is the principal nuclear reader of N6-methyladenosine (m6A), using a conserved aromatic cage to selectively recognize a 5'-GG(m6A)C consensus through a binding pocket unique among YTH-domain proteins [PMID:25242552, PMID:26318451]. High-resolution structural and biophysical work resolved the recognition mechanism in atomic detail: m6A is captured by the aromatic cage with cation-π-π stabilization of flanking nucleotides and water-mediated contacts that enforce the guanosine preference, and recognition of structured substrates requires local unfolding of RNA hairpins to present m6A in a single-stranded conformation [PMID:31670957, PMID:34258996, PMID:35166835]. The same domain binds N6-methyladenine in single-stranded DNA with even higher affinity and reads damage-induced N1-methyladenosine, extending YTHDC1's reach beyond mRNA [PMID:32663306, PMID:40037355]. Functionally, YTHDC1 governs multiple steps of nuclear RNA metabolism: it controls alternative splicing by recruiting SRSF3 while excluding SRSF10 from target transcripts [PMID:26876937], directs nuclear export of m6A-marked mRNAs via SRSF3 and NXF1 [PMID:28984244], and shapes alternative polyadenylation by interacting with 3'-end processing factors FIP1L1 and CPSF6 and antagonizing CPSF recruitment, a function coupled to m6A-driven liquid-liquid phase separation [PMID:29799838, PMID:36094741]. These activities are physiologically essential, as conditional knockouts cause defects in gametogenesis, embryonic stem cell identity, satellite-cell and muscle stem-cell proliferation, and cardiac sarcomere integrity, with splicing rescued only by m6A-binding-competent protein [PMID:29799838, PMID:33658714, PMID:34716659, PMID:36892464, PMID:36722312]. Through m6A reading of retrotransposon and LINE1 RNAs, YTHDC1 scaffolds SETDB1- and KAP1-mediated H3K9me3 to silence transposable elements and the 2C program [PMID:33658714, PMID:33886094]. YTHDC1 additionally executes m6A-independent functions: it promotes TopBP1-MRE11-ATR-mediated DNA damage repair [PMID:38177310], drives transcriptional elongation at TP53 and DNA-damage-response loci [PMID:38951610], and stabilizes PPARγ by shielding it from ARIH2-mediated degradation via its intrinsically disordered region [PMID:40355558]. Its activity is tuned by post-translational modification, including tyrosine phosphorylation that disperses it from nuclear YT bodies [PMID:10973987, PMID:15175272], O-GlcNAcylation at Ser396 promoting DNA-damage condensates [PMID:40242544], and K82 lactylation that enhances phase separation to protect oncogenic transcripts from the PAXT-exosome [PMID:40680722]. YTHDC1 is required for AML leukemia stem-cell self-renewal and is an actionable target, with structure-guided inhibitors validated against AML cells [PMID:34255814, PMID:38787793].","teleology":[{"year":1998,"claim":"Established YTHDC1 (YT521) as a nuclear protein physically associated with splicing machinery, first hinting at a role in RNA processing before any reader function was known.","evidence":"Yeast two-hybrid and Far Western showing interaction with splicing factors SC35 and SF2","pmids":["9473574"],"confidence":"Low","gaps":["Single-lab identification by indirect binding only","No functional splicing assay","No m6A connection established"]},{"year":1999,"claim":"Showed YTHDC1 acts as a dose-dependent splicing regulator within a signaling-responsive nuclear interaction network, placing it downstream of kinase control.","evidence":"Co-IP, yeast two-hybrid, in vivo splicing assays with Sam68 and SAF-B; p59(fyn) phosphorylation of Sam68 dissolves nuclear dots","pmids":["10564280"],"confidence":"High","gaps":["Mechanism of splice-site selection not defined","m6A dependence not yet known"]},{"year":2000,"claim":"Defined the subnuclear architecture and cell-cycle dynamics of YTHDC1, revealing it organizes into transcription-associated YT bodies requiring its low-complexity termini.","evidence":"Fluorescence microscopy, cell-cycle synchronization, deletion mapping, actinomycin D treatment","pmids":["10973987"],"confidence":"High","gaps":["Functional role of YT bodies in splicing not resolved","Relationship to later phase-separation behavior not yet linked"]},{"year":2004,"claim":"Identified tyrosine phosphorylation as a regulatory switch controlling YTHDC1 localization and splicing activity, connecting kinase signaling to its nuclear function.","evidence":"Kinase assays (c-Abl, c-Src, p59(fyn)), phosphosite mapping, fractionation, in vivo splicing of IL-4R/CD44/SRp20","pmids":["15175272"],"confidence":"High","gaps":["Phosphosites not mapped to structure","Interplay with m6A binding not addressed"]},{"year":2014,"claim":"Solved the structural basis of m6A recognition, defining YTHDC1 as a sequence-selective m6A reader via an aromatic cage and a unique 5' nucleotide pocket.","evidence":"X-ray crystallography of YTH-m6A RNA complex, binding assays, PAR-CLIP-seq","pmids":["25242552"],"confidence":"High","gaps":["Functional consequences of binding not yet connected to splicing/export","Did not address water networks or hairpin substrates"]},{"year":2015,"claim":"Confirmed that YTHDC1's selectivity for the 5'-GGm6AC motif is unique among YTH proteins, distinguishing it mechanistically from cytoplasmic readers.","evidence":"Comparative crystallography of YTHDF1/Pho92 YTH domains and ITC","pmids":["26318451"],"confidence":"High","gaps":["Did not establish in-cell functional divergence","Substrate context (hairpin vs single-strand) unaddressed"]},{"year":2016,"claim":"Defined YTHDC1's primary nuclear function as an m6A-dependent splicing regulator that recruits SRSF3 and excludes SRSF10 to promote exon inclusion.","evidence":"PAR-CLIP-seq, competitive in vitro pull-down, RNA-seq, m6A-binding-mutant reconstitution","pmids":["26876937"],"confidence":"High","gaps":["Genome-wide rules for SRSF3 vs SRSF10 outcomes incomplete","Did not connect to export"]},{"year":2017,"claim":"Extended YTHDC1 function to nuclear export of m6A mRNAs and to SAM-responsive mRNA stability, establishing it as a multifunctional hub of m6A-dependent RNA fate.","evidence":"Knockdown with fractionation, m6A-seq, co-IP with SRSF3/NXF1; METTL16 reconstitution and MAT2A stability assays","pmids":["28984244","29262316"],"confidence":"High","gaps":["Mechanism coupling splicing to export not fully integrated","Selectivity of export targets unresolved"]},{"year":2018,"claim":"Demonstrated in vivo physiological essentiality in gametogenesis and revealed YTHDC1 controls alternative polyadenylation in addition to splicing via 3'-end factors.","evidence":"Conditional knockout mouse, RNA-seq, m6A-seq, co-IP with CPSF6/SRSF3/SRSF7, m6A-mutant rescue","pmids":["29799838"],"confidence":"High","gaps":["Direct molecular mechanism of APA control not yet defined","Tissue-specific target spectrum incomplete"]},{"year":2021,"claim":"Established YTHDC1 as an upstream organizer of heterochromatin, reading m6A on retrotransposon and LINE1 RNAs to scaffold SETDB1/KAP1-mediated H3K9me3 and maintain stem-cell identity.","evidence":"Conditional ESC knockouts, RNA-seq, ChIP-seq, RIP/LACE-seq, epistasis with SETDB1 and NCL/KAP1 co-IP","pmids":["33658714","33886094"],"confidence":"High","gaps":["How RNA scaffolds direct chromatin writers spatially unresolved","Direct vs indirect chromatin recruitment not fully separated"]},{"year":2021,"claim":"Resolved the energetic and dynamic determinants of m6A recognition, identifying gating residues and structured water as contributors to specificity and affinity.","evidence":"Site-directed mutagenesis, ITC, NMR, MD simulations and free-energy calculations","pmids":["33472367","34258996","31670957"],"confidence":"High","gaps":["In-cell relevance of water-mediated specificity untested","Did not address DNA substrates"]},{"year":2021,"claim":"Linked YTHDC1 to disease-relevant gene regulation, including AML leukemia stem-cell self-renewal via MCM4 and tissue-specific splicing controlling cardiac sarcomere integrity.","evidence":"In vivo AML genetic deletion with MeRIP-seq (MCM4); cardiac-specific knockout with m6A/RIP/RNA-seq (Titin)","pmids":["34255814","34716659"],"confidence":"High","gaps":["Therapeutic window between LSC and HSC dependence narrow but mechanism incomplete","Causal contribution of each target not isolated"]},{"year":2020,"claim":"Showed the YTH domain reads N6-methyladenine in single-stranded DNA with high affinity, broadening YTHDC1's substrate repertoire beyond RNA.","evidence":"Two crystal structures of YTH-N6mA ssDNA complexes with FP/ITC binding","pmids":["32663306"],"confidence":"High","gaps":["Biological role of DNA binding not demonstrated in this work","In-cell N6mA targets unknown"]},{"year":2022,"claim":"Mechanistically defined YTHDC1's control of alternative polyadenylation through direct FIP1L1 interaction and m6A-driven phase separation, and uncovered context-dependent splicing switching by AURKA.","evidence":"Co-IP (FIP1L1), APA-seq, FRAP/phase-separation assays; AURKA-driven SRSF3-to-hnRNPK switch by co-IP/RIP/minigene","pmids":["36094741","35361747","35966596"],"confidence":"High","gaps":["Determinants selecting splicing vs APA vs export outcomes unresolved","AURKA switch validated in single context"]},{"year":2023,"claim":"Resolved how YTHDC1 reads structured RNA, showing recognition requires local unfolding of hairpins to expose m6A to the aromatic cage.","evidence":"NMR solution structure, X-ray crystallography, fluorescence-quenching binding assay","pmids":["35166835"],"confidence":"High","gaps":["Kinetics of unfolding-coupled binding in cells unknown","Generality across natural hairpin contexts untested"]},{"year":2023,"claim":"Established YTHDC1 as a key regulator of stem-cell proliferation programs through m6A-dependent splicing and export feeding into PI4K-Akt-mTOR signaling, with new partners hnRNPG and DDX5.","evidence":"Inducible satellite-cell and muscle-stem-cell knockouts, LACE-seq/RIP, splicing analysis, phospho-signaling; co-IP with hnRNPG and DDX5 (circRNA biogenesis)","pmids":["36892464","36722312","37019933"],"confidence":"High","gaps":["How partner selection is governed unclear","circRNA back-splicing role validated in single tumor context"]},{"year":2024,"claim":"Defined a genome-protective role: YTHDC1 reads damage-induced m1A/m6A and cooperates with the THO complex and DDX41-METTL3 to prevent RNA-damage-induced R-loops and DNA breaks.","evidence":"CRISPR-KO epistasis with THOC and XPG, RNA dealkylase rescue, R-loop detection; DDX41 KO/KI with METTL3-YTHDC1 co-IP","pmids":["40037355","38514771"],"confidence":"High","gaps":["How m1A reading is structurally accommodated incompletely defined","DDX41 recruitment mechanism shown in single lab"]},{"year":2024,"claim":"Distinguished m6A-independent activities of YTHDC1 in genome maintenance and transcription, including TopBP1-MRE11-ATR repair and TP53 transcriptional elongation.","evidence":"Conditional KO and m6A-binding-mutant analysis, co-IP (TopBP1-MRE11), ATR assays; CRISPR screen, ChIP at TSS, intron-retention analysis","pmids":["38177310","38951610"],"confidence":"High","gaps":["Structural basis of m6A-independent protein scaffolding unknown","How one protein partitions between RNA-reading and protein-scaffold roles unclear"]},{"year":2024,"claim":"Identified O-GlcNAcylation at Ser396 as a DNA-damage-responsive modification driving YTHDC1 chromatin recruitment, condensate formation, and HR repair.","evidence":"Site mutagenesis, RIP, FRAP, Rad51 foci and HR assays","pmids":["40242544"],"confidence":"High","gaps":["Enzyme adding/removing O-GlcNAc not defined here","Interplay with other PTMs unresolved"]},{"year":2025,"claim":"Revealed PTM-controlled phase separation as a regulatory layer, with K82 lactylation expanding nuclear condensates to protect oncogenic transcripts from PAXT-exosome degradation, and an IDR-mediated m6A-independent protection of PPARγ.","evidence":"Lactylome analysis, K82 mutagenesis, p300 modulation, FRAP, PAXT-exosome and RNA-stability assays; BAT conditional KO with YTHDC1-PPARγ/ARIH2 co-IP and domain mapping","pmids":["40680722","40355558"],"confidence":"High","gaps":["How condensate composition selects protected transcripts unclear","Relationship between lactylation, O-GlcNAcylation, and phosphorylation not integrated"]},{"year":2024,"claim":"Demonstrated YTHDC1 druggability with structure-guided, reader-selective inhibitors showing target engagement and antiproliferative activity in AML.","evidence":"Structure-based design with 1.6 Å crystal structure, CETSA, selectivity panel, AML antiproliferation; EPZ-5676 docking/biochemical inhibition in B-ALL","pmids":["38787793","39501105"],"confidence":"High","gaps":["In vivo efficacy and safety not established","Whether inhibition blocks m6A-independent functions unknown"]},{"year":null,"claim":"It remains unresolved how YTHDC1 partitions a single small reader domain and intrinsically disordered region among its many parallel roles—splicing, export, APA, heterochromatin scaffolding, DNA repair, and transcription—and how the combinatorial PTM and phase-separation code selects which outcome and which transcripts dominate in a given cellular context.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking PTMs, condensates, and functional output","Selectivity rules for partner and target choice undefined","In vivo therapeutic consequences of disrupting individual functions unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,1,7,11,23]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[13,34]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[35]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[7,8,25]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[25,32,41]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[2,3,8]},{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[3,5,7]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[35,37]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[7,8,25]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[35]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[14,15]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[32,34,37]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[10,14,27,29]}],"complexes":[],"partners":["SRSF3","SRSF10","NXF1","FIP1L1","METTL3","DDX5","TOPBP1","PPARG"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96MU7","full_name":"YTH domain-containing protein 1","aliases":["Splicing factor YT521","YT521-B"],"length_aa":727,"mass_kda":84.7,"function":"Regulator of alternative splicing that specifically recognizes and binds N6-methyladenosine (m6A)-containing RNAs (PubMed:25242552, PubMed:26318451, PubMed:26876937, PubMed:28984244). M6A is a modification present at internal sites of mRNAs and some non-coding RNAs and plays a role in the efficiency of mRNA splicing, processing and stability (PubMed:25242552, PubMed:26318451). Acts as a key regulator of exon-inclusion or exon-skipping during alternative splicing via interaction with mRNA splicing factors SRSF3 and SRSF10 (PubMed:26876937). Specifically binds m6A-containing mRNAs and promotes recruitment of SRSF3 to its mRNA-binding elements adjacent to m6A sites, leading to exon-inclusion during alternative splicing (PubMed:26876937). In contrast, interaction with SRSF3 prevents interaction with SRSF10, a splicing factor that promotes exon skipping: this prevents SRSF10 from binding to its mRNA-binding sites close to m6A-containing regions, leading to inhibit exon skipping during alternative splicing (PubMed:26876937). May also regulate alternative splice site selection (PubMed:20167602). Also involved in nuclear export of m6A-containing mRNAs via interaction with SRSF3: interaction with SRSF3 facilitates m6A-containing mRNA-binding to both SRSF3 and NXF1, promoting mRNA nuclear export (PubMed:28984244). Involved in S-adenosyl-L-methionine homeostasis by regulating expression of MAT2A transcripts, probably by binding m6A-containing MAT2A mRNAs (By similarity). Also recognizes and binds m6A on other RNA molecules (PubMed:27602518). Involved in random X inactivation mediated by Xist RNA: recognizes and binds m6A-containing Xist and promotes transcription repression activity of Xist (PubMed:27602518). Also recognizes and binds m6A-containing single-stranded DNA (PubMed:32663306). Involved in germline development: required for spermatogonial development in males and oocyte growth and maturation in females, probably via its role in alternative splicing (By similarity). Independently of its N6-methyladenosine-containing RNA reader activity, it regulates PPARG stability by preventing its interaction with the E3 ubiquitin ligase ARIH2, thereby protecting it from ubiquitin-mediated proteasomal degradation and contributing to brown adipose tissue (BAT) development and energy homeostasis (By similarity)","subcellular_location":"Nucleus; Nucleus speckle","url":"https://www.uniprot.org/uniprotkb/Q96MU7/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/YTHDC1","classification":"Common Essential","n_dependent_lines":641,"n_total_lines":1208,"dependency_fraction":0.5306291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CPSF6","stoichiometry":0.2},{"gene":"CSNK2B","stoichiometry":0.2},{"gene":"DDX21","stoichiometry":0.2},{"gene":"DDX39B","stoichiometry":0.2},{"gene":"PRPF4B","stoichiometry":0.2},{"gene":"RNF40","stoichiometry":0.2},{"gene":"SNRPA","stoichiometry":0.2},{"gene":"SNRPB","stoichiometry":0.2},{"gene":"SNRPC","stoichiometry":0.2},{"gene":"SNRPF","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/YTHDC1","total_profiled":1310},"omim":[{"mim_id":"617283","title":"YTH DOMAIN-CONTAINING PROTEIN 1; YTHDC1","url":"https://www.omim.org/entry/617283"},{"mim_id":"616504","title":"METHYLTRANSFERASE 14, N6-ADENOSINE-METHYLTRANSFERASE SUBUNIT; METTL14","url":"https://www.omim.org/entry/616504"},{"mim_id":"612602","title":"RNA-BINDING MOTIF PROTEIN 15B; RBM15B","url":"https://www.omim.org/entry/612602"},{"mim_id":"612472","title":"METHYLTRANSFERASE 3, N6-ADENOSINE-METHYLTRANSFERASE COMPLEX CATALYTIC SUBUNIT; METTL3","url":"https://www.omim.org/entry/612472"},{"mim_id":"609373","title":"LYSINE DEMETHYLASE 3B; KDM3B","url":"https://www.omim.org/entry/609373"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Plasma membrane","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/YTHDC1"},"hgnc":{"alias_symbol":["YT521","KIAA1966","YT521-B"],"prev_symbol":[]},"alphafold":{"accession":"Q96MU7","domains":[{"cath_id":"3.10.590.10","chopping":"341-512","consensus_level":"high","plddt":93.2137,"start":341,"end":512}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96MU7","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96MU7-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96MU7-F1-predicted_aligned_error_v6.png","plddt_mean":60.34},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=YTHDC1","jax_strain_url":"https://www.jax.org/strain/search?query=YTHDC1"},"sequence":{"accession":"Q96MU7","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96MU7.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96MU7/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96MU7"}},"corpus_meta":[{"pmid":"26876937","id":"PMC_26876937","title":"Nuclear 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\"method\": \"X-ray crystallography, biochemical binding assays, transcriptome-wide PAR-CLIP-seq\",\n      \"journal\": \"Nature chemical biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with functional validation, replicated and extended by multiple structural studies\",\n      \"pmids\": [\"25242552\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Structural comparison of YTH domain proteins revealed that only YTHDC1 harbors a distinctly selective binding pocket for the nucleotide preceding the m6A modification; all YTH domains use a conserved aromatic cage to recognize m6A, but YTHDC1's selectivity for 5'-GGm6AC is unique.\",\n      \"method\": \"X-ray crystallography of YTHDF1 and yeast Pho92 YTH domains in complex with m6A RNA, isothermal titration calorimetry binding assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structures plus binding assays, independently confirms YTHDC1 selectivity\",\n      \"pmids\": [\"26318451\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"YTHDC1 (YT521-B) interacts with Sam68 and scaffold attachment factor B in nuclear dots; the C-terminal glutamic acid/arginine-rich region mediates protein-protein interactions; Src family kinase p59(fyn)-mediated tyrosine phosphorylation of Sam68 negatively regulates its association with YT521-B and dissolves nuclear dots; overexpression of YT521-B modulates alternative splice site selection in a concentration-dependent manner in vivo.\",\n      \"method\": \"Co-immunoprecipitation, yeast two-hybrid, in vivo splicing assays, immunofluorescence, kinase overexpression\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal protein interactions, functional splicing assay, signaling pathway placement, multiple orthogonal methods\",\n      \"pmids\": [\"10564280\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"YTHDC1 (YT521-B) localizes to a novel subnuclear structure (YT bodies) that first appears at the beginning of S-phase and disperses during mitosis; YT bodies contain transcriptionally active sites and are in close contact with speckles and coiled bodies; actinomycin D disperses YT bodies; the N-terminal glutamic acid-rich domain and C-terminal glutamic acid/arginine-rich region are required for YT body formation.\",\n      \"method\": \"Fluorescence microscopy, cell cycle synchronization, deletion analysis, transcriptional inhibitor treatment\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct localization experiment with functional consequence, multiple orthogonal approaches, deletion mapping\",\n      \"pmids\": [\"10973987\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"YTHDC1 (YT521-B) interacts directly with emerin (a nuclear membrane protein) via a bipartite binding site in emerin; this interaction inhibits YT521-B-dependent splice site selection in vivo, suggesting emerin regulates splicing through YTHDC1.\",\n      \"method\": \"Yeast two-hybrid, pull-down assay, BIAcore biomolecular interaction analysis, in vivo splicing assay, alanine substitution mutagenesis\",\n      \"journal\": \"European journal of biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro binding confirmed by multiple methods, functional splicing consequence shown, single lab\",\n      \"pmids\": [\"12755701\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"YTHDC1 (YT521-B) is tyrosine-phosphorylated by c-Abl in the nucleus and by c-Src or p59(fyn) in the cytoplasm; tyrosine phosphorylation disperses YT521-B from YT bodies to an insoluble nucleoplasmic form; phosphorylation by c-Abl abolishes the concentration-dependent effect of YT521-B on alternative splice site selection of IL-4 receptor, CD44, and SRp20.\",\n      \"method\": \"Kinase assay, phosphorylation site mapping, subcellular fractionation, in vivo splicing assay, immunofluorescence\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct kinase assay identifies writer, multiple substrates tested, functional splicing consequence, localization link\",\n      \"pmids\": [\"15175272\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"YTHDC1 (YT521) was identified as an RA301-binding protein via yeast two-hybrid; Far Western blot showed YT521 protein interacts with splicing factors SC35 and SF2, suggesting a role in RNA splicing.\",\n      \"method\": \"Yeast two-hybrid, Far Western blot\",\n      \"journal\": \"Brain research. Molecular brain research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, initial identification by yeast two-hybrid and Far Western only\",\n      \"pmids\": [\"9473574\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Nuclear m6A reader YTHDC1 promotes exon inclusion by recruiting splicing factor SRSF3 while blocking SRSF10 binding to target mRNAs; YTHDC1 facilitates SRSF3 and represses SRSF10 in nuclear speckle localization and RNA-binding affinity; these effects require m6A-binding ability of YTHDC1 as shown by reconstitution with wild-type but not m6A-binding-defective YTHDC1.\",\n      \"method\": \"PAR-CLIP-seq, in vitro pull-down assay showing competitive SRSF3/SRSF10 binding, RNA-seq transcriptome analysis, knockdown/reconstitution with wild-type vs. m6A-binding-defective YTHDC1\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods, m6A-binding mutant rescue, transcriptome-wide and biochemical validation, broadly replicated\",\n      \"pmids\": [\"26876937\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"YTHDC1 mediates nuclear export of m6A-methylated mRNAs in HeLa cells; knockdown of YTHDC1 causes nuclear accumulation and cytoplasmic depletion of m6A-containing transcripts; YTHDC1 interacts with SRSF3 and NXF1 and facilitates RNA binding to both.\",\n      \"method\": \"YTHDC1 knockdown with nuclear/cytoplasmic fractionation, m6A-seq, co-immunoprecipitation with SRSF3 and NXF1, RNA binding assays\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal interactions, fractionation with functional consequence, multiple orthogonal methods, independently replicated concept\",\n      \"pmids\": [\"28984244\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"YTHDC1 reads m6A marks deposited by METTL16 in the 3' UTR of MAT2A mRNA; in response to SAM depletion, YTHDC1 and METTL16 together mediate SAM-responsive regulation of MAT2A mRNA stability; knockdown of YTHDC1 abolishes this regulation.\",\n      \"method\": \"In vitro methylation assay with recombinant METTL16, YTHDC1 knockdown, mutagenesis of METTL16 target adenines in 3' UTR, mRNA stability assay\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro reconstitution with recombinant METTL16, multiple mutagenesis experiments, functional mRNA stability assay\",\n      \"pmids\": [\"29262316\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"YTHDC1 is essential for spermatogonial development and oocyte growth/maturation in mice; loss of YTHDC1 causes extensive alternative polyadenylation (altering 3' UTR length) and massive alternative splicing defects in oocytes; YTHDC1 associates with 3' end processing factors CPSF6, SRSF3, and SRSF7; splicing defects are rescued by wild-type but not m6A-binding-deficient YTHDC1.\",\n      \"method\": \"Conditional knockout mouse model, RNA-seq, m6A sequencing, co-immunoprecipitation with CPSF6/SRSF3/SRSF7, rescue with wild-type vs. m6A-binding-deficient YTHDC1\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo knockout with multiple cellular phenotypes, m6A-binding mutant rescue, co-IP partners identified\",\n      \"pmids\": [\"29799838\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Atomistic simulations, X-ray crystallography, and isothermal titration calorimetry showed that m6A is captured by an aromatic cage of YTHDC1; 3' terminus nucleotides are stabilized by cation-π-π interactions; the 5' terminus remains flexible; the methyl group of m6A shifts conformational preferences of the oligoribonucleotide to a bound-like conformation facilitating association.\",\n      \"method\": \"Atomistic molecular dynamics simulations, X-ray crystallography, isothermal titration calorimetry\",\n      \"journal\": \"Journal of chemical theory and computation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure combined with ITC and MD simulations, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"31670957\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Metadherin interacts with YTHDC1, Sam68, and T-STAR in nuclear speckles and influences splice site selection in a dose-dependent manner in CD44v5-luc minigene reporter assays.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, minigene splicing reporter assay\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — yeast two-hybrid plus IP plus functional splicing assay, single lab\",\n      \"pmids\": [\"31450747\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The YTH domain of YTHDC1 binds N6-methyladenine in single-stranded DNA with ~10 nM Kd, stronger than its affinity for N6-methyladenosine RNA; crystal structures of YTHDC1 YTH domain bound to N6mA-containing ssDNA show methylated adenine binding in a single-stranded region flanked by duplexed DNA.\",\n      \"method\": \"X-ray crystallography (two structures), fluorescence polarization/ITC binding assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — two crystal structures with quantitative binding measurements, single lab but rigorous structural validation\",\n      \"pmids\": [\"32663306\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"YTHDC1 is required for maintenance of mouse ES cell identity in an m6A-dependent manner; depletion initiates reprogramming to a 2C-like state; YTHDC1 binds transcripts of retrotransposons (IAPs, ERVK, LINE1) and its depletion causes reactivation of silenced retrotransposons accompanied by global decrease in SETDB1-mediated H3K9me3; YTHDC1 and its target m6A RNAs act upstream of SETDB1 to repress retrotransposons and Dux.\",\n      \"method\": \"Conditional knockout in mouse ESCs, RNA-seq, ChIP-seq (H3K9me3), RIP-seq, epistasis analysis with SETDB1\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO with defined molecular phenotype, epistasis to SETDB1, multiple orthogonal sequencing approaches\",\n      \"pmids\": [\"33658714\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"YTHDC1 recognizes m6A on LINE1 RNAs in the nucleus and regulates formation of the LINE1-nucleolin (NCL) partnership and chromatin recruitment of KAP1; Ythdc1 depletion interrupts H3K9me3 establishment on 2C-related retrotransposons in ESCs and inner cell mass cells, increasing transcriptional activity of the 2C program.\",\n      \"method\": \"Conditional knockout in ESCs, LACE-seq, ChIP-seq, RIP, Co-IP (YTHDC1-NCL, YTHDC1-KAP1)\",\n      \"journal\": \"Protein & cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO with chromatin phenotype, protein complex identification by Co-IP, epistasis, multiple sequencing modalities\",\n      \"pmids\": [\"33886094\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"YTHDC1 regulates leukemogenesis through MCM4, a critical regulator of DNA replication; YTHDC1 is required for proliferation and survival of AML cells and self-renewal of leukemia stem cells in vivo; Ythdc1 haploinsufficiency reduces LSC but not HSC self-renewal.\",\n      \"method\": \"Genetic deletion of Ythdc1 in mouse AML models, YTHDC1 knockdown in primary AML cells, RNA-seq, m6A-MeRIP-seq identifying MCM4 as target\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic deletion, identification of downstream target MCM4, multiple AML models\",\n      \"pmids\": [\"34255814\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"YTHDC1 binds SQSTM1 mRNA in the nucleus and cooperates with ELAVL1/HuR to modulate its stability; knockdown of YTHDC1 drives SQSTM1 mRNA degradation in the nucleus, causing blockade of autophagic flux in keratinocytes.\",\n      \"method\": \"RIP assay (YTHDC1 binding to SQSTM1 mRNA), co-immunoprecipitation (YTHDC1-ELAVL1), YTHDC1 knockdown/overexpression, autophagic flux assays\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — RIP, Co-IP, functional autophagic flux readout, single lab\",\n      \"pmids\": [\"34657574\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"YTHDC1 facilitated the biogenesis of mature miR-30d via m6A-mediated regulation of mRNA stability in pancreatic cancer cells.\",\n      \"method\": \"RIP, MeRIP, RNA stability assay, YTHDC1 knockdown\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single RIP/stability approach without mechanistic dissection\",\n      \"pmids\": [\"34021267\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"YTHDC1 regulates splicing of Titin mRNA via m6A modification; cardiac-specific Ythdc1 knockout leads to aberrant Titin splicing, disordered sarcomere arrangement, and dilated cardiomyopathy in mice.\",\n      \"method\": \"Cardiac-specific conditional Ythdc1 knockout, m6A-MeRIP-seq, RIP-seq, mRNA-seq, integrated target identification\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo KO with defined molecular target (Titin splicing), multiple sequencing modalities\",\n      \"pmids\": [\"34716659\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In HIV-1 producer cells, YTHDC1 binds HIV-1 transcripts in a METTL3-dependent manner and controls unspliced/incompletely spliced HIV-1 RNA levels; YTHDC1 knockdown reduces Env and Vpu expression and leads to incorporation of unprocessed Env gp160 into viral particles, decreasing infectivity.\",\n      \"method\": \"YTHDC1 knockdown, RIP assay, RT-qPCR for HIV-1 RNA species, Western blot for viral proteins\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP confirms binding, functional splicing and protein expression consequences shown, single lab\",\n      \"pmids\": [\"33883220\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Site-directed mutagenesis and atomistic simulations identified four residues (Trp428, Met438, Ser378, Thr379) regulating m6A binding; Trp428 switches between two states to build/dismantle the aromatic cage; a structural water molecule synergistically binds YTHDC1 with m6A as a hydrogen-bond hub; Thr379Val significantly impairs binding and thermal stability.\",\n      \"method\": \"Site-directed mutagenesis, isothermal titration calorimetry, molecular dynamics simulations, free energy calculations\",\n      \"journal\": \"Journal of chemical theory and computation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis combined with ITC and MD simulations, mechanistic detail of aromatic cage dynamics\",\n      \"pmids\": [\"33472367\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"NMR and MD simulations showed that structured water molecules surrounding the bound RNA and the methylated substrate's ability to exclude bulk water contribute to YTHDC1's preference for m6A; the D479A mutant disrupts a water network and destabilizes m6A binding; YTHDC1's 5'-Gm6A-3' motif preference is partially facilitated by water-mediated interactions with the guanosine 2-amino group.\",\n      \"method\": \"Molecular dynamics simulations, NMR spectroscopy, isothermal titration calorimetry, site-directed mutagenesis (D479A)\",\n      \"journal\": \"The journal of physical chemistry. B\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR, ITC, MD simulations with mutagenesis, multiple orthogonal methods in single study\",\n      \"pmids\": [\"34258996\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"NMR solution structure of the (m6A)UCG hairpin and crystal structure of YTHDC1 bound to it revealed that YTHDC1 recognizes the (m6A)UC nucleotides in a single-stranded conformation by inserting m6A into the aromatic cage; recognition requires local unfolding of the upper stem region of the hairpin, shown by NMR and fluorescence quenching.\",\n      \"method\": \"NMR spectroscopy (solution structure), X-ray crystallography, fluorescence quenching binding assay\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure combined with NMR structure and binding assay, mechanistic model of hairpin unfolding validated\",\n      \"pmids\": [\"35166835\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Nuclear AURKA disrupts the binding of SRSF3 to YTHDC1 and recruits hnRNP K to YTHDC1 in a kinase-independent manner, switching from m6A-YTHDC1-SRSF3-mediated exon inclusion of RBM4-FL to m6A-YTHDC1-hnRNPK-dependent exon skipping to produce the short RBM4-S isoform that promotes lung cancer progression.\",\n      \"method\": \"Co-immunoprecipitation, RIP, RNA-seq, AURKA nuclear translocation experiments, minigene splicing assay\",\n      \"journal\": \"Signal transduction and targeted therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP for complex switching, functional splicing outcome, single lab\",\n      \"pmids\": [\"35361747\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"YTHDC1 suppresses proximal alternative polyadenylation (APA) sites by binding upstream m6A sites; YTHDC1 directly interacts with 3' end processing factor FIP1L1 and interferes with FIP1L1's ability to recruit CPSF4; m6A binding promotes liquid-liquid phase separation of YTHDC1 and FIP1L1.\",\n      \"method\": \"m6A-seq, APA analysis, co-immunoprecipitation (YTHDC1-FIP1L1), FRAP/phase separation assay, YTHDC1 knockdown\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct protein interaction, functional APA consequence, phase separation characterization, multiple orthogonal methods\",\n      \"pmids\": [\"36094741\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"YTHDC1 promotes nuclear export of SMAD3 mRNA in an m6A-dependent manner; YTHDC1 depletion causes nuclear retention of SMAD3 mRNA and reduced SMAD3 protein, impairing TGF-β-induced EMT and TNBC cell migration/invasion; m6A-binding defective YTHDC1 mutant cannot rescue the phenotype.\",\n      \"method\": \"RNA-seq, m6A-seq, RIP-seq, nuclear/cytoplasmic fractionation of SMAD3 mRNA, YTHDC1 KO with SMAD3 overexpression rescue, m6A-binding mutant\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — fractionation with functional rescue, m6A-binding mutant validation, multiple sequencing modalities\",\n      \"pmids\": [\"35966596\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"YTHDC1 is an essential regulator of skeletal muscle satellite cell (SC) activation and proliferation; transcriptome-wide LACE-seq identified m6A-mediated binding targets; YTHDC1 regulates splicing and nuclear export of target mRNAs; hnRNPG was identified as a bona fide interacting partner of YTHDC1 in myoblasts.\",\n      \"method\": \"Inducible YTHDC1 depletion in satellite cells, LACE-seq, splicing analysis, nuclear export analysis, interactome mapping, co-IP (hnRNPG)\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo KO with regeneration phenotype, transcriptome-wide binding and splicing analysis, interaction partner co-IP\",\n      \"pmids\": [\"36892464\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"The m6A reader YTHDC1 interacts with DDX5 RNA helicase; YTHDC1 and DDX5 together promote production of a common subset of circRNAs via back-splicing in rhabdomyosarcoma, and their depletion reduces RMS cell proliferation.\",\n      \"method\": \"Co-immunoprecipitation (YTHDC1-DDX5), circRNA-seq, YTHDC1/DDX5 knockdown, proliferation assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP interaction identified, functional circRNA and proliferation consequence, single lab\",\n      \"pmids\": [\"37019933\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"YTHDC1 promotes muscle stem cell proliferation via PI4K-Akt-mTOR signalling; Ythdc1 binds m6A-modified Pi4k2a and Pi4kb mRNAs and regulates their alternative splicing, thus controlling PI4K-Akt-mTOR signalling; Ythdc1-null muscle stem cells show deficiency in PIP3, phospho-Akt, and phospho-S6.\",\n      \"method\": \"Inducible Ythdc1 knockout in muscle stem cells, RIP (Pi4k2a, Pi4kb binding), splicing analysis, phospho-signaling Western blot\",\n      \"journal\": \"Cell proliferation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo KO, direct mRNA targets identified by RIP, pathway placement via signaling measurements\",\n      \"pmids\": [\"36722312\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"YTHDC1 binding to m6A sites in the FSP1 3'-UTR recruits alternative polyadenylation regulator CSTF3 to generate a less stable shorter 3'-UTR FSP1 mRNA; YTHDC1 downregulation generates longer 3'-UTR FSP1 mRNA stabilized by HuR, increasing FSP1 protein and ferroptosis resistance in lung cancer.\",\n      \"method\": \"RIP (YTHDC1-FSP1 mRNA), Co-IP (YTHDC1-CSTF3, FSP1-HuR), APA analysis, RNA stability assay, YTHDC1 knockdown\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple Co-IP interactions, functional APA and mRNA stability consequences, single lab\",\n      \"pmids\": [\"37903990\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"YTHDC1 promotes IAV replication by binding to influenza A virus NS segment m6A sites at the NS 3' splicing site and inhibiting NS mRNA splicing, thereby promoting viral replication and pathogenicity in vitro and in vivo.\",\n      \"method\": \"YTHDC1 knockdown/overexpression, m6A mapping on NS RNA, RIP assay, splicing assay, in vivo infection model\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP confirms binding at 3' splice site, functional splicing consequence, in vivo validation, single lab\",\n      \"pmids\": [\"37053288\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"YTHDC1 delays stress-induced pulmonary senescence and fibrosis in an m6A-independent manner by promoting interaction between TopBP1 and MRE11, thereby activating ATR and facilitating DNA damage repair; m6A-binding-defective YTHDC1 retains this function.\",\n      \"method\": \"Ythdc1 conditional KO mice, YTHDC1 overexpression with m6A-binding mutant, co-immunoprecipitation (TopBP1-MRE11 interaction), ATR activation assay\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo KO, m6A-binding mutant distinguishes mechanism, direct protein complex identified by Co-IP\",\n      \"pmids\": [\"38177310\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"YTHDC1 positively regulates PTEN expression by stabilizing PTEN mRNA in an m6A-dependent manner; YTHDC1 knockdown destabilizes PTEN mRNA and activates PI3K/AKT signaling, promoting cisplatin resistance in bladder cancer.\",\n      \"method\": \"RIP assay (YTHDC1-PTEN mRNA), RNA stability assay, YTHDC1 knockdown/overexpression, qPCR, Western blot\",\n      \"journal\": \"Cell proliferation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — RIP confirms binding, stability assay, functional signaling consequence, single lab\",\n      \"pmids\": [\"37070134\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"YTHDC1 cooperates with the THO complex (THOC) to prevent RNA-damage-induced DNA breaks (RDIBs); YTHDC1 binds to chemically induced N1-methyladenosine (m1A) in addition to m6A; without YTHDC1, alkylation-damaged RNA forms R-loops that are converted to DNA breaks by XPG nuclease; a nuclear RNA m1A methyltransferase is sufficient to induce DNA breaks in the absence of YTHDC1 or THOC.\",\n      \"method\": \"CRISPR-KO of YTHDC1 and THOC, comet assay, DNA break quantification, RNA dealkylase rescue experiment, R-loop detection, XPG nuclease epistasis\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple KO epistasis experiments, RNA-specific dealkylase rescue, XPG nuclease pathway placement, multiple orthogonal methods\",\n      \"pmids\": [\"40037355\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"YTHDC1 m6A-binding activity promotes transcriptional elongation at the TP53 locus and other DNA damage response genes, and prevents intron retention in key DDR factors; TP53 transcriptional pause-release by YTHDC1 is independent of m6A; YTHDC1 deficiency causes genomic instability and aberrant cancer cell proliferation.\",\n      \"method\": \"CRISPR-KO screen identifying YTHDC1 in p53 response, m6A binding mutant analysis, intron retention analysis, ChIP (YTHDC1 at transcription start sites), RNA-seq\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — CRISPR screen plus orthogonal mechanistic validation, m6A-independent function distinguished by mutant analysis, transcription-level mechanism shown by ChIP\",\n      \"pmids\": [\"38951610\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"DDX41 promotes the recruitment of YTHDC1 to R-loops by promoting binding between METTL3 and YTHDC1; DDX41 KO/KI cells show impaired METTL3-YTHDC1 interaction and increased m6A-methylated R-loops, leading to genomic instability.\",\n      \"method\": \"DDX41 KO and knock-in cell lines, Co-IP (DDX41-METTL3, METTL3-YTHDC1), m6A quantification, R-loop detection, primary patient samples\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP in multiple cell lines, patient samples, single lab\",\n      \"pmids\": [\"38514771\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"YTHDC1 is O-GlcNAcylated at Ser396 upon DNA damage, which is required for YTHDC1 chromatin binding, IRIF formation, and m6A RNA binding at DNA damage sites; O-GlcNAcylation promotes YTHDC1 condensate formation and HR-mediated DNA repair and Rad51 recruitment.\",\n      \"method\": \"Site-directed mutagenesis (Ser396), RIP showing O-GlcNAc-dependent m6A binding, FRAP analysis of condensate formation, Rad51 foci quantification, HR assay\",\n      \"journal\": \"Fundamental research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — mutagenesis of modification site, RIP, FRAP, HR functional assay, MD simulations, multiple methods in one study\",\n      \"pmids\": [\"40242544\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"YTHDC1 binds to and stabilizes m6A-modified KMT2C mRNA; KMT2C catalyzes H3K4 methylation required for DDR gene expression; YTHDC1 knockdown increases DNA damage in B-ALL cells; EPZ-5676 was identified as a YTHDC1 inhibitor by molecular docking and biochemical experiments.\",\n      \"method\": \"RIP (YTHDC1-KMT2C mRNA), ChIP-seq (H3K4me1/me3), RNA stability assay, molecular docking, biochemical YTHDC1 inhibitor assay, B-ALL xenograft\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP confirms binding, ChIP shows downstream histone consequence, small molecule target engagement, single lab\",\n      \"pmids\": [\"39501105\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Structure-based design produced YTHDC1 inhibitor compound 40 (Kd = 49 nM); crystal structure at 1.6 Å validated the binding mode; compound 40 is selective against cytoplasmic YTH readers and shows antiproliferative activity in AML cell lines; cellular thermal shift assay confirmed target engagement.\",\n      \"method\": \"X-ray crystallography (1.6 Å), biochemical binding assay, selectivity panel, cellular thermal shift assay, AML cell antiproliferative assay\",\n      \"journal\": \"Journal of medicinal chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure validates design, cellular target engagement confirmed by CETSA, antiproliferative correlation with affinity\",\n      \"pmids\": [\"38787793\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"YTHDC1 is lactylated at K82 by p300 under hypoxia; K82 lactylation (YTHDC1K82la) increases YTHDC1 phase separation and nuclear condensate expansion, protecting oncogenic transcripts BCL2 and E2F2 from degradation by the PAXT-exosome complex in renal cell carcinoma cells.\",\n      \"method\": \"Lactylome analysis, site-directed mutagenesis (K82), p300 inhibition/overexpression, FRAP phase separation assay, RNA stability assay, PAXT-exosome interaction\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — lactylome-identified modification, mutagenesis validates K82, phase separation mechanistically linked to mRNA protection, multiple orthogonal methods\",\n      \"pmids\": [\"40680722\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"YTHDC1 directly interacts with PPARγ through its intrinsically disordered region (IDR) and protects PPARγ from ARIH2 E3 ubiquitin ligase-mediated proteasomal degradation, in an m6A-independent manner; deletion of Ythdc1 in brown adipose tissue increases PPARγ degradation, impairing interscapular BAT development and thermogenesis.\",\n      \"method\": \"Conditional Ythdc1 KO in BAT, co-immunoprecipitation (YTHDC1-PPARγ, ARIH2-PPARγ), domain mapping (YTHDC1 IDR, PPARγ A/B domain), proteasomal degradation assay, energy expenditure measurements\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo KO, direct protein-protein interaction mapped to domains, proteasome pathway placed, m6A-independent function validated\",\n      \"pmids\": [\"40355558\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"YTHDC1 interacts with HP1BP3 (a nuclear RNA-binding protein); YTHDC1 deficiency causes significant alterations in microRNA levels and HSC apoptosis; overexpression of mir-125b, mir-99b, and let-7e partially rescues functional defects of YTHDC1-null HSCs, indicating YTHDC1 regulates HSC maintenance via HP1BP3-dependent microRNA maturation.\",\n      \"method\": \"Conditional Ythdc1 KO and Ythdc1/Mettl3 double KO mice, co-IP (YTHDC1-HP1BP3), small RNA-seq, miRNA rescue experiments\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo double KO, direct interaction identified, miRNA rescue epistatically places pathway\",\n      \"pmids\": [\"39414764\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"YTHDC1 is a nuclear m6A reader protein that uses an aromatic cage to selectively recognize N6-methyladenosine (and N1-methyladenosine) in RNA and DNA; it regulates pre-mRNA splicing by recruiting SRSF3 and blocking SRSF10, promotes nuclear export of m6A-modified mRNAs through SRSF3-NXF1, controls alternative polyadenylation by interacting with FIP1L1/CPSF6, silences retrotransposons by facilitating SETDB1-mediated H3K9me3 via LINE1 RNA scaffolds, and protects genomic integrity through cooperation with the THO complex against RNA-damage-induced R-loops, while also performing m6A-independent functions including promoting TopBP1-MRE11-ATR-mediated DNA damage repair, driving TP53 transcriptional elongation, and protecting PPARγ from ubiquitin-mediated degradation via its intrinsically disordered region; its activity is modulated by tyrosine phosphorylation (c-Abl, c-Src, p59(fyn)), O-GlcNAcylation at Ser396, and lysine lactylation at K82, the latter enhancing phase separation and nuclear condensate formation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"YTHDC1 is the principal nuclear reader of N6-methyladenosine (m6A), using a conserved aromatic cage to selectively recognize a 5'-GG(m6A)C consensus through a binding pocket unique among YTH-domain proteins [#0, #1]. High-resolution structural and biophysical work resolved the recognition mechanism in atomic detail: m6A is captured by the aromatic cage with cation-π-π stabilization of flanking nucleotides and water-mediated contacts that enforce the guanosine preference, and recognition of structured substrates requires local unfolding of RNA hairpins to present m6A in a single-stranded conformation [#11, #22, #23]. The same domain binds N6-methyladenine in single-stranded DNA with even higher affinity and reads damage-induced N1-methyladenosine, extending YTHDC1's reach beyond mRNA [#13, #34]. Functionally, YTHDC1 governs multiple steps of nuclear RNA metabolism: it controls alternative splicing by recruiting SRSF3 while excluding SRSF10 from target transcripts [#7], directs nuclear export of m6A-marked mRNAs via SRSF3 and NXF1 [#8], and shapes alternative polyadenylation by interacting with 3'-end processing factors FIP1L1 and CPSF6 and antagonizing CPSF recruitment, a function coupled to m6A-driven liquid-liquid phase separation [#10, #25]. These activities are physiologically essential, as conditional knockouts cause defects in gametogenesis, embryonic stem cell identity, satellite-cell and muscle stem-cell proliferation, and cardiac sarcomere integrity, with splicing rescued only by m6A-binding-competent protein [#10, #14, #19, #27, #29]. Through m6A reading of retrotransposon and LINE1 RNAs, YTHDC1 scaffolds SETDB1- and KAP1-mediated H3K9me3 to silence transposable elements and the 2C program [#14, #15]. YTHDC1 additionally executes m6A-independent functions: it promotes TopBP1-MRE11-ATR-mediated DNA damage repair [#32], drives transcriptional elongation at TP53 and DNA-damage-response loci [#35], and stabilizes PPARγ by shielding it from ARIH2-mediated degradation via its intrinsically disordered region [#41]. Its activity is tuned by post-translational modification, including tyrosine phosphorylation that disperses it from nuclear YT bodies [#3, #5], O-GlcNAcylation at Ser396 promoting DNA-damage condensates [#37], and K82 lactylation that enhances phase separation to protect oncogenic transcripts from the PAXT-exosome [#40]. YTHDC1 is required for AML leukemia stem-cell self-renewal and is an actionable target, with structure-guided inhibitors validated against AML cells [#16, #39].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Established YTHDC1 (YT521) as a nuclear protein physically associated with splicing machinery, first hinting at a role in RNA processing before any reader function was known.\",\n      \"evidence\": \"Yeast two-hybrid and Far Western showing interaction with splicing factors SC35 and SF2\",\n      \"pmids\": [\"9473574\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single-lab identification by indirect binding only\", \"No functional splicing assay\", \"No m6A connection established\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Showed YTHDC1 acts as a dose-dependent splicing regulator within a signaling-responsive nuclear interaction network, placing it downstream of kinase control.\",\n      \"evidence\": \"Co-IP, yeast two-hybrid, in vivo splicing assays with Sam68 and SAF-B; p59(fyn) phosphorylation of Sam68 dissolves nuclear dots\",\n      \"pmids\": [\"10564280\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of splice-site selection not defined\", \"m6A dependence not yet known\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Defined the subnuclear architecture and cell-cycle dynamics of YTHDC1, revealing it organizes into transcription-associated YT bodies requiring its low-complexity termini.\",\n      \"evidence\": \"Fluorescence microscopy, cell-cycle synchronization, deletion mapping, actinomycin D treatment\",\n      \"pmids\": [\"10973987\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional role of YT bodies in splicing not resolved\", \"Relationship to later phase-separation behavior not yet linked\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Identified tyrosine phosphorylation as a regulatory switch controlling YTHDC1 localization and splicing activity, connecting kinase signaling to its nuclear function.\",\n      \"evidence\": \"Kinase assays (c-Abl, c-Src, p59(fyn)), phosphosite mapping, fractionation, in vivo splicing of IL-4R/CD44/SRp20\",\n      \"pmids\": [\"15175272\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Phosphosites not mapped to structure\", \"Interplay with m6A binding not addressed\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Solved the structural basis of m6A recognition, defining YTHDC1 as a sequence-selective m6A reader via an aromatic cage and a unique 5' nucleotide pocket.\",\n      \"evidence\": \"X-ray crystallography of YTH-m6A RNA complex, binding assays, PAR-CLIP-seq\",\n      \"pmids\": [\"25242552\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequences of binding not yet connected to splicing/export\", \"Did not address water networks or hairpin substrates\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Confirmed that YTHDC1's selectivity for the 5'-GGm6AC motif is unique among YTH proteins, distinguishing it mechanistically from cytoplasmic readers.\",\n      \"evidence\": \"Comparative crystallography of YTHDF1/Pho92 YTH domains and ITC\",\n      \"pmids\": [\"26318451\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish in-cell functional divergence\", \"Substrate context (hairpin vs single-strand) unaddressed\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined YTHDC1's primary nuclear function as an m6A-dependent splicing regulator that recruits SRSF3 and excludes SRSF10 to promote exon inclusion.\",\n      \"evidence\": \"PAR-CLIP-seq, competitive in vitro pull-down, RNA-seq, m6A-binding-mutant reconstitution\",\n      \"pmids\": [\"26876937\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Genome-wide rules for SRSF3 vs SRSF10 outcomes incomplete\", \"Did not connect to export\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Extended YTHDC1 function to nuclear export of m6A mRNAs and to SAM-responsive mRNA stability, establishing it as a multifunctional hub of m6A-dependent RNA fate.\",\n      \"evidence\": \"Knockdown with fractionation, m6A-seq, co-IP with SRSF3/NXF1; METTL16 reconstitution and MAT2A stability assays\",\n      \"pmids\": [\"28984244\", \"29262316\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism coupling splicing to export not fully integrated\", \"Selectivity of export targets unresolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrated in vivo physiological essentiality in gametogenesis and revealed YTHDC1 controls alternative polyadenylation in addition to splicing via 3'-end factors.\",\n      \"evidence\": \"Conditional knockout mouse, RNA-seq, m6A-seq, co-IP with CPSF6/SRSF3/SRSF7, m6A-mutant rescue\",\n      \"pmids\": [\"29799838\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct molecular mechanism of APA control not yet defined\", \"Tissue-specific target spectrum incomplete\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Established YTHDC1 as an upstream organizer of heterochromatin, reading m6A on retrotransposon and LINE1 RNAs to scaffold SETDB1/KAP1-mediated H3K9me3 and maintain stem-cell identity.\",\n      \"evidence\": \"Conditional ESC knockouts, RNA-seq, ChIP-seq, RIP/LACE-seq, epistasis with SETDB1 and NCL/KAP1 co-IP\",\n      \"pmids\": [\"33658714\", \"33886094\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How RNA scaffolds direct chromatin writers spatially unresolved\", \"Direct vs indirect chromatin recruitment not fully separated\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Resolved the energetic and dynamic determinants of m6A recognition, identifying gating residues and structured water as contributors to specificity and affinity.\",\n      \"evidence\": \"Site-directed mutagenesis, ITC, NMR, MD simulations and free-energy calculations\",\n      \"pmids\": [\"33472367\", \"34258996\", \"31670957\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In-cell relevance of water-mediated specificity untested\", \"Did not address DNA substrates\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Linked YTHDC1 to disease-relevant gene regulation, including AML leukemia stem-cell self-renewal via MCM4 and tissue-specific splicing controlling cardiac sarcomere integrity.\",\n      \"evidence\": \"In vivo AML genetic deletion with MeRIP-seq (MCM4); cardiac-specific knockout with m6A/RIP/RNA-seq (Titin)\",\n      \"pmids\": [\"34255814\", \"34716659\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Therapeutic window between LSC and HSC dependence narrow but mechanism incomplete\", \"Causal contribution of each target not isolated\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showed the YTH domain reads N6-methyladenine in single-stranded DNA with high affinity, broadening YTHDC1's substrate repertoire beyond RNA.\",\n      \"evidence\": \"Two crystal structures of YTH-N6mA ssDNA complexes with FP/ITC binding\",\n      \"pmids\": [\"32663306\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Biological role of DNA binding not demonstrated in this work\", \"In-cell N6mA targets unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Mechanistically defined YTHDC1's control of alternative polyadenylation through direct FIP1L1 interaction and m6A-driven phase separation, and uncovered context-dependent splicing switching by AURKA.\",\n      \"evidence\": \"Co-IP (FIP1L1), APA-seq, FRAP/phase-separation assays; AURKA-driven SRSF3-to-hnRNPK switch by co-IP/RIP/minigene\",\n      \"pmids\": [\"36094741\", \"35361747\", \"35966596\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Determinants selecting splicing vs APA vs export outcomes unresolved\", \"AURKA switch validated in single context\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Resolved how YTHDC1 reads structured RNA, showing recognition requires local unfolding of hairpins to expose m6A to the aromatic cage.\",\n      \"evidence\": \"NMR solution structure, X-ray crystallography, fluorescence-quenching binding assay\",\n      \"pmids\": [\"35166835\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinetics of unfolding-coupled binding in cells unknown\", \"Generality across natural hairpin contexts untested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established YTHDC1 as a key regulator of stem-cell proliferation programs through m6A-dependent splicing and export feeding into PI4K-Akt-mTOR signaling, with new partners hnRNPG and DDX5.\",\n      \"evidence\": \"Inducible satellite-cell and muscle-stem-cell knockouts, LACE-seq/RIP, splicing analysis, phospho-signaling; co-IP with hnRNPG and DDX5 (circRNA biogenesis)\",\n      \"pmids\": [\"36892464\", \"36722312\", \"37019933\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How partner selection is governed unclear\", \"circRNA back-splicing role validated in single tumor context\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined a genome-protective role: YTHDC1 reads damage-induced m1A/m6A and cooperates with the THO complex and DDX41-METTL3 to prevent RNA-damage-induced R-loops and DNA breaks.\",\n      \"evidence\": \"CRISPR-KO epistasis with THOC and XPG, RNA dealkylase rescue, R-loop detection; DDX41 KO/KI with METTL3-YTHDC1 co-IP\",\n      \"pmids\": [\"40037355\", \"38514771\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How m1A reading is structurally accommodated incompletely defined\", \"DDX41 recruitment mechanism shown in single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Distinguished m6A-independent activities of YTHDC1 in genome maintenance and transcription, including TopBP1-MRE11-ATR repair and TP53 transcriptional elongation.\",\n      \"evidence\": \"Conditional KO and m6A-binding-mutant analysis, co-IP (TopBP1-MRE11), ATR assays; CRISPR screen, ChIP at TSS, intron-retention analysis\",\n      \"pmids\": [\"38177310\", \"38951610\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of m6A-independent protein scaffolding unknown\", \"How one protein partitions between RNA-reading and protein-scaffold roles unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified O-GlcNAcylation at Ser396 as a DNA-damage-responsive modification driving YTHDC1 chromatin recruitment, condensate formation, and HR repair.\",\n      \"evidence\": \"Site mutagenesis, RIP, FRAP, Rad51 foci and HR assays\",\n      \"pmids\": [\"40242544\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Enzyme adding/removing O-GlcNAc not defined here\", \"Interplay with other PTMs unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Revealed PTM-controlled phase separation as a regulatory layer, with K82 lactylation expanding nuclear condensates to protect oncogenic transcripts from PAXT-exosome degradation, and an IDR-mediated m6A-independent protection of PPARγ.\",\n      \"evidence\": \"Lactylome analysis, K82 mutagenesis, p300 modulation, FRAP, PAXT-exosome and RNA-stability assays; BAT conditional KO with YTHDC1-PPARγ/ARIH2 co-IP and domain mapping\",\n      \"pmids\": [\"40680722\", \"40355558\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How condensate composition selects protected transcripts unclear\", \"Relationship between lactylation, O-GlcNAcylation, and phosphorylation not integrated\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrated YTHDC1 druggability with structure-guided, reader-selective inhibitors showing target engagement and antiproliferative activity in AML.\",\n      \"evidence\": \"Structure-based design with 1.6 Å crystal structure, CETSA, selectivity panel, AML antiproliferation; EPZ-5676 docking/biochemical inhibition in B-ALL\",\n      \"pmids\": [\"38787793\", \"39501105\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo efficacy and safety not established\", \"Whether inhibition blocks m6A-independent functions unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how YTHDC1 partitions a single small reader domain and intrinsically disordered region among its many parallel roles—splicing, export, APA, heterochromatin scaffolding, DNA repair, and transcription—and how the combinatorial PTM and phase-separation code selects which outcome and which transcripts dominate in a given cellular context.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking PTMs, condensates, and functional output\", \"Selectivity rules for partner and target choice undefined\", \"In vivo therapeutic consequences of disrupting individual functions unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 1, 7, 11, 23]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [13, 34]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [35]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [7, 8, 25]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [25, 32, 41]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [2, 3, 8]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [3, 5, 7]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [35, 37]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [7, 8, 25]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [35]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [14, 15]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [32, 34, 37]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [10, 14, 27, 29]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"SRSF3\", \"SRSF10\", \"NXF1\", \"FIP1L1\", \"METTL3\", \"DDX5\", \"TopBP1\", \"PPARG\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":9,"faith_total":9,"faith_pct":100.0}}