{"gene":"YTHDC1","run_date":"2026-04-28T23:00:23","timeline":{"discoveries":[{"year":2014,"finding":"Crystal structure of the YTHDC1 YTH domain in complex with m6A-containing RNA revealed the specific mode of m6A recognition, including an aromatic cage that captures the N6-methyl group and a selective binding pocket that confers preferential recognition of GG(m6A)C sequences.","method":"X-ray crystallography, biochemical binding assays, transcriptome-wide PAR-CLIP-seq","journal":"Nature chemical biology","confidence":"High","confidence_rationale":"Tier 1 — crystal structure with functional validation and transcriptome-wide binding data","pmids":["25242552"],"is_preprint":false},{"year":2015,"finding":"Structural comparison showed that YTHDC1 uniquely harbors a selective binding pocket for the nucleotide preceding m6A (preferring G), distinguishing it from other YTH domain proteins (YTHDF1, YTHDF2, YTHDF3, yeast Pho92), all of which use a conserved aromatic cage but lack the position-specific selectivity of YTHDC1.","method":"X-ray crystallography, isothermal titration calorimetry, binding affinity measurements","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — multiple crystal structures with quantitative binding data across family members","pmids":["26318451"],"is_preprint":false},{"year":1999,"finding":"YTHDC1 (YT521-B) interacts with the splicing-associated scaffold attachment factor B (SAF-B) and Sam68, localizes to 5–20 large nuclear dots, and modulates alternative splice site selection in a concentration-dependent manner; the Src family kinase p59(fyn)-mediated tyrosine phosphorylation of Sam68 negatively regulates its association with YTHDC1 and dissolves these nuclear dots.","method":"Co-immunoprecipitation, in vivo splicing assays, overexpression of p59(fyn), deletion analysis, RNA in situ hybridization","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 — reciprocal interactions, functional splicing assays, kinase perturbation, replicated across multiple methods in one study","pmids":["10564280"],"is_preprint":false},{"year":2000,"finding":"YTHDC1 (YT521-B) localizes to a novel subnuclear structure called YT bodies, which appear at the beginning of S-phase, disperse during mitosis, and are sensitive to actinomycin D (transcription inhibitor), suggesting association with transcriptionally active sites; the glutamic acid-rich N-terminal domain and the C-terminal glutamic acid/arginine-rich domain are required for YT body formation.","method":"Live-cell imaging, immunofluorescence, cell cycle synchronization, transcription inhibitor treatment, deletion analysis","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 — direct localization experiments with functional consequence (cell-cycle dependence, transcription linkage)","pmids":["10973987"],"is_preprint":false},{"year":2003,"finding":"Emerin (nuclear membrane protein mutated in Emery-Dreifuss muscular dystrophy) directly binds the C-terminal functional domain of YTHDC1 (YT521-B), demonstrated by yeast two-hybrid, pull-down and BIAcore; emerin overexpression inhibits YTHDC1-dependent splice site selection in vivo, defining a bipartite emerin binding site for YTHDC1.","method":"Yeast two-hybrid, pull-down assay, BIAcore biomolecular interaction analysis, in vivo splicing assay","journal":"European journal of biochemistry","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal binding methods plus functional splicing assay","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 YTHDC1 from YT bodies to the nucleoplasm into an insoluble form, and abolishes its ability to alter alternative splice site selection of IL-4 receptor, CD44, and SRp20.","method":"In vivo kinase assays, differential solubility fractionation, alternative splicing reporter assays, nuclear-cytoplasmic shuttling experiments","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 1-2 — identified kinases, multiple substrates, functional splicing readout, subcellular localization consequence","pmids":["15175272"],"is_preprint":false},{"year":2016,"finding":"Nuclear m6A reader YTHDC1 promotes exon inclusion in targeted mRNAs by recruiting splicing factor SRSF3 while blocking SRSF7/SRSF10 binding; YTHDC1 facilitates SRSF3 nuclear speckle localization and RNA binding, and represses SRSF10 localization and binding; these effects require the m6A-binding ability of YTHDC1 and were mapped transcriptome-wide by PAR-CLIP-seq.","method":"PAR-CLIP-seq, in vitro pull-down (competitive binding of SRSF3 and SRSF10 to YTHDC1), knockdown/rescue with wild-type vs. m6A-binding-defective YTHDC1, nuclear speckle localization assays","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods, transcriptome-wide, rescue with separation-of-function mutant; highly cited foundational study","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; mechanistically, YTHDC1 interacts with splicing factor/nuclear export adaptor SRSF3 and facilitates RNA binding to both SRSF3 and the export receptor NXF1.","method":"YTHDC1 knockdown, nuclear/cytoplasmic fractionation, m6A-seq, Co-IP (YTHDC1–SRSF3–NXF1)","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 — clean KD with defined localization phenotype, reciprocal binding partners identified; highly cited","pmids":["28984244"],"is_preprint":false},{"year":2017,"finding":"YTHDC1 reads METTL16-deposited m6A marks in the 3′ UTR of MAT2A mRNA to promote its degradation; when SAM is depleted, METTL16 methylation of MAT2A is reduced, YTHDC1-dependent decay is relieved, and MAT2A mRNA is stabilized, thus upregulating SAM synthesis as a feedback mechanism.","method":"In vitro methylation assays with recombinant METTL16, YTHDC1 knockdown, MAT2A mRNA stability assays, 3′ UTR mutagenesis of m6A target adenines","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1-2 — reconstituted in vitro methylation, mutagenesis, and cellular stability assays defining a feedback axis","pmids":["29262316"],"is_preprint":false},{"year":2018,"finding":"YTHDC1 is essential for spermatogonial development and oocyte growth/maturation in mice; loss of YTHDC1 in oocytes causes extensive alternative polyadenylation (altered 3′ UTR length) and massive alternative splicing defects; splicing defects are rescued by wild-type but not m6A-binding-deficient YTHDC1; YTHDC1 associates with pre-mRNA 3′ end processing factors CPSF6, SRSF3, and SRSF7.","method":"Conditional knockout mouse, RNA-seq, alternative splicing analysis, polyadenylation analysis, Co-IP (YTHDC1–CPSF6/SRSF3/SRSF7), rescue with separation-of-function mutant","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 — in vivo KO with multiple transcriptome-wide readouts, protein interactions, and mutant rescue","pmids":["29799838"],"is_preprint":false},{"year":2019,"finding":"Atomistic simulations and X-ray crystallography show that the m6A methyl group is captured by the aromatic cage of YTHDC1 (Trp377/Trp428), the 3′ terminus nucleotides are stabilized by cation-π-π interactions, and the 5′ terminus remains flexible; the methyl group of m6A pre-organizes the RNA into a bound-like conformation, facilitating association.","method":"X-ray crystallography, atomistic molecular dynamics simulations, isothermal titration calorimetry","journal":"Journal of chemical theory and computation","confidence":"High","confidence_rationale":"Tier 1 — crystal structure plus simulation and calorimetry with mechanistic interpretation","pmids":["31670957"],"is_preprint":false},{"year":2019,"finding":"Oncogene metadherin (MTDH) interacts with YTHDC1, Sam68, and T-STAR in nuclear speckles and influences alternative splice site selection of CD44 in a dose-dependent manner.","method":"Yeast two-hybrid, co-immunoprecipitation, CD44v5-luc minigene splicing reporter assay","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 3 — single Co-IP plus functional splicing reporter","pmids":["31450747"],"is_preprint":false},{"year":2020,"finding":"The YTH domain of YTHDC1 binds N6-methyladenine in single-stranded DNA with ~10 nM Kd, approximately 5-fold stronger than the equivalent m6A RNA under the same conditions; crystal structures of YTHDC1 YTH in complex with N6mA-containing ssDNA showed recognition of methylated adenine in a single-stranded region flanked by duplexed DNA.","method":"Fluorescence polarization binding assay, X-ray crystallography (two structures)","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 — reconstituted in vitro binding assays plus two crystal structures","pmids":["32663306"],"is_preprint":false},{"year":2021,"finding":"YTHDC1 is required for maintenance of mouse embryonic stem cells; deletion triggers reprogramming to a 2C-like state; mechanistically, YTHDC1 binds m6A-modified retrotransposon (IAP, ERVK, LINE1) transcripts and its depletion results in reactivation of these elements 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 ESCs, RNA-seq, m6A-seq, YTHDC1 RIP, H3K9me3 ChIP-seq, genetic epistasis (YTHDC1 → SETDB1 → H3K9me3)","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal genomic methods, genetic epistasis, replicated across ESC and ICM contexts","pmids":["33658714"],"is_preprint":false},{"year":2021,"finding":"YTHDC1 recognizes m6A on LINE1 RNAs in the nucleus, regulates the formation of the LINE1–nucleolin (NCL) RNA scaffold partnership, promotes chromatin recruitment of KAP1, and is required for H3K9me3 establishment on 2C-related retrotransposons; YTHDC1 is also required for sufficient rRNA synthesis in ESCs.","method":"Conditional Ythdc1 KO in ESCs, RIP, Co-IP (LINE1 RNA–NCL–KAP1 complex), H3K9me3 ChIP-seq, rRNA synthesis assay","journal":"Protein & cell","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods, consistent with independent Nature paper on same topic","pmids":["33886094"],"is_preprint":false},{"year":2021,"finding":"YTHDC1 regulates leukemogenesis through MCM4, a critical regulator of DNA replication; genetic deletion of Ythdc1 blocks AML development and LSC self-renewal in vivo; haploinsufficiency reduces LSC but not normal HSC self-renewal.","method":"Conditional Ythdc1 KO mouse models, in vivo AML transplantation, YTHDC1 knockdown in primary AML cells, MCM4 target identification","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 — in vivo genetic models with defined mechanistic target (MCM4) and quantitative stem cell assays","pmids":["34255814"],"is_preprint":false},{"year":2021,"finding":"Trp428 of YTHDC1 switches between two conformational states to build and dismantle the aromatic cage for m6A binding; Met438 and Ser378 modulate binding enthalpy-entropy compensation without changing affinity; Thr379Val mutation significantly reduces thermal stability and m6A binding capability; a structural water molecule synergistically binds YTHDC1 with m6A as a hydrogen-bond hub.","method":"Atomistic MD simulations, site-directed mutagenesis, thermal shift assay, isothermal titration calorimetry, free energy calculations","journal":"Journal of chemical theory and computation","confidence":"High","confidence_rationale":"Tier 1 — mutagenesis plus biophysical experiments with quantitative mechanistic analysis","pmids":["33472367"],"is_preprint":false},{"year":2021,"finding":"YTHDC1 interacts with ELAVL1/HuR to modulate SQSTM1 mRNA stability in the nucleus; YTHDC1 knockdown causes SQSTM1 mRNA degradation in the nucleus, blocking autophagic flux; overexpression of YTHDC1 rescues the autophagic flux blockade induced by high glucose in keratinocytes.","method":"Co-IP (YTHDC1–ELAVL1), RIP-qPCR (YTHDC1 binding to SQSTM1 mRNA), YTHDC1 KD/OE, autophagic flux assays (LC3, autophagosome imaging), in vivo Ythdc1/Sqstm1 knockdown","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2-3 — Co-IP and RIP plus functional autophagic readout; single lab","pmids":["34657574"],"is_preprint":false},{"year":2021,"finding":"Molecular dynamics and NMR analysis of the YTHDC1 YTH–m6A RNA complex revealed that structured water molecules surrounding the bound RNA contribute to m6A selectivity; bulk water intrusions disrupt unmethylated adenosine binding; the 5′-G preference of YTHDC1 is partially mediated by a water-mediated hydrogen bond network between the guanosine 2-amino group and binding pocket residues; D479A mutation disrupts this water network.","method":"MD simulations, NMR spectroscopy, isothermal titration calorimetry","journal":"The journal of physical chemistry. B","confidence":"High","confidence_rationale":"Tier 1 — combined MD, NMR, and ITC with mutagenesis validation","pmids":["34258996"],"is_preprint":false},{"year":2021,"finding":"YTHDC1 facilitates biogenesis of mature miR-30d via m6A-mediated regulation of mRNA stability; mature miR-30d then inhibits aerobic glycolysis by reducing SLC2A1 and HK1 expression through targeting transcription factor RUNX1.","method":"MeRIP, RIP, RNA stability assay, miRNA maturation analysis, luciferase reporter assay","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 3 — single lab, RIP and stability assays without reconstitution","pmids":["34021267"],"is_preprint":false},{"year":2022,"finding":"NMR solution structure of the m6A-modified AUCG tetraloop hairpin of Xist A-repeats showed that m6A extends 5′ stacking of the helical stem; crystal structure of YTHDC1 bound to the (m6A)UCG tetraloop showed recognition in single-stranded conformation requiring local unfolding of the upper stem; fluorescence quenching confirmed that binding requires local stem unfolding.","method":"NMR structure determination, X-ray crystallography, fluorescence quenching experiments","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 — two independent structural methods plus biophysical validation","pmids":["35166835"],"is_preprint":false},{"year":2022,"finding":"Nuclear AURKA disrupts binding of SRSF3 to YTHDC1 (blocking m6A-YTHDC1-SRSF3-dependent RBM4-FL production) and instead recruits hnRNP K to YTHDC1, creating an m6A-YTHDC1-hnRNP K complex that promotes exon skipping to produce the oncogenic RBM4-S isoform; AURKA nuclear translocation is required but its kinase activity is not.","method":"Co-IP (AURKA–YTHDC1–SRSF3/hnRNP K complexes), alternative splicing analysis, nuclear translocation blocking experiments, kinase-dead mutants","journal":"Signal transduction and targeted therapy","confidence":"Medium","confidence_rationale":"Tier 2-3 — Co-IP plus functional splicing readout; single lab","pmids":["35361747"],"is_preprint":false},{"year":2022,"finding":"SRSF3 binding to YTHDC1 is regulated by the phosphorylation status of SRSF3's arginine/serine-rich (RS) domain; dephosphorylation-mimic serine-to-alanine mutants of SRSF3 revealed multiple phosphorylation positions; YTHDC1 binding involves both YTHDC1 N- and C-terminal residues as well as the RS domain and additional regions of SRSF3.","method":"Co-immunoprecipitation with deletion mutants, dephosphorylation-mimic mutagenesis (S→A), domain mapping","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2-3 — multiple mutants and domain mapping via Co-IP; single lab","pmids":["35563766"],"is_preprint":false},{"year":2022,"finding":"YTHDC1 suppresses proximal alternative polyadenylation (APA) sites to produce longer 3′ UTR transcripts; mechanistically, YTHDC1 directly interacts with 3′ end processing factor FIP1L1 and interferes with its ability to recruit CPSF4; m6A binding promotes liquid-liquid phase separation of YTHDC1 and FIP1L1.","method":"APA analysis (RNA-seq), Co-IP (YTHDC1–FIP1L1), RIP, phase separation assays (in vitro droplet formation), YTHDC1 KD","journal":"EMBO reports","confidence":"Medium","confidence_rationale":"Tier 2 — protein interaction, APA phenotype, and phase separation assay in single study","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 lower SMAD3 protein levels, impairing TGF-β-induced EMT and TNBC cell migration; m6A-binding-defective YTHDC1 cannot rescue these phenotypes.","method":"YTHDC1 KO/rescue with m6A-binding mutant, nuclear/cytoplasmic fractionation, RIP-seq, m6A-seq, cell migration/invasion assays, in vivo metastasis model","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2 — separation-of-function mutant rescue, fractionation, multiple transcriptome analyses; single lab","pmids":["35966596"],"is_preprint":false},{"year":2022,"finding":"YTHDC1 binding to m6A sites on HIV-1 transcripts (in a METTL3-dependent manner) regulates viral RNA biogenesis: YTHDC1 knockdown increases unspliced and incompletely spliced HIV-1 RNAs, reduces Env and Vpu protein expression, leads to incorporation of unprocessed gp160 into virions, and reduces virion infectivity.","method":"YTHDC1 knockdown, HIV-1 RNA splicing analysis, viral protein Western blot, RIP (YTHDC1 binding to HIV-1 transcripts), viral infectivity assay","journal":"Retrovirology","confidence":"Medium","confidence_rationale":"Tier 2-3 — clean KD with multiple defined phenotypes; METTL3-dependence established","pmids":["35101069"],"is_preprint":false},{"year":2023,"finding":"YTHDC1 is an essential regulator of satellite cell (muscle stem cell) activation and proliferation; YTHDC1 depletion nearly abolishes regenerative capacity; YTHDC1 regulates mRNA splicing and nuclear export of target transcripts; hnRNPG is identified as a bona fide YTHDC1 interacting partner in myoblasts.","method":"Inducible Ythdc1 KO in satellite cells, LACE-seq (transcriptome-wide binding), splicing analysis, nuclear export analysis, Co-IP interactome mapping","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 — in vivo KO, transcriptome-wide target identification, multiple mechanistic readouts, protein partner identified","pmids":["36892464"],"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, leading to elevated FSP1 protein and ferroptosis resistance in lung cancer.","method":"RIP (YTHDC1–FSP1 mRNA), APA analysis, Co-IP (YTHDC1–CSTF3), RNA stability assays, HuR interaction assays, YTHDC1 KD rescue experiments","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2-3 — multiple interaction assays and APA readout; single lab","pmids":["37903990"],"is_preprint":false},{"year":2023,"finding":"YTHDC1 and the RNA helicase DDX5 interact directly and cooperate to promote the production of a common subset of circRNAs in rhabdomyosarcoma cells through the back-splicing reaction; DDX5 acts as a co-factor of the m6A regulatory network downstream of YTHDC1.","method":"Co-IP (YTHDC1–DDX5), circRNA-seq, YTHDC1/DDX5 depletion, back-splicing assays","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2-3 — Co-IP plus functional circRNA production phenotype; single lab","pmids":["37019933"],"is_preprint":false},{"year":2023,"finding":"YTHDC1 regulates muscle stem cell quiescence exit via PI4K-Akt-mTOR signaling; Ythdc1-null satellite cells cannot exit quiescence; mechanistically, YTHDC1 binds m6A-modified Pi4k2a and Pi4kb mRNAs to regulate their alternative splicing, sustaining PI4K-Akt-mTOR pathway activity.","method":"Conditional Ythdc1 KO in satellite cells, phospho-signaling assays (p-Akt, p-S6), splicing analysis of Pi4k2a/Pi4kb, RIP","journal":"Cell proliferation","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo KO with pathway-level signaling readout and target mRNA splicing linkage","pmids":["36722312"],"is_preprint":false},{"year":2023,"finding":"YTHDC1 delays stress-induced pulmonary senescence and fibrosis through an m6A-independent mechanism: it promotes interaction between TopBP1 and MRE11, thereby activating ATR and facilitating DNA damage repair; this function is independent of m6A-binding ability.","method":"Co-IP (YTHDC1–TopBP1–MRE11), ATR activation assays, YTHDC1 KO/OE in mice, rescue with m6A-binding-defective YTHDC1 mutant","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 2 — protein complex identified by Co-IP, separation-of-function rescue, in vivo model; single lab","pmids":["38177310"],"is_preprint":false},{"year":2023,"finding":"YTHDC1 inhibits influenza A virus NS segment splicing by binding to the NS 3′ splicing site in an m6A-dependent manner, thereby promoting viral replication and pathogenicity; YTHDC1 levels are enhanced by IAV infection, and its depletion reduces viral replication.","method":"YTHDC1 KD/OE, NS mRNA splicing analysis, RIP (YTHDC1–NS RNA), in vivo IAV infection model","journal":"PLoS pathogens","confidence":"Medium","confidence_rationale":"Tier 2-3 — RIP confirming binding plus splicing phenotype in vitro and in vivo","pmids":["37053288"],"is_preprint":false},{"year":2023,"finding":"YTHDC1 promotes the nuclear export of m6A-modified circRNAs (e.g., circKcnk9) in an m6A-dependent manner; siYTHDC1 increases nuclear staining of circKcnk9, which is reversed by wild-type but not m6A-binding-defective YTHDC1.","method":"RNA FISH, siRNA KD, YTHDC1 wild-type vs. mutant rescue, YTHDC1 RIP on circKcnk9","journal":"Molecular pain","confidence":"Medium","confidence_rationale":"Tier 2-3 — FISH-based localization with separation-of-function rescue; single lab","pmids":["36443649"],"is_preprint":false},{"year":2023,"finding":"YTHDC1 regulates the splicing of HOXB-AS3 precursor RNA via m6A modification, upregulating the NR_033205.1 spliceosome isoform, which accelerates leukemic stem cell self-renewal and AML progression.","method":"m6A-MeRIP, RIP (YTHDC1 binding to HOXB-AS3), splicing analysis, KD/OE functional assays in THP-1 and mouse models","journal":"International journal of biological macromolecules","confidence":"Medium","confidence_rationale":"Tier 2-3 — RIP plus splicing analysis and in vivo xenograft; single lab","pmids":["36906205"],"is_preprint":false},{"year":2023,"finding":"YTHDC1 binds to the transcription start sites of TP53 and other DNA damage response genes, promoting their transcriptional elongation in an m6A-independent manner; YTHDC1 also reduces intron retention in m6A-dependent fashion for key DDR factors; YTHDC1 deficiency causes genomic instability.","method":"CRISPR-KO screen, YTHDC1 ChIP (TSS binding), RNA-seq (intron retention analysis), m6A-dependent vs -independent rescue experiments","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP evidence for TSS binding, RNA-seq intron retention, two mechanistically distinct YTHDC1 functions defined; single lab","pmids":["38951610"],"is_preprint":false},{"year":2023,"finding":"Depletion of YTHDC1 in cardiomyocytes causes dilated cardiomyopathy; YTHDC1 binds m6A-modified Titin mRNA and its depletion results in aberrant splicing of Titin, leading to disordered sarcomere arrangement and decreased cardiomyocyte contractility.","method":"Cardiac-specific conditional Ythdc1 KO, m6A-MeRIP-seq, RIP-seq, mRNA-seq, sarcomere imaging","journal":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo cardiac KO with multiple transcriptome methods identifying Titin as target; single lab","pmids":["34716659"],"is_preprint":false},{"year":2023,"finding":"YTHDC1 O-GlcNAcylation at Ser396 (mediated upon DNA damage) promotes YTHDC1 chromatin binding, IRIF formation, m6A RNA binding, and liquid-liquid phase separation of YTHDC1 condensates at damage sites; O-GlcNAcylated YTHDC1 promotes homologous recombination-mediated repair and recruitment of Rad51.","method":"Site-directed mutagenesis (Ser396), RIP (m6A binding), Co-IP, FRAP, IRIF immunofluorescence, HR reporter assay, molecular dynamics simulations","journal":"Fundamental research","confidence":"Medium","confidence_rationale":"Tier 2 — mutagenesis of modification site, multiple functional assays, and simulations; single lab","pmids":["40242544"],"is_preprint":false},{"year":2024,"finding":"YTHDC1 interacts with the THO complex (THOC) and, in addition to binding m6A, binds chemically damaged N1-methyladenosine (m1A) in RNA; without YTHDC1 or THOC, damaged nuclear RNA accumulates R-loops that are converted to DNA breaks (RDIBs) by the XPG nuclease; an RNA-specific dealkylase rescues the DNA break phenotype, establishing that RNA damage drives genome instability.","method":"In vitro binding assays (m1A vs m6A), Co-IP (YTHDC1–THOC), R-loop immunofluorescence, comet assay, XPG epistasis, RNA dealkylase rescue","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1-2 — reconstituted binding, genetic epistasis (XPG, dealkylase rescue), mechanistic pathway defined","pmids":["40037355"],"is_preprint":false},{"year":2024,"finding":"DDX41 promotes YTHDC1 recruitment to m6A-methylated R-loops by facilitating the interaction between METTL3 and YTHDC1; DDX41 loss (KO or patient mutations R525H/Y259C) impairs this interaction, leading to increased m6A-RNA methylated R-loops and genomic instability.","method":"DDX41 KO and knock-in cell lines, Co-IP (DDX41–METTL3–YTHDC1 complex), m6A quantification, R-loop immunofluorescence, primary MDS patient samples","journal":"Leukemia","confidence":"Medium","confidence_rationale":"Tier 2 — protein complex defined by Co-IP, genetic models, and clinical validation; single lab","pmids":["38514771"],"is_preprint":false},{"year":2024,"finding":"YTHDC1 binds m6A-modified KMT2C mRNA to stabilize it; KMT2C catalyzes H3K4 methylation required for expression of DNA damage response genes; YTHDC1 knockdown decreases YTHDC1 protein stability, reduces KMT2C levels, and attenuates DDR gene expression, sensitizing B-ALL cells to chemotherapy.","method":"RIP-qPCR (YTHDC1–KMT2C mRNA), RNA stability assay, H3K4 ChIP, YTHDC1/KMT2C KD, B-ALL xenograft model, molecular docking for inhibitor identification","journal":"Leukemia","confidence":"Medium","confidence_rationale":"Tier 2-3 — RIP and stability data plus epigenetic readout; single lab","pmids":["39501105"],"is_preprint":false},{"year":2024,"finding":"YTHDC1 interacts with HP1BP3 (a nuclear RNA binding protein involved in microRNA maturation); YTHDC1 deficiency in HSCs causes significant alterations in microRNA levels (including mir-125b, mir-99b, let-7e); overexpression of these miRNAs partially rescues YTHDC1-null HSC functional defects, establishing a YTHDC1–HP1BP3–microRNA maturation axis for HSC maintenance.","method":"Conditional Ythdc1 KO, Ythdc1/Mettl3 double KO, Co-IP (YTHDC1–HP1BP3), small RNA-seq, miRNA rescue experiments","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo KO, protein interaction, and miRNA rescue define the axis; single lab","pmids":["39414764"],"is_preprint":false},{"year":2024,"finding":"KAP1 (TRIM28) forms a complex with YTHDC1 and METTL3 to stabilize m6A-modified MYCN mRNA; KAP1 depletion decreases YTHDC1 protein stability and promotes MYCN mRNA degradation; MYCN in turn transcriptionally activates KAP1, forming a positive feedback loop.","method":"Co-IP/mass spectrometry (KAP1–YTHDC1–METTL3 complex), RIP-qPCR, RNA stability assay, Western blot, xenograft model","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2-3 — complex identified by MS/Co-IP plus functional stability assay; single lab","pmids":["38745192"],"is_preprint":false},{"year":2025,"finding":"Lysine lactylation of YTHDC1 at K82 (mediated by p300 under hypoxia) increases YTHDC1 phase separation and expansion of nuclear condensates, protecting oncogenic BCL2 and E2F2 mRNAs from degradation by the PAXT-exosome complex in renal cell carcinoma cells.","method":"Lactylome mass spectrometry, K82 mutagenesis, phase separation assays (in vitro droplets, nuclear condensate imaging), RIP (YTHDC1–BCL2/E2F2 mRNA), PAXT-exosome interaction assays, in vivo RCC models","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1-2 — PTM site identified by proteomics, site-specific mutagenesis, phase separation reconstitution, target mRNA protection mechanism; multiple methods in one study","pmids":["40680722"],"is_preprint":false},{"year":2025,"finding":"YTHDC1 directly interacts with PPARγ through its intrinsically disordered region (IDR), protecting PPARγ from ARIH2 E3 ubiquitin ligase-mediated ubiquitination and proteasomal degradation; the ARIH2 RING2 domain is essential for PPARγ degradation, and the PPARγ A/B domain mediates the interaction with ARIH2; this function is independent of YTHDC1's m6A-binding ability.","method":"Co-IP (YTHDC1–PPARγ–ARIH2), domain mapping, ubiquitination assays, Ythdc1 KO in brown adipose tissue, m6A-binding-defective YTHDC1 rescue","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 2 — protein-protein interaction, ubiquitination mechanism, in vivo KO, separation-of-function rescue; single lab","pmids":["40355558"],"is_preprint":false},{"year":2025,"finding":"Phase-separating YTHDC1 forms a nuclear pore complex with SRSF3, ALYREF, and exportin-5 (XPO5) to promote nuclear export of m6A-modified lncRNA lnc668; this process requires YTHDC1 phase separation and is dependent on METTL3-mediated m6A modification of lnc668.","method":"Co-IP (YTHDC1–SRSF3–ALYREF–XPO5), phase separation assays, FISH (nuclear/cytoplasmic lnc668), MeRIP, YTHDC1 KD in fibrosis models","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2-3 — nuclear export complex defined by Co-IP and FISH; phase separation link; single lab","pmids":["40221424"],"is_preprint":false},{"year":2024,"finding":"Structure-based medicinal chemistry yielded YTHDC1 inhibitor compound 40 (Kd = 49 nM), validated by a 1.6 Å crystal structure of the complex; compound 40 is selective over cytoplasmic YTHDF1-3 and YTHDC2, shows antiproliferative activity against AML cell lines, and engages YTHDC1 in cells (confirmed by CETSA).","method":"X-ray crystallography (1.6 Å), biochemical binding assay, selectivity panel, antiproliferative assay, cellular thermal shift assay (CETSA)","journal":"Journal of medicinal chemistry","confidence":"High","confidence_rationale":"Tier 1 — crystal structure plus cellular target engagement validation; selectivity demonstrated","pmids":["38787793"],"is_preprint":false},{"year":1998,"finding":"YTHDC1 (YT521) was identified as an RA301 (Sam68 paralog) binding protein by yeast two-hybrid screening; far Western blot showed that YT521 protein interacts with RA301, and also with splicing factors SC35 and SF2, suggesting a role as an RNA splicing-related protein; YT521 mRNA is induced by hypoxia/reoxygenation through reactive oxygen species.","method":"Yeast two-hybrid screening, far Western blot (YT521–RA301, SC35, SF2 interactions)","journal":"Brain research. Molecular brain research","confidence":"Medium","confidence_rationale":"Tier 3 — far Western interaction data; early foundational identification study","pmids":["9473574"],"is_preprint":false}],"current_model":"YTHDC1 is a nuclear m6A RNA reader whose YTH domain selectively recognizes N6-methyladenosine (especially in GG(m6A)C contexts) via an aromatic cage, and uses this binding to regulate multiple steps of RNA metabolism: it promotes exon inclusion by recruiting SRSF3 and blocking SRSF7/SRSF10; facilitates mRNA nuclear export via an SRSF3–NXF1 axis; suppresses proximal APA sites by interacting with FIP1L1/CPSF4; stabilizes or destabilizes specific target mRNAs (e.g., SQSTM1, MAT2A, KMT2C) in concert with partners such as ELAVL1/HuR; silences retrotransposons by binding m6A-modified LINE1/ERVK RNAs and promoting SETDB1-dependent H3K9me3; undergoes post-translational regulation (tyrosine phosphorylation by c-Abl/c-Src, O-GlcNAcylation at Ser396, lysine lactylation at K82) that modulates its localization, m6A-binding capacity, and phase-separation into nuclear condensates; and also functions in an m6A-independent manner to promote DNA damage repair (by facilitating TopBP1–MRE11–ATR signaling and cooperating with the THO complex to prevent RNA-damage-induced DNA breaks) and PPARγ stabilization."},"narrative":{"teleology":[{"year":1998,"claim":"Initial identification of YTHDC1 as a nuclear splicing-associated factor established that it interacts with Sam68 family members and classical SR splicing factors, placing it at the intersection of RNA binding and pre-mRNA processing.","evidence":"Yeast two-hybrid screen and far Western blotting in rat brain cDNA library","pmids":["9473574"],"confidence":"Medium","gaps":["Interaction with SC35/SF2 shown only by far Western without reciprocal validation","No direct RNA binding or m6A recognition yet known","Functional consequence for splicing not demonstrated"]},{"year":1999,"claim":"Demonstration that YTHDC1 modulates alternative splice site selection and that its activity is regulated by Src-family kinase phosphorylation of partner Sam68 established YTHDC1 as a functional splicing regulator whose nuclear organization is dynamically controlled.","evidence":"Co-immunoprecipitation, in vivo splicing reporters, p59(fyn) kinase perturbation in mammalian cells","pmids":["10564280"],"confidence":"High","gaps":["RNA substrates not identified transcriptome-wide","Direct RNA-binding activity not yet shown","Whether YTHDC1 itself is a kinase substrate unknown"]},{"year":2000,"claim":"Discovery that YTHDC1 concentrates in novel cell-cycle-regulated nuclear bodies (YT bodies) that depend on active transcription linked its function to transcriptionally active chromatin and defined the domain architecture required for condensate formation.","evidence":"Live-cell imaging, actinomycin D treatment, cell cycle synchronization, deletion analysis","pmids":["10973987"],"confidence":"High","gaps":["Molecular composition of YT bodies unknown","Relationship to known nuclear bodies (speckles, paraspeckles) unclear","Mechanism of cell-cycle regulation undefined"]},{"year":2004,"claim":"Identification of c-Abl and c-Src as direct kinases that phosphorylate YTHDC1, dispersing it from YT bodies and abolishing its splicing activity, established that tyrosine phosphorylation is a major switch controlling YTHDC1 nuclear organization and function.","evidence":"In vivo kinase assays, differential solubility fractionation, splicing reporters for IL-4R/CD44/SRp20","pmids":["15175272"],"confidence":"High","gaps":["Specific tyrosine residues phosphorylated not mapped","Physiological signals triggering phosphorylation unknown","Whether phosphorylation affects RNA binding directly untested"]},{"year":2014,"claim":"The crystal structure of YTHDC1-YTH bound to m6A RNA revealed the aromatic cage mechanism of methyl-group recognition and sequence-context selectivity (GG(m6A)C preference), transforming understanding of YTHDC1 from a generic splicing factor to an m6A-specific reader.","evidence":"X-ray crystallography, biochemical binding assays, PAR-CLIP-seq","pmids":["25242552"],"confidence":"High","gaps":["How m6A reading connects mechanistically to splicing regulation unknown","Full-length protein structure unavailable","Contribution of disordered regions to function undefined"]},{"year":2016,"claim":"The mechanistic basis of YTHDC1-dependent splicing was resolved: m6A-bound YTHDC1 recruits SRSF3 to promote exon inclusion while competitively excluding SRSF7/SRSF10, directly connecting m6A reading to splice-site choice at a transcriptome-wide scale.","evidence":"PAR-CLIP-seq, competitive in vitro pull-down of SRSF3 vs SRSF10, knockdown/rescue with m6A-binding-defective mutant","pmids":["26876937"],"confidence":"High","gaps":["Whether YTHDC1–SRSF3 interaction is direct or RNA-bridged not fully resolved","Structural basis of SRSF3/SRSF7 selectivity unknown","Contribution to alternative polyadenylation not yet examined"]},{"year":2017,"claim":"YTHDC1 was shown to mediate nuclear export of m6A-modified mRNAs through SRSF3 and the NXF1 export receptor, expanding its role beyond splicing to mRNA trafficking and explaining why m6A-marked transcripts accumulate in the nucleus upon YTHDC1 depletion.","evidence":"YTHDC1 knockdown with nuclear/cytoplasmic fractionation, m6A-seq, Co-IP of YTHDC1–SRSF3–NXF1 in HeLa cells","pmids":["28984244"],"confidence":"High","gaps":["Whether export function is separable from splicing function unclear","Role of ALYREF and other export adaptors not examined","Selectivity for specific m6A transcripts vs bulk effect unknown"]},{"year":2017,"claim":"YTHDC1 was found to read METTL16-deposited m6A marks on MAT2A mRNA to trigger its degradation, establishing that YTHDC1 also controls mRNA stability and participates in a SAM-sensing metabolic feedback loop.","evidence":"In vitro METTL16 methylation, YTHDC1 knockdown, MAT2A mRNA stability assays, 3′ UTR m6A site mutagenesis","pmids":["29262316"],"confidence":"High","gaps":["Degradation machinery recruited by YTHDC1 for MAT2A decay not identified","Generality of YTHDC1-mediated mRNA decay beyond MAT2A unclear","Whether nuclear or cytoplasmic decay pathway is involved unknown"]},{"year":2018,"claim":"Conditional knockout in mouse oocytes demonstrated that YTHDC1 is essential for gametogenesis and controls both alternative splicing and alternative polyadenylation in vivo, with m6A-binding ability required for rescue, firmly establishing its physiological necessity.","evidence":"Conditional Ythdc1 KO mouse, RNA-seq (splicing and APA), Co-IP with CPSF6/SRSF3/SRSF7, mutant rescue","pmids":["29799838"],"confidence":"High","gaps":["Relative contribution of splicing vs APA defects to phenotype unresolved","Whether YTHDC1 directly interacts with cleavage/polyadenylation machinery not tested biochemically"]},{"year":2021,"claim":"Two independent studies demonstrated that YTHDC1 silences retrotransposons (LINE1, ERVK, IAP) in embryonic stem cells by binding their m6A-modified transcripts and promoting SETDB1/KAP1-dependent H3K9me3 deposition, revealing a chromatin-regulatory function that maintains ESC identity and prevents reprogramming to a totipotent-like state.","evidence":"Conditional Ythdc1 KO ESCs, m6A-seq, RIP, H3K9me3 ChIP-seq, genetic epistasis (YTHDC1→SETDB1→H3K9me3), NCL–KAP1 complex analysis","pmids":["33658714","33886094"],"confidence":"High","gaps":["Mechanism by which m6A-RNA recruits SETDB1 to chromatin not fully delineated","Whether RNA acts in cis vs trans at retrotransposon loci unresolved","Generality beyond ESC context unknown"]},{"year":2022,"claim":"YTHDC1 was shown to suppress proximal alternative polyadenylation sites by interacting with FIP1L1 and blocking CPSF4 recruitment, with m6A binding promoting liquid-liquid phase separation of YTHDC1–FIP1L1, providing a mechanistic framework for the APA phenotypes observed in knockout models.","evidence":"APA analysis by RNA-seq, Co-IP of YTHDC1–FIP1L1, in vitro phase separation droplet assays","pmids":["36094741"],"confidence":"Medium","gaps":["Phase separation reconstitution done in vitro; in vivo relevance of droplets to APA regulation not confirmed","Whether FIP1L1 interaction requires m6A or is constitutive not fully resolved","Structural basis of YTHDC1–FIP1L1 interaction unknown"]},{"year":2023,"claim":"An m6A-independent function was uncovered: YTHDC1 promotes TopBP1–MRE11 interaction to activate ATR-mediated DNA damage repair, as demonstrated by rescue with m6A-binding-defective mutants, establishing a dual-function paradigm for YTHDC1.","evidence":"Co-IP (YTHDC1–TopBP1–MRE11), ATR activation assays, in vivo Ythdc1 KO/OE mice, m6A-binding-defective mutant rescue","pmids":["38177310"],"confidence":"Medium","gaps":["Whether YTHDC1 bridges TopBP1–MRE11 directly or through an RNA scaffold unknown","Relative contribution of m6A-dependent vs -independent DDR functions not quantified","Single lab finding awaiting independent replication"]},{"year":2023,"claim":"YTHDC1's post-translational regulation was further expanded: O-GlcNAcylation at Ser396 upon DNA damage promotes chromatin binding, phase separation, m6A-RNA association, and homologous recombination repair, showing that distinct PTMs tune YTHDC1 to different nuclear functions.","evidence":"Ser396 mutagenesis, RIP, FRAP, IRIF imaging, HR reporter assay, molecular dynamics simulations","pmids":["40242544"],"confidence":"Medium","gaps":["Writer/eraser enzymes for O-GlcNAcylation at this site not fully defined","Interplay between O-GlcNAcylation and tyrosine phosphorylation not examined","Single lab finding"]},{"year":2024,"claim":"A genome-protective pathway was defined in which YTHDC1 cooperates with the THO complex to bind chemically damaged RNA (m1A-containing), preventing R-loop accumulation and XPG-dependent conversion of RNA damage into DNA breaks, revealing that YTHDC1 reads not only m6A but also damage-modified nucleotides.","evidence":"In vitro m1A binding assays, Co-IP (YTHDC1–THOC), R-loop imaging, comet assay, XPG epistasis, RNA dealkylase rescue","pmids":["40037355"],"confidence":"High","gaps":["Whether m1A binding uses the same aromatic cage as m6A not structurally resolved","Quantitative contribution of YTHDC1 vs other repair pathways to genome stability unknown","Whether damaged RNA clearance is transcriptome-wide or locus-specific undetermined"]},{"year":2025,"claim":"Lysine lactylation at K82 by p300 under hypoxia was found to expand YTHDC1 nuclear condensates, protecting oncogenic mRNAs (BCL2, E2F2) from PAXT-exosome-mediated decay, establishing a metabolically responsive PTM–phase separation–mRNA stabilization axis.","evidence":"Lactylome MS, K82 mutagenesis, in vitro droplet assays, nuclear condensate imaging, RIP, PAXT interaction assays, in vivo RCC models","pmids":["40680722"],"confidence":"High","gaps":["Whether lactylation and O-GlcNAcylation cooperate or compete not examined","PAXT-exosome substrate selection rules in context of YTHDC1 condensates unknown","Generality beyond renal cell carcinoma not established"]},{"year":2025,"claim":"An m6A-independent protein-stabilization function was revealed: YTHDC1 uses its intrinsically disordered region to bind PPARγ and shield it from ARIH2-mediated ubiquitination and proteasomal degradation, expanding the functional repertoire of YTHDC1 beyond RNA metabolism.","evidence":"Co-IP and domain mapping (YTHDC1–PPARγ–ARIH2), ubiquitination assays, brown adipose tissue-specific Ythdc1 KO, m6A-binding-defective rescue","pmids":["40355558"],"confidence":"Medium","gaps":["Structural basis of IDR–PPARγ interaction undefined","Whether other transcription factors are similarly protected unknown","Single lab finding"]},{"year":null,"claim":"The full-length structure of YTHDC1 (including disordered regions) and the rules governing how PTMs, phase separation, and RNA/protein partner selection are integrated to allocate YTHDC1 among its many nuclear functions remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No full-length YTHDC1 structure available","Decision logic for m6A-dependent vs m6A-independent function allocation unknown","How phase separation properties are coordinated across multiple PTMs simultaneously is undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,6,7,8,9,13,14,37]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[12]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[6,23,43]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[2,3,5,6,7,13,36]},{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[5,6,34]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[6,7,8,9,23,26,28]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[34]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[30,36,37]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[13,14]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[17]}],"complexes":["YTHDC1–SRSF3–NXF1 export complex","YTHDC1–FIP1L1 APA regulatory complex","YTHDC1–THO complex"],"partners":["SRSF3","SRSF7","KHDRBS1","FIP1L1","NXF1","DDX5","ELAVL1","EMD"],"other_free_text":[]},"mechanistic_narrative":"YTHDC1 is a nuclear N6-methyladenosine (m6A) reader that orchestrates multiple co-transcriptional and post-transcriptional RNA processing events, including alternative splicing, alternative polyadenylation, mRNA nuclear export, mRNA stability, circRNA biogenesis, and microRNA maturation, while also performing m6A-independent functions in DNA damage repair and protein stabilization. Its YTH domain recognizes m6A through a Trp377/Trp428 aromatic cage with preferential binding to GG(m6A)C sequences, and structural water networks contribute to selectivity over unmethylated adenosine [PMID:25242552, PMID:26318451, PMID:34258996]. YTHDC1 promotes exon inclusion by recruiting SRSF3 while antagonizing SRSF7/SRSF10, facilitates nuclear export of m6A-modified mRNAs and circRNAs through an SRSF3–NXF1 axis, suppresses proximal polyadenylation by sequestering FIP1L1 from CPSF4, and silences retrotransposons by promoting SETDB1-dependent H3K9me3 at LINE1/ERVK loci [PMID:26876937, PMID:28984244, PMID:36094741, PMID:33658714]. Its activity is modulated by post-translational modifications—tyrosine phosphorylation by c-Abl/c-Src disperses nuclear condensates and abolishes splicing regulation, O-GlcNAcylation at Ser396 promotes chromatin binding and homologous recombination repair, and lysine lactylation at K82 enhances phase separation to protect oncogenic mRNAs from PAXT-exosome degradation [PMID:15175272, PMID:40242544, PMID:40680722]."},"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 m(6)A Reader YTHDC1 Regulates mRNA Splicing.","date":"2016","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/26876937","citation_count":1673,"is_preprint":false},{"pmid":"28984244","id":"PMC_28984244","title":"YTHDC1 mediates nuclear export of N6-methyladenosine methylated mRNAs.","date":"2017","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/28984244","citation_count":1037,"is_preprint":false},{"pmid":"25242552","id":"PMC_25242552","title":"Structural basis for selective binding of m6A RNA by the YTHDC1 YTH domain.","date":"2014","source":"Nature chemical biology","url":"https://pubmed.ncbi.nlm.nih.gov/25242552","citation_count":592,"is_preprint":false},{"pmid":"29799838","id":"PMC_29799838","title":"Nuclear m6A reader YTHDC1 regulates alternative polyadenylation and splicing during mouse oocyte development.","date":"2018","source":"PLoS 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role of lncRNA MEG3 on pyroptosis through interacting with EZH2 and YTHDC1 in postoperative cognitive dysfunction.","date":"2024","source":"Brain research bulletin","url":"https://pubmed.ncbi.nlm.nih.gov/39236791","citation_count":6,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":51735,"output_tokens":11721,"usd":0.16551},"stage2":{"model":"claude-opus-4-6","input_tokens":15907,"output_tokens":4565,"usd":0.29049},"total_usd":0.456,"stage1_batch_id":"msgbatch_01BparvgRZ9S2LMidvaoo86K","stage2_batch_id":"msgbatch_01NkBfv9SVZWthhS7j6mU6G3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2014,\n      \"finding\": \"Crystal structure of the YTHDC1 YTH domain in complex with m6A-containing RNA revealed the specific mode of m6A recognition, including an aromatic cage that captures the N6-methyl group and a selective binding pocket that confers preferential recognition of GG(m6A)C sequences.\",\n      \"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 — crystal structure with functional validation and transcriptome-wide binding data\",\n      \"pmids\": [\"25242552\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Structural comparison showed that YTHDC1 uniquely harbors a selective binding pocket for the nucleotide preceding m6A (preferring G), distinguishing it from other YTH domain proteins (YTHDF1, YTHDF2, YTHDF3, yeast Pho92), all of which use a conserved aromatic cage but lack the position-specific selectivity of YTHDC1.\",\n      \"method\": \"X-ray crystallography, isothermal titration calorimetry, binding affinity measurements\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — multiple crystal structures with quantitative binding data across family members\",\n      \"pmids\": [\"26318451\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"YTHDC1 (YT521-B) interacts with the splicing-associated scaffold attachment factor B (SAF-B) and Sam68, localizes to 5–20 large nuclear dots, and modulates alternative splice site selection in a concentration-dependent manner; the Src family kinase p59(fyn)-mediated tyrosine phosphorylation of Sam68 negatively regulates its association with YTHDC1 and dissolves these nuclear dots.\",\n      \"method\": \"Co-immunoprecipitation, in vivo splicing assays, overexpression of p59(fyn), deletion analysis, RNA in situ hybridization\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal interactions, functional splicing assays, kinase perturbation, replicated across multiple methods in one study\",\n      \"pmids\": [\"10564280\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"YTHDC1 (YT521-B) localizes to a novel subnuclear structure called YT bodies, which appear at the beginning of S-phase, disperse during mitosis, and are sensitive to actinomycin D (transcription inhibitor), suggesting association with transcriptionally active sites; the glutamic acid-rich N-terminal domain and the C-terminal glutamic acid/arginine-rich domain are required for YT body formation.\",\n      \"method\": \"Live-cell imaging, immunofluorescence, cell cycle synchronization, transcription inhibitor treatment, deletion analysis\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct localization experiments with functional consequence (cell-cycle dependence, transcription linkage)\",\n      \"pmids\": [\"10973987\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Emerin (nuclear membrane protein mutated in Emery-Dreifuss muscular dystrophy) directly binds the C-terminal functional domain of YTHDC1 (YT521-B), demonstrated by yeast two-hybrid, pull-down and BIAcore; emerin overexpression inhibits YTHDC1-dependent splice site selection in vivo, defining a bipartite emerin binding site for YTHDC1.\",\n      \"method\": \"Yeast two-hybrid, pull-down assay, BIAcore biomolecular interaction analysis, in vivo splicing assay\",\n      \"journal\": \"European journal of biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal binding methods plus functional splicing assay\",\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 YTHDC1 from YT bodies to the nucleoplasm into an insoluble form, and abolishes its ability to alter alternative splice site selection of IL-4 receptor, CD44, and SRp20.\",\n      \"method\": \"In vivo kinase assays, differential solubility fractionation, alternative splicing reporter assays, nuclear-cytoplasmic shuttling experiments\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — identified kinases, multiple substrates, functional splicing readout, subcellular localization consequence\",\n      \"pmids\": [\"15175272\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Nuclear m6A reader YTHDC1 promotes exon inclusion in targeted mRNAs by recruiting splicing factor SRSF3 while blocking SRSF7/SRSF10 binding; YTHDC1 facilitates SRSF3 nuclear speckle localization and RNA binding, and represses SRSF10 localization and binding; these effects require the m6A-binding ability of YTHDC1 and were mapped transcriptome-wide by PAR-CLIP-seq.\",\n      \"method\": \"PAR-CLIP-seq, in vitro pull-down (competitive binding of SRSF3 and SRSF10 to YTHDC1), knockdown/rescue with wild-type vs. m6A-binding-defective YTHDC1, nuclear speckle localization assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods, transcriptome-wide, rescue with separation-of-function mutant; highly cited foundational study\",\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; mechanistically, YTHDC1 interacts with splicing factor/nuclear export adaptor SRSF3 and facilitates RNA binding to both SRSF3 and the export receptor NXF1.\",\n      \"method\": \"YTHDC1 knockdown, nuclear/cytoplasmic fractionation, m6A-seq, Co-IP (YTHDC1–SRSF3–NXF1)\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KD with defined localization phenotype, reciprocal binding partners identified; highly cited\",\n      \"pmids\": [\"28984244\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"YTHDC1 reads METTL16-deposited m6A marks in the 3′ UTR of MAT2A mRNA to promote its degradation; when SAM is depleted, METTL16 methylation of MAT2A is reduced, YTHDC1-dependent decay is relieved, and MAT2A mRNA is stabilized, thus upregulating SAM synthesis as a feedback mechanism.\",\n      \"method\": \"In vitro methylation assays with recombinant METTL16, YTHDC1 knockdown, MAT2A mRNA stability assays, 3′ UTR mutagenesis of m6A target adenines\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — reconstituted in vitro methylation, mutagenesis, and cellular stability assays defining a feedback axis\",\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 in oocytes causes extensive alternative polyadenylation (altered 3′ UTR length) and massive alternative splicing defects; splicing defects are rescued by wild-type but not m6A-binding-deficient YTHDC1; YTHDC1 associates with pre-mRNA 3′ end processing factors CPSF6, SRSF3, and SRSF7.\",\n      \"method\": \"Conditional knockout mouse, RNA-seq, alternative splicing analysis, polyadenylation analysis, Co-IP (YTHDC1–CPSF6/SRSF3/SRSF7), rescue with separation-of-function mutant\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo KO with multiple transcriptome-wide readouts, protein interactions, and mutant rescue\",\n      \"pmids\": [\"29799838\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Atomistic simulations and X-ray crystallography show that the m6A methyl group is captured by the aromatic cage of YTHDC1 (Trp377/Trp428), the 3′ terminus nucleotides are stabilized by cation-π-π interactions, and the 5′ terminus remains flexible; the methyl group of m6A pre-organizes the RNA into a bound-like conformation, facilitating association.\",\n      \"method\": \"X-ray crystallography, atomistic molecular dynamics simulations, isothermal titration calorimetry\",\n      \"journal\": \"Journal of chemical theory and computation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure plus simulation and calorimetry with mechanistic interpretation\",\n      \"pmids\": [\"31670957\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Oncogene metadherin (MTDH) interacts with YTHDC1, Sam68, and T-STAR in nuclear speckles and influences alternative splice site selection of CD44 in a dose-dependent manner.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, CD44v5-luc minigene splicing reporter assay\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single Co-IP plus functional splicing reporter\",\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, approximately 5-fold stronger than the equivalent m6A RNA under the same conditions; crystal structures of YTHDC1 YTH in complex with N6mA-containing ssDNA showed recognition of methylated adenine in a single-stranded region flanked by duplexed DNA.\",\n      \"method\": \"Fluorescence polarization binding assay, X-ray crystallography (two structures)\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted in vitro binding assays plus two crystal structures\",\n      \"pmids\": [\"32663306\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"YTHDC1 is required for maintenance of mouse embryonic stem cells; deletion triggers reprogramming to a 2C-like state; mechanistically, YTHDC1 binds m6A-modified retrotransposon (IAP, ERVK, LINE1) transcripts and its depletion results in reactivation of these elements 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 ESCs, RNA-seq, m6A-seq, YTHDC1 RIP, H3K9me3 ChIP-seq, genetic epistasis (YTHDC1 → SETDB1 → H3K9me3)\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal genomic methods, genetic epistasis, replicated across ESC and ICM contexts\",\n      \"pmids\": [\"33658714\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"YTHDC1 recognizes m6A on LINE1 RNAs in the nucleus, regulates the formation of the LINE1–nucleolin (NCL) RNA scaffold partnership, promotes chromatin recruitment of KAP1, and is required for H3K9me3 establishment on 2C-related retrotransposons; YTHDC1 is also required for sufficient rRNA synthesis in ESCs.\",\n      \"method\": \"Conditional Ythdc1 KO in ESCs, RIP, Co-IP (LINE1 RNA–NCL–KAP1 complex), H3K9me3 ChIP-seq, rRNA synthesis assay\",\n      \"journal\": \"Protein & cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods, consistent with independent Nature paper on same topic\",\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; genetic deletion of Ythdc1 blocks AML development and LSC self-renewal in vivo; haploinsufficiency reduces LSC but not normal HSC self-renewal.\",\n      \"method\": \"Conditional Ythdc1 KO mouse models, in vivo AML transplantation, YTHDC1 knockdown in primary AML cells, MCM4 target identification\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo genetic models with defined mechanistic target (MCM4) and quantitative stem cell assays\",\n      \"pmids\": [\"34255814\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Trp428 of YTHDC1 switches between two conformational states to build and dismantle the aromatic cage for m6A binding; Met438 and Ser378 modulate binding enthalpy-entropy compensation without changing affinity; Thr379Val mutation significantly reduces thermal stability and m6A binding capability; a structural water molecule synergistically binds YTHDC1 with m6A as a hydrogen-bond hub.\",\n      \"method\": \"Atomistic MD simulations, site-directed mutagenesis, thermal shift assay, isothermal titration calorimetry, free energy calculations\",\n      \"journal\": \"Journal of chemical theory and computation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — mutagenesis plus biophysical experiments with quantitative mechanistic analysis\",\n      \"pmids\": [\"33472367\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"YTHDC1 interacts with ELAVL1/HuR to modulate SQSTM1 mRNA stability in the nucleus; YTHDC1 knockdown causes SQSTM1 mRNA degradation in the nucleus, blocking autophagic flux; overexpression of YTHDC1 rescues the autophagic flux blockade induced by high glucose in keratinocytes.\",\n      \"method\": \"Co-IP (YTHDC1–ELAVL1), RIP-qPCR (YTHDC1 binding to SQSTM1 mRNA), YTHDC1 KD/OE, autophagic flux assays (LC3, autophagosome imaging), in vivo Ythdc1/Sqstm1 knockdown\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP and RIP plus functional autophagic readout; single lab\",\n      \"pmids\": [\"34657574\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Molecular dynamics and NMR analysis of the YTHDC1 YTH–m6A RNA complex revealed that structured water molecules surrounding the bound RNA contribute to m6A selectivity; bulk water intrusions disrupt unmethylated adenosine binding; the 5′-G preference of YTHDC1 is partially mediated by a water-mediated hydrogen bond network between the guanosine 2-amino group and binding pocket residues; D479A mutation disrupts this water network.\",\n      \"method\": \"MD simulations, NMR spectroscopy, isothermal titration calorimetry\",\n      \"journal\": \"The journal of physical chemistry. B\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — combined MD, NMR, and ITC with mutagenesis validation\",\n      \"pmids\": [\"34258996\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"YTHDC1 facilitates biogenesis of mature miR-30d via m6A-mediated regulation of mRNA stability; mature miR-30d then inhibits aerobic glycolysis by reducing SLC2A1 and HK1 expression through targeting transcription factor RUNX1.\",\n      \"method\": \"MeRIP, RIP, RNA stability assay, miRNA maturation analysis, luciferase reporter assay\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single lab, RIP and stability assays without reconstitution\",\n      \"pmids\": [\"34021267\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"NMR solution structure of the m6A-modified AUCG tetraloop hairpin of Xist A-repeats showed that m6A extends 5′ stacking of the helical stem; crystal structure of YTHDC1 bound to the (m6A)UCG tetraloop showed recognition in single-stranded conformation requiring local unfolding of the upper stem; fluorescence quenching confirmed that binding requires local stem unfolding.\",\n      \"method\": \"NMR structure determination, X-ray crystallography, fluorescence quenching experiments\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — two independent structural methods plus biophysical validation\",\n      \"pmids\": [\"35166835\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Nuclear AURKA disrupts binding of SRSF3 to YTHDC1 (blocking m6A-YTHDC1-SRSF3-dependent RBM4-FL production) and instead recruits hnRNP K to YTHDC1, creating an m6A-YTHDC1-hnRNP K complex that promotes exon skipping to produce the oncogenic RBM4-S isoform; AURKA nuclear translocation is required but its kinase activity is not.\",\n      \"method\": \"Co-IP (AURKA–YTHDC1–SRSF3/hnRNP K complexes), alternative splicing analysis, nuclear translocation blocking experiments, kinase-dead mutants\",\n      \"journal\": \"Signal transduction and targeted therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP plus functional splicing readout; single lab\",\n      \"pmids\": [\"35361747\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SRSF3 binding to YTHDC1 is regulated by the phosphorylation status of SRSF3's arginine/serine-rich (RS) domain; dephosphorylation-mimic serine-to-alanine mutants of SRSF3 revealed multiple phosphorylation positions; YTHDC1 binding involves both YTHDC1 N- and C-terminal residues as well as the RS domain and additional regions of SRSF3.\",\n      \"method\": \"Co-immunoprecipitation with deletion mutants, dephosphorylation-mimic mutagenesis (S→A), domain mapping\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — multiple mutants and domain mapping via Co-IP; single lab\",\n      \"pmids\": [\"35563766\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"YTHDC1 suppresses proximal alternative polyadenylation (APA) sites to produce longer 3′ UTR transcripts; mechanistically, YTHDC1 directly interacts with 3′ end processing factor FIP1L1 and interferes with its ability to recruit CPSF4; m6A binding promotes liquid-liquid phase separation of YTHDC1 and FIP1L1.\",\n      \"method\": \"APA analysis (RNA-seq), Co-IP (YTHDC1–FIP1L1), RIP, phase separation assays (in vitro droplet formation), YTHDC1 KD\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — protein interaction, APA phenotype, and phase separation assay in single study\",\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 lower SMAD3 protein levels, impairing TGF-β-induced EMT and TNBC cell migration; m6A-binding-defective YTHDC1 cannot rescue these phenotypes.\",\n      \"method\": \"YTHDC1 KO/rescue with m6A-binding mutant, nuclear/cytoplasmic fractionation, RIP-seq, m6A-seq, cell migration/invasion assays, in vivo metastasis model\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — separation-of-function mutant rescue, fractionation, multiple transcriptome analyses; single lab\",\n      \"pmids\": [\"35966596\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"YTHDC1 binding to m6A sites on HIV-1 transcripts (in a METTL3-dependent manner) regulates viral RNA biogenesis: YTHDC1 knockdown increases unspliced and incompletely spliced HIV-1 RNAs, reduces Env and Vpu protein expression, leads to incorporation of unprocessed gp160 into virions, and reduces virion infectivity.\",\n      \"method\": \"YTHDC1 knockdown, HIV-1 RNA splicing analysis, viral protein Western blot, RIP (YTHDC1 binding to HIV-1 transcripts), viral infectivity assay\",\n      \"journal\": \"Retrovirology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — clean KD with multiple defined phenotypes; METTL3-dependence established\",\n      \"pmids\": [\"35101069\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"YTHDC1 is an essential regulator of satellite cell (muscle stem cell) activation and proliferation; YTHDC1 depletion nearly abolishes regenerative capacity; YTHDC1 regulates mRNA splicing and nuclear export of target transcripts; hnRNPG is identified as a bona fide YTHDC1 interacting partner in myoblasts.\",\n      \"method\": \"Inducible Ythdc1 KO in satellite cells, LACE-seq (transcriptome-wide binding), splicing analysis, nuclear export analysis, Co-IP interactome mapping\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo KO, transcriptome-wide target identification, multiple mechanistic readouts, protein partner identified\",\n      \"pmids\": [\"36892464\"],\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, leading to elevated FSP1 protein and ferroptosis resistance in lung cancer.\",\n      \"method\": \"RIP (YTHDC1–FSP1 mRNA), APA analysis, Co-IP (YTHDC1–CSTF3), RNA stability assays, HuR interaction assays, YTHDC1 KD rescue experiments\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — multiple interaction assays and APA readout; single lab\",\n      \"pmids\": [\"37903990\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"YTHDC1 and the RNA helicase DDX5 interact directly and cooperate to promote the production of a common subset of circRNAs in rhabdomyosarcoma cells through the back-splicing reaction; DDX5 acts as a co-factor of the m6A regulatory network downstream of YTHDC1.\",\n      \"method\": \"Co-IP (YTHDC1–DDX5), circRNA-seq, YTHDC1/DDX5 depletion, back-splicing assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP plus functional circRNA production phenotype; single lab\",\n      \"pmids\": [\"37019933\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"YTHDC1 regulates muscle stem cell quiescence exit via PI4K-Akt-mTOR signaling; Ythdc1-null satellite cells cannot exit quiescence; mechanistically, YTHDC1 binds m6A-modified Pi4k2a and Pi4kb mRNAs to regulate their alternative splicing, sustaining PI4K-Akt-mTOR pathway activity.\",\n      \"method\": \"Conditional Ythdc1 KO in satellite cells, phospho-signaling assays (p-Akt, p-S6), splicing analysis of Pi4k2a/Pi4kb, RIP\",\n      \"journal\": \"Cell proliferation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo KO with pathway-level signaling readout and target mRNA splicing linkage\",\n      \"pmids\": [\"36722312\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"YTHDC1 delays stress-induced pulmonary senescence and fibrosis through an m6A-independent mechanism: it promotes interaction between TopBP1 and MRE11, thereby activating ATR and facilitating DNA damage repair; this function is independent of m6A-binding ability.\",\n      \"method\": \"Co-IP (YTHDC1–TopBP1–MRE11), ATR activation assays, YTHDC1 KO/OE in mice, rescue with m6A-binding-defective YTHDC1 mutant\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — protein complex identified by Co-IP, separation-of-function rescue, in vivo model; single lab\",\n      \"pmids\": [\"38177310\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"YTHDC1 inhibits influenza A virus NS segment splicing by binding to the NS 3′ splicing site in an m6A-dependent manner, thereby promoting viral replication and pathogenicity; YTHDC1 levels are enhanced by IAV infection, and its depletion reduces viral replication.\",\n      \"method\": \"YTHDC1 KD/OE, NS mRNA splicing analysis, RIP (YTHDC1–NS RNA), in vivo IAV infection model\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — RIP confirming binding plus splicing phenotype in vitro and in vivo\",\n      \"pmids\": [\"37053288\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"YTHDC1 promotes the nuclear export of m6A-modified circRNAs (e.g., circKcnk9) in an m6A-dependent manner; siYTHDC1 increases nuclear staining of circKcnk9, which is reversed by wild-type but not m6A-binding-defective YTHDC1.\",\n      \"method\": \"RNA FISH, siRNA KD, YTHDC1 wild-type vs. mutant rescue, YTHDC1 RIP on circKcnk9\",\n      \"journal\": \"Molecular pain\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — FISH-based localization with separation-of-function rescue; single lab\",\n      \"pmids\": [\"36443649\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"YTHDC1 regulates the splicing of HOXB-AS3 precursor RNA via m6A modification, upregulating the NR_033205.1 spliceosome isoform, which accelerates leukemic stem cell self-renewal and AML progression.\",\n      \"method\": \"m6A-MeRIP, RIP (YTHDC1 binding to HOXB-AS3), splicing analysis, KD/OE functional assays in THP-1 and mouse models\",\n      \"journal\": \"International journal of biological macromolecules\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — RIP plus splicing analysis and in vivo xenograft; single lab\",\n      \"pmids\": [\"36906205\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"YTHDC1 binds to the transcription start sites of TP53 and other DNA damage response genes, promoting their transcriptional elongation in an m6A-independent manner; YTHDC1 also reduces intron retention in m6A-dependent fashion for key DDR factors; YTHDC1 deficiency causes genomic instability.\",\n      \"method\": \"CRISPR-KO screen, YTHDC1 ChIP (TSS binding), RNA-seq (intron retention analysis), m6A-dependent vs -independent rescue experiments\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP evidence for TSS binding, RNA-seq intron retention, two mechanistically distinct YTHDC1 functions defined; single lab\",\n      \"pmids\": [\"38951610\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Depletion of YTHDC1 in cardiomyocytes causes dilated cardiomyopathy; YTHDC1 binds m6A-modified Titin mRNA and its depletion results in aberrant splicing of Titin, leading to disordered sarcomere arrangement and decreased cardiomyocyte contractility.\",\n      \"method\": \"Cardiac-specific conditional Ythdc1 KO, m6A-MeRIP-seq, RIP-seq, mRNA-seq, sarcomere imaging\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo cardiac KO with multiple transcriptome methods identifying Titin as target; single lab\",\n      \"pmids\": [\"34716659\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"YTHDC1 O-GlcNAcylation at Ser396 (mediated upon DNA damage) promotes YTHDC1 chromatin binding, IRIF formation, m6A RNA binding, and liquid-liquid phase separation of YTHDC1 condensates at damage sites; O-GlcNAcylated YTHDC1 promotes homologous recombination-mediated repair and recruitment of Rad51.\",\n      \"method\": \"Site-directed mutagenesis (Ser396), RIP (m6A binding), Co-IP, FRAP, IRIF immunofluorescence, HR reporter assay, molecular dynamics simulations\",\n      \"journal\": \"Fundamental research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mutagenesis of modification site, multiple functional assays, and simulations; single lab\",\n      \"pmids\": [\"40242544\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"YTHDC1 interacts with the THO complex (THOC) and, in addition to binding m6A, binds chemically damaged N1-methyladenosine (m1A) in RNA; without YTHDC1 or THOC, damaged nuclear RNA accumulates R-loops that are converted to DNA breaks (RDIBs) by the XPG nuclease; an RNA-specific dealkylase rescues the DNA break phenotype, establishing that RNA damage drives genome instability.\",\n      \"method\": \"In vitro binding assays (m1A vs m6A), Co-IP (YTHDC1–THOC), R-loop immunofluorescence, comet assay, XPG epistasis, RNA dealkylase rescue\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — reconstituted binding, genetic epistasis (XPG, dealkylase rescue), mechanistic pathway defined\",\n      \"pmids\": [\"40037355\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"DDX41 promotes YTHDC1 recruitment to m6A-methylated R-loops by facilitating the interaction between METTL3 and YTHDC1; DDX41 loss (KO or patient mutations R525H/Y259C) impairs this interaction, leading to increased m6A-RNA methylated R-loops and genomic instability.\",\n      \"method\": \"DDX41 KO and knock-in cell lines, Co-IP (DDX41–METTL3–YTHDC1 complex), m6A quantification, R-loop immunofluorescence, primary MDS patient samples\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — protein complex defined by Co-IP, genetic models, and clinical validation; single lab\",\n      \"pmids\": [\"38514771\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"YTHDC1 binds m6A-modified KMT2C mRNA to stabilize it; KMT2C catalyzes H3K4 methylation required for expression of DNA damage response genes; YTHDC1 knockdown decreases YTHDC1 protein stability, reduces KMT2C levels, and attenuates DDR gene expression, sensitizing B-ALL cells to chemotherapy.\",\n      \"method\": \"RIP-qPCR (YTHDC1–KMT2C mRNA), RNA stability assay, H3K4 ChIP, YTHDC1/KMT2C KD, B-ALL xenograft model, molecular docking for inhibitor identification\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — RIP and stability data plus epigenetic readout; single lab\",\n      \"pmids\": [\"39501105\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"YTHDC1 interacts with HP1BP3 (a nuclear RNA binding protein involved in microRNA maturation); YTHDC1 deficiency in HSCs causes significant alterations in microRNA levels (including mir-125b, mir-99b, let-7e); overexpression of these miRNAs partially rescues YTHDC1-null HSC functional defects, establishing a YTHDC1–HP1BP3–microRNA maturation axis for HSC maintenance.\",\n      \"method\": \"Conditional Ythdc1 KO, Ythdc1/Mettl3 double KO, Co-IP (YTHDC1–HP1BP3), small RNA-seq, miRNA rescue experiments\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo KO, protein interaction, and miRNA rescue define the axis; single lab\",\n      \"pmids\": [\"39414764\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"KAP1 (TRIM28) forms a complex with YTHDC1 and METTL3 to stabilize m6A-modified MYCN mRNA; KAP1 depletion decreases YTHDC1 protein stability and promotes MYCN mRNA degradation; MYCN in turn transcriptionally activates KAP1, forming a positive feedback loop.\",\n      \"method\": \"Co-IP/mass spectrometry (KAP1–YTHDC1–METTL3 complex), RIP-qPCR, RNA stability assay, Western blot, xenograft model\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — complex identified by MS/Co-IP plus functional stability assay; single lab\",\n      \"pmids\": [\"38745192\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Lysine lactylation of YTHDC1 at K82 (mediated by p300 under hypoxia) increases YTHDC1 phase separation and expansion of nuclear condensates, protecting oncogenic BCL2 and E2F2 mRNAs from degradation by the PAXT-exosome complex in renal cell carcinoma cells.\",\n      \"method\": \"Lactylome mass spectrometry, K82 mutagenesis, phase separation assays (in vitro droplets, nuclear condensate imaging), RIP (YTHDC1–BCL2/E2F2 mRNA), PAXT-exosome interaction assays, in vivo RCC models\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — PTM site identified by proteomics, site-specific mutagenesis, phase separation reconstitution, target mRNA protection mechanism; multiple methods in one study\",\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), protecting PPARγ from ARIH2 E3 ubiquitin ligase-mediated ubiquitination and proteasomal degradation; the ARIH2 RING2 domain is essential for PPARγ degradation, and the PPARγ A/B domain mediates the interaction with ARIH2; this function is independent of YTHDC1's m6A-binding ability.\",\n      \"method\": \"Co-IP (YTHDC1–PPARγ–ARIH2), domain mapping, ubiquitination assays, Ythdc1 KO in brown adipose tissue, m6A-binding-defective YTHDC1 rescue\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — protein-protein interaction, ubiquitination mechanism, in vivo KO, separation-of-function rescue; single lab\",\n      \"pmids\": [\"40355558\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Phase-separating YTHDC1 forms a nuclear pore complex with SRSF3, ALYREF, and exportin-5 (XPO5) to promote nuclear export of m6A-modified lncRNA lnc668; this process requires YTHDC1 phase separation and is dependent on METTL3-mediated m6A modification of lnc668.\",\n      \"method\": \"Co-IP (YTHDC1–SRSF3–ALYREF–XPO5), phase separation assays, FISH (nuclear/cytoplasmic lnc668), MeRIP, YTHDC1 KD in fibrosis models\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — nuclear export complex defined by Co-IP and FISH; phase separation link; single lab\",\n      \"pmids\": [\"40221424\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Structure-based medicinal chemistry yielded YTHDC1 inhibitor compound 40 (Kd = 49 nM), validated by a 1.6 Å crystal structure of the complex; compound 40 is selective over cytoplasmic YTHDF1-3 and YTHDC2, shows antiproliferative activity against AML cell lines, and engages YTHDC1 in cells (confirmed by CETSA).\",\n      \"method\": \"X-ray crystallography (1.6 Å), biochemical binding assay, selectivity panel, antiproliferative assay, cellular thermal shift assay (CETSA)\",\n      \"journal\": \"Journal of medicinal chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure plus cellular target engagement validation; selectivity demonstrated\",\n      \"pmids\": [\"38787793\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"YTHDC1 (YT521) was identified as an RA301 (Sam68 paralog) binding protein by yeast two-hybrid screening; far Western blot showed that YT521 protein interacts with RA301, and also with splicing factors SC35 and SF2, suggesting a role as an RNA splicing-related protein; YT521 mRNA is induced by hypoxia/reoxygenation through reactive oxygen species.\",\n      \"method\": \"Yeast two-hybrid screening, far Western blot (YT521–RA301, SC35, SF2 interactions)\",\n      \"journal\": \"Brain research. Molecular brain research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — far Western interaction data; early foundational identification study\",\n      \"pmids\": [\"9473574\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"YTHDC1 is a nuclear m6A RNA reader whose YTH domain selectively recognizes N6-methyladenosine (especially in GG(m6A)C contexts) via an aromatic cage, and uses this binding to regulate multiple steps of RNA metabolism: it promotes exon inclusion by recruiting SRSF3 and blocking SRSF7/SRSF10; facilitates mRNA nuclear export via an SRSF3–NXF1 axis; suppresses proximal APA sites by interacting with FIP1L1/CPSF4; stabilizes or destabilizes specific target mRNAs (e.g., SQSTM1, MAT2A, KMT2C) in concert with partners such as ELAVL1/HuR; silences retrotransposons by binding m6A-modified LINE1/ERVK RNAs and promoting SETDB1-dependent H3K9me3; undergoes post-translational regulation (tyrosine phosphorylation by c-Abl/c-Src, O-GlcNAcylation at Ser396, lysine lactylation at K82) that modulates its localization, m6A-binding capacity, and phase-separation into nuclear condensates; and also functions in an m6A-independent manner to promote DNA damage repair (by facilitating TopBP1–MRE11–ATR signaling and cooperating with the THO complex to prevent RNA-damage-induced DNA breaks) and PPARγ stabilization.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"YTHDC1 is a nuclear N6-methyladenosine (m6A) reader that orchestrates multiple co-transcriptional and post-transcriptional RNA processing events, including alternative splicing, alternative polyadenylation, mRNA nuclear export, mRNA stability, circRNA biogenesis, and microRNA maturation, while also performing m6A-independent functions in DNA damage repair and protein stabilization. Its YTH domain recognizes m6A through a Trp377/Trp428 aromatic cage with preferential binding to GG(m6A)C sequences, and structural water networks contribute to selectivity over unmethylated adenosine [PMID:25242552, PMID:26318451, PMID:34258996]. YTHDC1 promotes exon inclusion by recruiting SRSF3 while antagonizing SRSF7/SRSF10, facilitates nuclear export of m6A-modified mRNAs and circRNAs through an SRSF3–NXF1 axis, suppresses proximal polyadenylation by sequestering FIP1L1 from CPSF4, and silences retrotransposons by promoting SETDB1-dependent H3K9me3 at LINE1/ERVK loci [PMID:26876937, PMID:28984244, PMID:36094741, PMID:33658714]. Its activity is modulated by post-translational modifications—tyrosine phosphorylation by c-Abl/c-Src disperses nuclear condensates and abolishes splicing regulation, O-GlcNAcylation at Ser396 promotes chromatin binding and homologous recombination repair, and lysine lactylation at K82 enhances phase separation to protect oncogenic mRNAs from PAXT-exosome degradation [PMID:15175272, PMID:40242544, PMID:40680722].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Initial identification of YTHDC1 as a nuclear splicing-associated factor established that it interacts with Sam68 family members and classical SR splicing factors, placing it at the intersection of RNA binding and pre-mRNA processing.\",\n      \"evidence\": \"Yeast two-hybrid screen and far Western blotting in rat brain cDNA library\",\n      \"pmids\": [\"9473574\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Interaction with SC35/SF2 shown only by far Western without reciprocal validation\", \"No direct RNA binding or m6A recognition yet known\", \"Functional consequence for splicing not demonstrated\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Demonstration that YTHDC1 modulates alternative splice site selection and that its activity is regulated by Src-family kinase phosphorylation of partner Sam68 established YTHDC1 as a functional splicing regulator whose nuclear organization is dynamically controlled.\",\n      \"evidence\": \"Co-immunoprecipitation, in vivo splicing reporters, p59(fyn) kinase perturbation in mammalian cells\",\n      \"pmids\": [\"10564280\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"RNA substrates not identified transcriptome-wide\", \"Direct RNA-binding activity not yet shown\", \"Whether YTHDC1 itself is a kinase substrate unknown\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Discovery that YTHDC1 concentrates in novel cell-cycle-regulated nuclear bodies (YT bodies) that depend on active transcription linked its function to transcriptionally active chromatin and defined the domain architecture required for condensate formation.\",\n      \"evidence\": \"Live-cell imaging, actinomycin D treatment, cell cycle synchronization, deletion analysis\",\n      \"pmids\": [\"10973987\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular composition of YT bodies unknown\", \"Relationship to known nuclear bodies (speckles, paraspeckles) unclear\", \"Mechanism of cell-cycle regulation undefined\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Identification of c-Abl and c-Src as direct kinases that phosphorylate YTHDC1, dispersing it from YT bodies and abolishing its splicing activity, established that tyrosine phosphorylation is a major switch controlling YTHDC1 nuclear organization and function.\",\n      \"evidence\": \"In vivo kinase assays, differential solubility fractionation, splicing reporters for IL-4R/CD44/SRp20\",\n      \"pmids\": [\"15175272\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific tyrosine residues phosphorylated not mapped\", \"Physiological signals triggering phosphorylation unknown\", \"Whether phosphorylation affects RNA binding directly untested\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"The crystal structure of YTHDC1-YTH bound to m6A RNA revealed the aromatic cage mechanism of methyl-group recognition and sequence-context selectivity (GG(m6A)C preference), transforming understanding of YTHDC1 from a generic splicing factor to an m6A-specific reader.\",\n      \"evidence\": \"X-ray crystallography, biochemical binding assays, PAR-CLIP-seq\",\n      \"pmids\": [\"25242552\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How m6A reading connects mechanistically to splicing regulation unknown\", \"Full-length protein structure unavailable\", \"Contribution of disordered regions to function undefined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"The mechanistic basis of YTHDC1-dependent splicing was resolved: m6A-bound YTHDC1 recruits SRSF3 to promote exon inclusion while competitively excluding SRSF7/SRSF10, directly connecting m6A reading to splice-site choice at a transcriptome-wide scale.\",\n      \"evidence\": \"PAR-CLIP-seq, competitive in vitro pull-down of SRSF3 vs SRSF10, knockdown/rescue with m6A-binding-defective mutant\",\n      \"pmids\": [\"26876937\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether YTHDC1–SRSF3 interaction is direct or RNA-bridged not fully resolved\", \"Structural basis of SRSF3/SRSF7 selectivity unknown\", \"Contribution to alternative polyadenylation not yet examined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"YTHDC1 was shown to mediate nuclear export of m6A-modified mRNAs through SRSF3 and the NXF1 export receptor, expanding its role beyond splicing to mRNA trafficking and explaining why m6A-marked transcripts accumulate in the nucleus upon YTHDC1 depletion.\",\n      \"evidence\": \"YTHDC1 knockdown with nuclear/cytoplasmic fractionation, m6A-seq, Co-IP of YTHDC1–SRSF3–NXF1 in HeLa cells\",\n      \"pmids\": [\"28984244\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether export function is separable from splicing function unclear\", \"Role of ALYREF and other export adaptors not examined\", \"Selectivity for specific m6A transcripts vs bulk effect unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"YTHDC1 was found to read METTL16-deposited m6A marks on MAT2A mRNA to trigger its degradation, establishing that YTHDC1 also controls mRNA stability and participates in a SAM-sensing metabolic feedback loop.\",\n      \"evidence\": \"In vitro METTL16 methylation, YTHDC1 knockdown, MAT2A mRNA stability assays, 3′ UTR m6A site mutagenesis\",\n      \"pmids\": [\"29262316\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Degradation machinery recruited by YTHDC1 for MAT2A decay not identified\", \"Generality of YTHDC1-mediated mRNA decay beyond MAT2A unclear\", \"Whether nuclear or cytoplasmic decay pathway is involved unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Conditional knockout in mouse oocytes demonstrated that YTHDC1 is essential for gametogenesis and controls both alternative splicing and alternative polyadenylation in vivo, with m6A-binding ability required for rescue, firmly establishing its physiological necessity.\",\n      \"evidence\": \"Conditional Ythdc1 KO mouse, RNA-seq (splicing and APA), Co-IP with CPSF6/SRSF3/SRSF7, mutant rescue\",\n      \"pmids\": [\"29799838\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of splicing vs APA defects to phenotype unresolved\", \"Whether YTHDC1 directly interacts with cleavage/polyadenylation machinery not tested biochemically\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Two independent studies demonstrated that YTHDC1 silences retrotransposons (LINE1, ERVK, IAP) in embryonic stem cells by binding their m6A-modified transcripts and promoting SETDB1/KAP1-dependent H3K9me3 deposition, revealing a chromatin-regulatory function that maintains ESC identity and prevents reprogramming to a totipotent-like state.\",\n      \"evidence\": \"Conditional Ythdc1 KO ESCs, m6A-seq, RIP, H3K9me3 ChIP-seq, genetic epistasis (YTHDC1→SETDB1→H3K9me3), NCL–KAP1 complex analysis\",\n      \"pmids\": [\"33658714\", \"33886094\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which m6A-RNA recruits SETDB1 to chromatin not fully delineated\", \"Whether RNA acts in cis vs trans at retrotransposon loci unresolved\", \"Generality beyond ESC context unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"YTHDC1 was shown to suppress proximal alternative polyadenylation sites by interacting with FIP1L1 and blocking CPSF4 recruitment, with m6A binding promoting liquid-liquid phase separation of YTHDC1–FIP1L1, providing a mechanistic framework for the APA phenotypes observed in knockout models.\",\n      \"evidence\": \"APA analysis by RNA-seq, Co-IP of YTHDC1–FIP1L1, in vitro phase separation droplet assays\",\n      \"pmids\": [\"36094741\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Phase separation reconstitution done in vitro; in vivo relevance of droplets to APA regulation not confirmed\", \"Whether FIP1L1 interaction requires m6A or is constitutive not fully resolved\", \"Structural basis of YTHDC1–FIP1L1 interaction unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"An m6A-independent function was uncovered: YTHDC1 promotes TopBP1–MRE11 interaction to activate ATR-mediated DNA damage repair, as demonstrated by rescue with m6A-binding-defective mutants, establishing a dual-function paradigm for YTHDC1.\",\n      \"evidence\": \"Co-IP (YTHDC1–TopBP1–MRE11), ATR activation assays, in vivo Ythdc1 KO/OE mice, m6A-binding-defective mutant rescue\",\n      \"pmids\": [\"38177310\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether YTHDC1 bridges TopBP1–MRE11 directly or through an RNA scaffold unknown\", \"Relative contribution of m6A-dependent vs -independent DDR functions not quantified\", \"Single lab finding awaiting independent replication\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"YTHDC1's post-translational regulation was further expanded: O-GlcNAcylation at Ser396 upon DNA damage promotes chromatin binding, phase separation, m6A-RNA association, and homologous recombination repair, showing that distinct PTMs tune YTHDC1 to different nuclear functions.\",\n      \"evidence\": \"Ser396 mutagenesis, RIP, FRAP, IRIF imaging, HR reporter assay, molecular dynamics simulations\",\n      \"pmids\": [\"40242544\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Writer/eraser enzymes for O-GlcNAcylation at this site not fully defined\", \"Interplay between O-GlcNAcylation and tyrosine phosphorylation not examined\", \"Single lab finding\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"A genome-protective pathway was defined in which YTHDC1 cooperates with the THO complex to bind chemically damaged RNA (m1A-containing), preventing R-loop accumulation and XPG-dependent conversion of RNA damage into DNA breaks, revealing that YTHDC1 reads not only m6A but also damage-modified nucleotides.\",\n      \"evidence\": \"In vitro m1A binding assays, Co-IP (YTHDC1–THOC), R-loop imaging, comet assay, XPG epistasis, RNA dealkylase rescue\",\n      \"pmids\": [\"40037355\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether m1A binding uses the same aromatic cage as m6A not structurally resolved\", \"Quantitative contribution of YTHDC1 vs other repair pathways to genome stability unknown\", \"Whether damaged RNA clearance is transcriptome-wide or locus-specific undetermined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Lysine lactylation at K82 by p300 under hypoxia was found to expand YTHDC1 nuclear condensates, protecting oncogenic mRNAs (BCL2, E2F2) from PAXT-exosome-mediated decay, establishing a metabolically responsive PTM–phase separation–mRNA stabilization axis.\",\n      \"evidence\": \"Lactylome MS, K82 mutagenesis, in vitro droplet assays, nuclear condensate imaging, RIP, PAXT interaction assays, in vivo RCC models\",\n      \"pmids\": [\"40680722\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether lactylation and O-GlcNAcylation cooperate or compete not examined\", \"PAXT-exosome substrate selection rules in context of YTHDC1 condensates unknown\", \"Generality beyond renal cell carcinoma not established\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"An m6A-independent protein-stabilization function was revealed: YTHDC1 uses its intrinsically disordered region to bind PPARγ and shield it from ARIH2-mediated ubiquitination and proteasomal degradation, expanding the functional repertoire of YTHDC1 beyond RNA metabolism.\",\n      \"evidence\": \"Co-IP and domain mapping (YTHDC1–PPARγ–ARIH2), ubiquitination assays, brown adipose tissue-specific Ythdc1 KO, m6A-binding-defective rescue\",\n      \"pmids\": [\"40355558\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of IDR–PPARγ interaction undefined\", \"Whether other transcription factors are similarly protected unknown\", \"Single lab finding\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The full-length structure of YTHDC1 (including disordered regions) and the rules governing how PTMs, phase separation, and RNA/protein partner selection are integrated to allocate YTHDC1 among its many nuclear functions remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No full-length YTHDC1 structure available\", \"Decision logic for m6A-dependent vs m6A-independent function allocation unknown\", \"How phase separation properties are coordinated across multiple PTMs simultaneously is undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 6, 7, 8, 9, 13, 14, 37]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [12]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [6, 23, 43]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [2, 3, 5, 6, 7, 13, 36]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [5, 6, 34]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [6, 7, 8, 9, 23, 26, 28]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [34]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [30, 36, 37]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [13, 14]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [17]}\n    ],\n    \"complexes\": [\n      \"YTHDC1–SRSF3–NXF1 export complex\",\n      \"YTHDC1–FIP1L1 APA regulatory complex\",\n      \"YTHDC1–THO complex\"\n    ],\n    \"partners\": [\n      \"SRSF3\",\n      \"SRSF7\",\n      \"KHDRBS1\",\n      \"FIP1L1\",\n      \"NXF1\",\n      \"DDX5\",\n      \"ELAVL1\",\n      \"EMD\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}