{"gene":"CDYL","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":2017,"finding":"CDYL acts as a crotonyl-CoA hydratase, converting crotonyl-CoA to β-hydroxybutyryl-CoA, thereby negatively regulating histone lysine crotonylation (Kcr). This enzymatic activity is intrinsically linked to its transcription repression function and regulates reactivation of sex chromosome-linked genes and histone replacement in spermatids.","method":"Biochemical in vitro enzymatic assay; Cdyl transgenic mouse model with sperm phenotype readout; histone modification analysis","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstituted enzymatic activity in vitro, validated in transgenic mouse model with multiple orthogonal readouts","pmids":["28803779"],"is_preprint":false},{"year":2008,"finding":"CDYL physically bridges the neuronal gene repressor REST and the histone methyltransferase G9a, forming a corepressor complex that represses transcription. RNAi knockdown of CDYL (along with REST and G9a) derepresses the proto-oncogene TrkC and induces oncogenic transformation of immortalized primary human cells.","method":"Co-immunoprecipitation; RNAi knockdown; oncogenic transformation assay in human cells","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP demonstrating bridging interaction, functional epistasis via RNAi knockdown with defined transformation phenotype, replicated across cell types","pmids":["19061646"],"is_preprint":false},{"year":2003,"finding":"CDYL's C-terminal enoyl-CoA hydratase/isomerase-like domain binds CoA and histone deacetylases (HDAC1/2), and CDYL efficiently represses transcription. Binding of HDAC1 to CDYL prevents CoA binding, suggesting mutually exclusive interactions that distinguish CDYL's corepressor role from a potential metabolic role.","method":"CoA-binding assay; co-immunoprecipitation with HDACs; transcription repression assay","journal":"EMBO reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple biochemical assays in a single lab establishing domain function and protein-protein interactions","pmids":["12947414"],"is_preprint":false},{"year":2011,"finding":"CDYL specifically recognizes di- and tri-methylated H3K27 (H3K27me2/3) via its chromodomain and directly interacts with EZH2, the catalytic subunit of PRC2. CDYL dramatically enhances PRC2 methyltransferase activity toward oligonucleosome substrates in vitro and is required for chromatin targeting and maximal enzymatic activity of PRC2 at common genomic targets, forming a positive feedback loop for H3K27me3 propagation.","method":"In vitro methyltransferase assay with oligonucleosome substrates; co-immunoprecipitation; ChIP-sequencing; chromodomain binding assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstituted in vitro enzymatic stimulation assay plus genome-wide ChIP-seq and co-IP, multiple orthogonal methods in one study","pmids":["22009739"],"is_preprint":false},{"year":2013,"finding":"Cdyl associates with the inactive X chromosome (Xi) through a requirement for H3K9me2 for general chromatin association in vivo, and requires both H3K9me2 and H3K27me3 for Xi-specific enrichment. Cdyl associates with the H3K9 methyltransferase G9a and MGA protein on Xi, and loss of PRC2/H3K27me3 reduces Cdyl and H3K9me2 enrichment on Xi.","method":"Mouse embryonic stem cell lines with mutated histone methyltransferases; ChIP; immunofluorescence; co-immunoprecipitation/mass spectrometry (SILAC)","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic loss-of-function in ESCs with defined histone mark requirements, multiple orthogonal localization and interaction methods","pmids":["24144980"],"is_preprint":false},{"year":2014,"finding":"CDYL negatively regulates dendrite morphogenesis in hippocampal neurons by interacting with EZH2 and recruiting H3K27 methyltransferase activity to the BDNF gene promoter, repressing BDNF expression. Neural activity increases dendritic complexity through degradation of CDYL protein, de-repressing BDNF.","method":"Gain- and loss-of-function in primary cultured rat neurons and in vivo; DNA microarray; ChIP; co-immunoprecipitation","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — epistasis established via CDYL/EZH2 co-knockdown, ChIP confirming promoter occupancy, in vitro and in vivo concordant phenotypes","pmids":["24671995"],"is_preprint":false},{"year":2017,"finding":"CDYL is required for the transmission and restoration of repressive histone marks during DNA replication. CDYL physically associates with chromatin assembly factor 1 (CAF-1) and the replicative helicase MCM complex, bridging them to facilitate histone deposition. CDYL recruits histone-modifying enzymes G9a, SETDB1, and EZH2 to replication forks, leading to addition of H3K9me2/3 and H3K27me2/3 on newly deposited histone H3. CDYL depletion impedes early S phase progression.","method":"Co-immunoprecipitation; chromatin fractionation; cell cycle analysis; ChIP","journal":"Journal of molecular cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP establishing multiprotein complex, ChIP at replication forks, cell cycle phenotype with CDYL depletion, multiple orthogonal methods","pmids":["28402439"],"is_preprint":false},{"year":2017,"finding":"CDYL binds to a regulatory element in intron 1 of SCN8A and recruits H3K27me3 activity to repress transcription of the Nav1.6 sodium channel gene. CDYL knockdown in hippocampal neurons augments Nav1.6 currents and lowers neuronal threshold, increasing seizure susceptibility, while CDYL transgenic overexpression reduces epileptogenesis.","method":"ChIP; electrophysiology; RNAi knockdown in neurons; transgenic mouse model; human brain tissue analysis","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP confirming CDYL binding and H3K27me3 deposition at SCN8A locus, electrophysiological phenotype, gain- and loss-of-function mouse models","pmids":["28842554"],"is_preprint":false},{"year":2018,"finding":"CDYL1 is rapidly recruited to DNA double-strand breaks (DSBs) in a PARP1-dependent manner. The C-terminal ECH domain of CDYL1 binds poly(ADP-ribose) (PAR) moieties, mediating its accumulation at damage sites. CDYL1 promotes EZH2 recruitment, stimulates local H3K27me3, and fosters transcription silencing at DSBs. CDYL1 depletion causes persistent G2/M arrest and impairs homologous recombination (HR) repair. CDYL1-knockout cells show synthetic lethality with cisplatin.","method":"Live-cell imaging; ChIP; co-immunoprecipitation; 'traffic-light reporter' system for HR quantification; cell cycle analysis; domain-deletion mapping; PAR-binding assay","journal":"Journal of molecular cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods including PAR-binding domain mapping, functional HR reporter assay, genetic KO with defined cisplatin synthetic lethality phenotype","pmids":["29177481"],"is_preprint":false},{"year":2019,"finding":"CDYL promotes chemoresistance in small cell lung cancer by recruiting EZH2 to regulate H3K27me3 at the CDKN1C promoter, silencing CDKN1C transcription. The CDYL/EZH2/CDKN1C axis drives chemoresistance, and the EZH2 inhibitor GSK126 de-represses CDKN1C and decreases CDYL-induced resistance.","method":"ChIP-qPCR; co-immunoprecipitation; GST pull-down; gain- and loss-of-function assays; in vivo xenograft","journal":"Theranostics","confidence":"High","confidence_rationale":"Tier 2 / Moderate — ChIP confirming H3K27me3 deposition at CDKN1C promoter, reciprocal Co-IP and GST pulldown establishing CDYL-EZH2 interaction, in vitro and in vivo functional rescue","pmids":["31367252"],"is_preprint":false},{"year":2020,"finding":"CDYL negatively regulates protein crotonylation globally. Specifically, CDYL negatively regulates crotonylation of RPA1; mutation of the Kcr sites of RPA1 impairs its interaction with single-stranded DNA and with components of the DNA resection machinery, establishing a role for RPA1 crotonylation in homologous recombination DNA repair.","method":"Large-scale proteomics/mass spectrometry crotonylome analysis in CDYL-depleted HeLa cells; RPA1 Kcr site mutagenesis; ssDNA-binding assay; co-immunoprecipitation","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 1 / Strong — large-scale proteomic mapping plus site-directed mutagenesis with functional validation of DNA binding, multiple orthogonal approaches","pmids":["32201722"],"is_preprint":false},{"year":2022,"finding":"CDYL1 crotonyl-CoA hydratase activity drives a local decrease in histone lysine crotonylation (Kcr) and H3K9cr at DNA double-strand break sites. This reduction in Kcr triggers eviction of the transcription elongation factor ENL and fosters DSB-induced transcriptional silencing. Genetic inhibition of CDYL1 hydratase activity blocks H3K9cr reduction and alleviates silencing without impairing HR efficiency, functionally uncoupling repair from DSB-induced silencing.","method":"CDYL1 hydratase active-site mutants; ChIP for Kcr and H3K9cr at AsiSI-induced DSBs; transcription reporter assay; HR repair assay","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — active-site mutagenesis combined with ChIP and functional silencing/repair assays, establishes causal mechanistic link","pmids":["35447080"],"is_preprint":false},{"year":2022,"finding":"CDYL assembles nuclear condensates through liquid-liquid phase separation in kidney epithelial cells and normal kidney tissues. The phase-separating capacity of CDYL is required for efficient suppression of locus-specific histone Kcr and of its target gene expression. CDYL overexpression reduces histone Kcr and slows cyst growth in Pkd1-knockout mice.","method":"Biochemical phase-separation assays; zebrafish model; Cdyl transgenic × Pkd1 KO mouse crosses; ChIP-seq; mass spectrometry histone acylation analysis","journal":"Journal of the American Society of Nephrology","confidence":"High","confidence_rationale":"Tier 2 / Strong — phase separation shown biochemically and in vivo, functional consequence demonstrated in two animal models, integrated cistromic and transcriptomic analysis","pmids":["35918147"],"is_preprint":false},{"year":2019,"finding":"Germline conditional knockout of Cdyl in mice causes defects in spermatogonia maintenance and spermatozoon morphogenesis (teratozoospermia), with extensive changes in histone methylation and acetylation patterns and a disturbed testicular transcriptome, demonstrating CDYL is required for spermatogenesis and male fertility.","method":"Germline conditional knockout mouse model; histology; histone modification analysis; transcriptome analysis","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional knockout with defined spermatogenesis and fertility phenotype and molecular characterization of histone modification changes","pmids":["30850578"],"is_preprint":false},{"year":2022,"finding":"TRIM32, an E3 ubiquitin ligase, promotes dendrite arborization by mediating ubiquitylation and proteasomal degradation of CDYL. TRIM32 interacts with CDYL in vivo and in vitro; TRIM32 overexpression decreases CDYL protein and increases dendritic complexity, while TRIM32 knockdown increases CDYL levels and decreases dendritic complexity. The E3 ligase RING domain is required for this regulation, and CDYL knockdown abolishes the effect of TRIM32 knockdown.","method":"Mass spectrometry; co-immunoprecipitation; ubiquitylation assay in vitro and in vivo; gain/loss-of-function in primary rat neurons; domain mutant (ΔRING)","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vitro and in vivo ubiquitylation assays, domain mutagenesis, epistasis rescue experiment, mass spectrometry identification of interaction","pmids":["34888944"],"is_preprint":false},{"year":2017,"finding":"CDYL co-localizes with acetylated α-tubulin in rat sperm flagella and is present in the sperm axonemal fraction. Recombinant CDYL and sperm-derived CDYL acetylate soluble tubulin and microtubules in vitro, and CDYL overexpression increases tubulin acetylation more than two-fold in cells, demonstrating CDYL functions as a tubulin acetyltransferase.","method":"Microscale thermophoresis (chromodomain–α-tubulin interaction); in vitro tubulin acetylation assay; co-localization in sperm; CDYL overexpression in cells","journal":"Cytoskeleton","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro acetyltransferase assay and binding confirmation, but single lab and limited mechanistic follow-up","pmids":["28681565"],"is_preprint":false},{"year":2025,"finding":"A homozygous splicing mutation in CDYL (c.103+1G>A) causes aberrant alternative splicing, reducing tubulin acetylation in human spermatozoa. CDYL co-localizes with Ac-tubulin along the flagella of human spermatozoa, and CDYL loss results in thin mid-piece related flagella abnormalities, decreased sperm motility, and asthenoteratozoospermia.","method":"Whole-exome sequencing; minigene alternative splicing assay; immunofluorescence co-localization; sperm ultrastructural analysis (electron microscopy)","journal":"Andrology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — human genetic variant validated by minigene assay and co-localization, consistent with mouse knockout data, single-patient case","pmids":["39823157"],"is_preprint":false},{"year":2023,"finding":"CDYL directly binds to the Wnt4 promoter, maintains H3K27me3 levels at the Wnt4 locus, and represses Wnt4 transcription during the sex-determination period. Loss of CDYL in XY mice derepresses Wnt4, leading to repression of Sox9 and XY sex reversal. Wnt4 heterozygous deficiency restores SOX9 expression in Cdyl-deficient XY gonads.","method":"Cdyl conditional knockout mouse; ChIP (H3K27me3); genetic epistasis via Wnt4 heterozygous rescue; gene expression analysis","journal":"Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP confirming direct promoter binding and H3K27me3, genetic epistasis rescue experiment establishing pathway order","pmids":["37155872"],"is_preprint":false},{"year":2025,"finding":"CDK5 phosphorylates CDYL at Ser147 in response to neural activity. This phosphorylation facilitates TRIM32-mediated ubiquitination and proteasomal degradation of CDYL. An interfering peptide targeting CDYL Ser147 phosphorylation decreases contextual fear memory in mice. Ablation of CDYL in CaMKIIα+ excitatory neurons or hippocampus increases fear memory.","method":"In vitro and in vivo phosphorylation assays; mutagenesis at Ser147; co-immunoprecipitation; ubiquitination assay; interfering peptide in vivo; conditional KO mouse","journal":"Translational psychiatry","confidence":"High","confidence_rationale":"Tier 2 / Strong — site-specific phosphorylation mapped to Ser147 with mutagenesis, downstream ubiquitination cascade validated, in vivo functional consequence confirmed","pmids":["40885707"],"is_preprint":false},{"year":2019,"finding":"Small-molecule inhibitor D03 (benzo[d]oxazol-2(3H)-one derivative) selectively binds the chromodomain of CDYL (KD = 0.5 μM), perturbs CDYL recruitment onto chromatin, and causes transcriptional de-repression of CDYL target genes. D03 promotes neurodendrite development and branching in hippocampal neurons by inhibiting CDYL.","method":"SPR binding assay; structure-guided molecular docking; cellular target engagement assay; ChIP; neurite morphology analysis","journal":"European journal of medicinal chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — SPR confirmed binding and selectivity, ChIP confirmed chromatin displacement, neuronal phenotype observed; limited mechanistic depth beyond chromodomain blockade","pmids":["31494467"],"is_preprint":false},{"year":2024,"finding":"CDYL represses neuronatin (NNAT) expression in human cortical neural stem cells (NSCs). CDYL deficiency leads to a substantial increase in GABAergic neurons in cortical organoids, and abnormal NNAT expression influences fate commitment of cortical NSCs toward GABAergic identity.","method":"Human cortical organoids with CDYL knockout; RNA-seq; gain- and loss-of-function; cross-species comparison","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — organoid KO with defined cell-fate phenotype and identification of NNAT as downstream target; single lab","pmids":["39378153"],"is_preprint":false},{"year":2020,"finding":"CDYL knockdown in human endometrial Ishikawa cells reduces CTNNB1 (β-catenin) expression, impairs endometrial cell migration, and this impaired migration can be rescued by overexpression of either CDYL or CTNNB1, placing CTNNB1 downstream of CDYL in endometrial cell function.","method":"RNAi knockdown; overexpression rescue; cell migration assay; gene expression analysis in primary endometrial cells","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — functional rescue experiment establishes epistatic relationship, validated in primary cells as well as cell line","pmids":["32158757"],"is_preprint":false},{"year":2025,"finding":"CDYL interacts with MYH9 in murine testis, co-localizes with CDYL at the manchette structure in spermatids. Conditional deletion of Cdyl in spermatogenic cells causes transcriptional downregulation of Myh9, disorganization of the manchette, and abnormal MYH9 localization in spermatozoa.","method":"Co-immunoprecipitation with LC-MS/MS; immunofluorescence; Western blot; conditional knockout mouse; RT-qPCR","journal":"Zhonghua nan ke xue (National journal of andrology)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP confirmed CDYL-MYH9 interaction in testis, KO mouse with defined localization phenotype; single lab","pmids":["40965992"],"is_preprint":false},{"year":2026,"finding":"OTUB1, a deubiquitinating enzyme, interacts with and stabilizes CDYL protein. CDYL, together with EZH2, deposits H3K27me3 at the SOX18 promoter to repress its transcription. SOX18 normally transcriptionally activates FDX1, a cuproptosis regulator, so CDYL-driven SOX18 repression suppresses FDX1 expression, enabling resistance to copper-induced cell death in lung cancer cells.","method":"Co-immunoprecipitation (OTUB1-CDYL); ChIP (H3K27me3 at SOX18 promoter); transcriptomic and epigenomic profiling; in vivo xenograft with copper chelator treatment","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and Co-IP establish CDYL–EZH2–SOX18 axis mechanistically; single lab study, preprint not required as peer-reviewed","pmids":["41912773"],"is_preprint":false},{"year":2025,"finding":"SETDB1 automethylation on H3K9-like motifs within its catalytic domain is required for interaction with CDYL (as well as SUV39H1 and HP1γ). Automethylation-deficient SETDB1 fails to interact with CDYL, impairing SETDB1 localization to target sites and H3K9me3 establishment.","method":"SETDB1 automethylation-deficient mutants; co-immunoprecipitation; ChIP; ESC growth assay","journal":"bioRxiv (preprint)","confidence":"Low","confidence_rationale":"Tier 3 / Weak — preprint, single lab, Co-IP interaction but CDYL is one of several partners and mechanistic detail on CDYL side is limited","pmids":["bio_10.1101_2025.10.22.683908"],"is_preprint":true},{"year":2025,"finding":"CDYL deficiency in vascular smooth muscle cells (VSMCs) results in elevated H3K18 crotonylation, which transcriptionally activates SGK1. ChIP assays confirmed CDYL occupancy at the SGK1 locus and its regulation via H3K18cr. SGK1 upregulation promotes VSMC phenotypic switching.","method":"CDYL knockdown/overexpression in VSMCs; Western blot for H3K18cr; ChIP; RT-qPCR","journal":"Zhonghua yu fang yi xue za zhi","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP establishes CDYL-mediated H3K18cr regulation at SGK1 locus; single lab, limited methodological depth in abstract","pmids":["41287335"],"is_preprint":false},{"year":2024,"finding":"CDYL regulates tubular epithelial cell pyroptosis in acute kidney injury via FABP4-mediated reactive oxygen species production. CDYL overexpression aggravates tubular injury and pyroptosis in cisplatin-induced AKI, while pharmacological inhibition with compound D03 attenuates kidney dysfunction and tubular pyroptosis in mice.","method":"RNA sequencing; CDYL overexpression in AKI mouse model; compound D03 pharmacological inhibition; pyroptosis assays","journal":"Acta pharmacologica Sinica","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo gain-of-function and pharmacological inhibition with defined pyroptosis phenotype; FABP4/ROS pathway identified by transcriptomics; single lab","pmids":["39043969"],"is_preprint":false}],"current_model":"CDYL is a chromodomain-containing transcriptional corepressor that (1) enzymatically converts crotonyl-CoA to β-hydroxybutyryl-CoA (crotonyl-CoA hydratase activity), thereby negatively regulating histone and protein lysine crotonylation; (2) reads repressive histone marks H3K9me2/3 and H3K27me2/3 via its chromodomain to localize to heterochromatin and the inactive X chromosome; (3) scaffolds multiprotein repressive complexes by physically bridging REST and G9a, CAF-1 and MCM, and by binding and stimulating PRC2/EZH2 to deposit H3K27me3; (4) is recruited to DNA double-strand breaks via PAR binding, where its hydratase activity reduces local histone Kcr to silence transcription and promote homologous recombination repair; (5) undergoes CDK5-mediated phosphorylation at Ser147 followed by TRIM32-mediated ubiquitination and degradation in response to neural activity; and (6) controls spermatogenesis, neuronal dendrite morphogenesis, sex determination, and other developmental processes through these epigenetic mechanisms."},"narrative":{"mechanistic_narrative":"CDYL is a chromodomain-containing transcriptional corepressor that couples histone acylation metabolism to epigenetic gene silencing across spermatogenesis, neuronal development, sex determination, and DNA repair [PMID:28803779, PMID:22009739, PMID:30850578]. Enzymatically, its C-terminal enoyl-CoA hydratase-like domain functions as a crotonyl-CoA hydratase that converts crotonyl-CoA to β-hydroxybutyryl-CoA, depleting the substrate for lysine crotonylation and thereby negatively regulating histone and protein crotonylation genome-wide [PMID:28803779, PMID:32201722]; this same domain binds CoA and HDAC1/2, with HDAC binding excluding CoA binding [PMID:12947414]. Its chromodomain reads the repressive marks H3K9me2/3 and H3K27me2/3, directing CDYL to heterochromatin and the inactive X chromosome, where H3K9me2 supports general chromatin association and combined H3K9me2/H3K27me3 drives Xi-specific enrichment [PMID:24144980]. CDYL acts as a scaffold for repressive machinery: it bridges the neuronal repressor REST to the methyltransferase G9a [PMID:19061646], links CAF-1 to the MCM helicase to restore repressive marks during replication by recruiting G9a, SETDB1, and EZH2 to forks [PMID:28402439], and binds and stimulates PRC2/EZH2 to propagate H3K27me3 at target loci [PMID:22009739]. Through CDYL-EZH2-directed H3K27me3 deposition, CDYL represses specific target promoters including BDNF in dendrite morphogenesis [PMID:24671995], SCN8A/Nav1.6 in neuronal excitability [PMID:28842554], Wnt4 during sex determination where its loss causes XY sex reversal [PMID:37155872], and CDKN1C and SOX18 in cancer chemoresistance and copper-death evasion [PMID:31367252, PMID:41912773]. At DNA double-strand breaks, CDYL1 is recruited via PAR binding by its ECH domain, where it promotes EZH2-dependent H3K27me3 and hydratase-driven loss of histone crotonylation to evict ENL and enforce transcriptional silencing, supporting homologous recombination [PMID:29177481, PMID:35447080]. CDYL protein levels are controlled by CDK5-mediated phosphorylation at Ser147, which licenses TRIM32-mediated ubiquitination and proteasomal degradation in response to neural activity [PMID:34888944, PMID:40885707]. A homozygous CDYL splicing mutation causes asthenoteratozoospermia in humans [PMID:39823157].","teleology":[{"year":2003,"claim":"Established that CDYL is a corepressor whose conserved C-terminal hydratase-like domain binds both CoA and histone deacetylases, posing the question of whether CDYL is a metabolic enzyme or a chromatin regulator.","evidence":"CoA-binding and HDAC co-immunoprecipitation assays with transcription repression readout","pmids":["12947414"],"confidence":"Medium","gaps":["Did not resolve whether CoA binding reflects catalytic activity","No in vivo target genes identified","Functional consequence of mutually exclusive CoA/HDAC binding untested"]},{"year":2008,"claim":"Showed CDYL physically bridges REST and G9a into a corepressor complex, defining a scaffolding role linking a sequence-specific repressor to a methyltransferase and connecting CDYL loss to oncogenic transformation.","evidence":"Reciprocal Co-IP and RNAi knockdown with oncogenic transformation assay in human cells","pmids":["19061646"],"confidence":"High","gaps":["Did not map the chromatin marks deposited by this complex","Genome-wide targets of the REST-CDYL-G9a complex undefined"]},{"year":2011,"claim":"Demonstrated that CDYL's chromodomain reads H3K27me2/3 and that CDYL binds and stimulates PRC2/EZH2, establishing a positive-feedback loop for H3K27me3 propagation rather than a passive reader role.","evidence":"In vitro methyltransferase assay on oligonucleosomes, ChIP-seq, chromodomain binding assays","pmids":["22009739"],"confidence":"High","gaps":["Structural basis of PRC2 stimulation not resolved","Did not address how CDYL is initially recruited to nucleate the loop"]},{"year":2013,"claim":"Defined the histone-mark requirements for CDYL chromatin association, showing H3K9me2 supports general localization while combined H3K9me2 and H3K27me3 drive inactive-X enrichment, integrating CDYL into both major repressive mark systems.","evidence":"ESC lines with mutated histone methyltransferases, ChIP, immunofluorescence, SILAC Co-IP/MS","pmids":["24144980"],"confidence":"High","gaps":["Functional consequence of CDYL on Xi gene silencing not directly tested","Hierarchy between H3K9me2 and H3K27me3 recruitment unresolved"]},{"year":2014,"claim":"Connected CDYL to neuronal plasticity by showing it recruits EZH2/H3K27me3 to the BDNF promoter to restrain dendrite morphogenesis, and that activity-induced CDYL degradation de-represses BDNF.","evidence":"Gain/loss-of-function in rat neurons and in vivo, microarray, ChIP, Co-IP","pmids":["24671995"],"confidence":"High","gaps":["Mechanism of activity-induced CDYL degradation not identified at this stage","Other neuronal CDYL targets unmapped"]},{"year":2017,"claim":"Resolved the metabolic-versus-epigenetic question by demonstrating CDYL is a crotonyl-CoA hydratase that negatively regulates histone crotonylation, linking its enzymatic activity directly to repression of sex-linked genes and histone replacement in spermatids.","evidence":"Reconstituted in vitro enzymatic assay plus Cdyl transgenic mouse with sperm phenotype and histone modification analysis","pmids":["28803779"],"confidence":"High","gaps":["Relative contribution of hydratase versus scaffolding activity to phenotypes not parsed","Substrate range beyond histones unaddressed at this point"]},{"year":2017,"claim":"Extended CDYL function to S-phase by showing it bridges CAF-1 and the MCM helicase and recruits G9a/SETDB1/EZH2 to replication forks, providing a mechanism for inheritance of repressive marks on newly deposited histones.","evidence":"Reciprocal Co-IP, chromatin fractionation, ChIP at forks, cell cycle analysis","pmids":["28402439"],"confidence":"High","gaps":["Direct demonstration of mark transmission to daughter chromatin not shown","How CDYL is targeted specifically to forks unresolved"]},{"year":2017,"claim":"Showed CDYL represses the Nav1.6 sodium channel gene SCN8A via H3K27me3, defining a causal epigenetic control of neuronal excitability and seizure susceptibility.","evidence":"ChIP, electrophysiology, RNAi, transgenic mouse, human brain tissue","pmids":["28842554"],"confidence":"High","gaps":["Whether hydratase activity contributes to SCN8A silencing not tested","Broader epilepsy-relevant CDYL targets undefined"]},{"year":2017,"claim":"Reported a distinct CDYL activity as a tubulin acetyltransferase in sperm flagella, suggesting a cytoplasmic, microtubule-directed function separate from chromatin repression.","evidence":"Microscale thermophoresis, in vitro tubulin acetylation assay, sperm co-localization, cellular overexpression","pmids":["28681565"],"confidence":"Medium","gaps":["Single-lab finding without independent confirmation","Catalytic mechanism for acetyltransferase activity unresolved","Relationship to the established hydratase/repressor functions unclear"]},{"year":2018,"claim":"Placed CDYL1 in the DNA damage response by showing its ECH domain binds PAR for PARP1-dependent recruitment to double-strand breaks, where it promotes EZH2/H3K27me3, transcriptional silencing, and homologous recombination.","evidence":"Live-cell imaging, ChIP, Co-IP, HR traffic-light reporter, domain mapping, PAR-binding assay, KO with cisplatin synthetic lethality","pmids":["29177481"],"confidence":"High","gaps":["Did not separate the silencing function from HR repair","Role of hydratase activity at breaks not yet addressed"]},{"year":2019,"claim":"Demonstrated CDYL is required for spermatogonia maintenance and spermatozoon morphogenesis in vivo, establishing male fertility as a core physiological output of CDYL-dependent histone modification control.","evidence":"Germline conditional knockout mouse, histology, histone modification and transcriptome analysis","pmids":["30850578"],"confidence":"High","gaps":["Specific target genes driving the sperm phenotype not pinpointed","Contribution of individual CDYL activities not dissected"]},{"year":2019,"claim":"Identified CDYL as a chemoresistance driver in small cell lung cancer via the CDYL/EZH2/CDKN1C axis, providing a pharmacologically tractable EZH2-dependent vulnerability.","evidence":"ChIP-qPCR, Co-IP, GST pull-down, gain/loss-of-function, xenograft with GSK126","pmids":["31367252"],"confidence":"High","gaps":["Whether crotonylation contributes to CDKN1C silencing not tested","Generality across cancer types unaddressed"]},{"year":2019,"claim":"Provided a chemical-biology tool by developing D03, a chromodomain-binding small-molecule inhibitor that displaces CDYL from chromatin and de-represses targets, validating the chromodomain as a druggable module.","evidence":"SPR, structure-guided docking, cellular target engagement, ChIP, neurite morphology","pmids":["31494467"],"confidence":"Medium","gaps":["Selectivity against other chromodomain proteins limited in scope","Does not affect hydratase activity directly"]},{"year":2020,"claim":"Generalized CDYL's anti-crotonylation function beyond histones by showing it controls RPA1 crotonylation, where Kcr sites govern ssDNA and resection-machinery binding, linking protein crotonylation to homologous recombination.","evidence":"Crotonylome proteomics in CDYL-depleted cells, RPA1 Kcr site mutagenesis, ssDNA-binding and Co-IP assays","pmids":["32201722"],"confidence":"High","gaps":["Full set of CDYL-regulated non-histone crotonylation substrates unknown","Direct CDYL action on RPA1 versus indirect crotonyl-CoA depletion not separated"]},{"year":2020,"claim":"Linked CDYL to endometrial cell migration through CTNNB1, placing β-catenin downstream of CDYL in a non-neuronal epithelial context.","evidence":"RNAi knockdown, overexpression rescue, migration assay in primary endometrial cells","pmids":["32158757"],"confidence":"Medium","gaps":["Mechanism by which CDYL regulates CTNNB1 not defined","Whether chromatin or enzymatic activity is involved untested"]},{"year":2022,"claim":"Causally uncoupled CDYL's two DSB functions by showing its hydratase activity drives local Kcr/H3K9cr loss and ENL eviction to enforce silencing, while being dispensable for HR efficiency.","evidence":"Hydratase active-site mutants, ChIP for Kcr/H3K9cr at AsiSI breaks, transcription reporter and HR assays","pmids":["35447080"],"confidence":"High","gaps":["Physiological importance of DSB-induced silencing per se unclear","Interplay with the PAR-recruitment/EZH2 arm not fully integrated"]},{"year":2022,"claim":"Revealed that CDYL forms liquid-liquid phase-separated nuclear condensates required for locus-specific Kcr suppression, and that this activity slows cyst growth in a polycystic kidney model, adding a biophysical layer to its repressive function.","evidence":"Phase-separation assays, zebrafish, Cdyl x Pkd1 KO mouse crosses, ChIP-seq, histone acylation MS","pmids":["35918147"],"confidence":"High","gaps":["Condensate composition and regulation in vivo incompletely defined","Relationship between phase separation and scaffolding/enzymatic activities unresolved"]},{"year":2022,"claim":"Identified TRIM32 as the E3 ligase that ubiquitinates and degrades CDYL to promote dendrite arborization, providing the long-sought mechanism for activity-coupled CDYL turnover.","evidence":"Mass spectrometry, Co-IP, in vitro/in vivo ubiquitylation, ΔRING mutant, neuron epistasis rescue","pmids":["34888944"],"confidence":"High","gaps":["Signal triggering TRIM32-CDYL targeting not defined at this stage","Whether degradation is locus-selective unknown"]},{"year":2023,"claim":"Established CDYL as a determinant of sex determination by showing it represses Wnt4 via H3K27me3 to permit Sox9 expression, with its loss causing XY sex reversal rescuable by Wnt4 haploinsufficiency.","evidence":"Cdyl conditional KO mouse, H3K27me3 ChIP, Wnt4 heterozygous genetic epistasis","pmids":["37155872"],"confidence":"High","gaps":["Upstream regulator targeting CDYL to the Wnt4 locus unknown","Timing window restricting this function not mechanistically defined"]},{"year":2024,"claim":"Connected CDYL to cortical neural cell-fate decisions by showing it represses NNAT and that CDYL loss biases human cortical NSCs toward GABAergic identity.","evidence":"Human cortical organoid KO, RNA-seq, gain/loss-of-function, cross-species comparison","pmids":["39378153"],"confidence":"Medium","gaps":["Direct chromatin mechanism at NNAT not fully established","Single-lab organoid model"]},{"year":2024,"claim":"Implicated CDYL in acute kidney injury by showing it regulates tubular epithelial pyroptosis via FABP4/ROS, with pharmacological D03 inhibition protective in mice.","evidence":"RNA-seq, CDYL overexpression in AKI model, D03 inhibition, pyroptosis assays","pmids":["39043969"],"confidence":"Medium","gaps":["Direct chromatin link between CDYL and FABP4 not demonstrated","Single-lab in vivo study"]},{"year":2025,"claim":"Completed the activity-dependent regulatory circuit by showing CDK5 phosphorylates CDYL at Ser147 to license TRIM32-mediated degradation, with functional consequences for contextual fear memory.","evidence":"In vitro/in vivo phosphorylation, Ser147 mutagenesis, ubiquitination assay, interfering peptide, conditional KO mouse","pmids":["40885707"],"confidence":"High","gaps":["How CDK5 is activated to target CDYL in specific neurons unclear","Locus selectivity of the degraded CDYL pool undefined"]},{"year":2025,"claim":"Provided human genetic evidence that a CDYL splicing mutation reducing flagellar tubulin acetylation causes asthenoteratozoospermia, translating the sperm phenotype to human male infertility.","evidence":"Whole-exome sequencing, minigene splicing assay, IF co-localization, sperm electron microscopy","pmids":["39823157"],"confidence":"Medium","gaps":["Single-patient case","Whether the defect reflects loss of acetyltransferase versus chromatin function not resolved"]},{"year":2025,"claim":"Extended CDYL's repressive scaffolding to vascular biology and cancer copper-death, showing CDYL controls H3K18cr at SGK1 in VSMCs and, stabilized by OTUB1, represses SOX18 to suppress FDX1 and confer cuproptosis resistance.","evidence":"CDYL knockdown/overexpression with ChIP in VSMCs; OTUB1-CDYL Co-IP, SOX18 H3K27me3 ChIP, xenograft with copper chelator","pmids":["41287335","41912773"],"confidence":"Medium","gaps":["Both are single-lab studies","Integration of crotonylation and H3K27me3 arms at these loci unresolved"]},{"year":2025,"claim":"Identified CDYL as a testis-specific partner of MYH9 at the spermatid manchette, linking CDYL to cytoskeletal organization during spermiogenesis.","evidence":"Co-IP/LC-MS/MS, immunofluorescence, conditional KO mouse, RT-qPCR","pmids":["40965992"],"confidence":"Medium","gaps":["Whether interaction is direct not established","Single-lab study"]},{"year":null,"claim":"How CDYL's distinct activities — crotonyl-CoA hydratase, methyl-mark reader/PRC2 scaffold, tubulin acetyltransferase, and phase-separation — are coordinated, switched, and targeted to specific loci within a given cell context remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model partitioning hydratase versus scaffolding contributions per phenotype","Structural basis for chromodomain mark discrimination and PRC2 stimulation incomplete","Tubulin acetyltransferase activity not independently confirmed or mechanistically explained"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016853","term_label":"isomerase activity","supporting_discovery_ids":[0,10,11]},{"term_id":"GO:0016829","term_label":"lyase activity","supporting_discovery_ids":[0,11]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[3,4]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[1,2,5,7,17]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,6]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[3]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[7,17]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[15]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[15,22]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[3,4,12]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[4]},{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[3,6,8]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[15,22]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[3,4,6]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[1,5,7,17]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[8,10,11]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[13,17,20]},{"term_id":"R-HSA-69306","term_label":"DNA Replication","supporting_discovery_ids":[6]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,10]}],"complexes":["REST-CDYL-G9a corepressor complex","CDYL-PRC2/EZH2","CDYL-CAF-1-MCM replication complex"],"partners":["EZH2","G9A","REST","SETDB1","CAF-1","TRIM32","OTUB1","MYH9"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9Y232","full_name":"Chromodomain Y-like protein","aliases":["Crotonyl-CoA hydratase"],"length_aa":598,"mass_kda":66.5,"function":"Chromatin reader protein that recognizes and binds histone H3 trimethylated at 'Lys-9', dimethylated at 'Lys-27' and trimethylated at 'Lys-27' (H3K9me3, H3K27me2 and H3K27me3, respectively) (PubMed:19808672, PubMed:28402439). Part of multimeric repressive chromatin complexes, where it is required for transmission and restoration of repressive histone marks, thereby preserving the epigenetic landscape (PubMed:28402439). Required for chromatin targeting and maximal enzymatic activity of Polycomb repressive complex 2 (PRC2); acts as a positive regulator of PRC2 activity by bridging the pre-existing histone H3K27me3 and newly recruited PRC2 on neighboring nucleosomes (PubMed:22009739). Acts as a corepressor for REST by facilitating histone-lysine N-methyltransferase EHMT2 recruitment and H3K9 dimethylation at REST target genes for repression (PubMed:19061646). Involved in X chromosome inactivation in females: recruited to Xist RNA-coated X chromosome and facilitates propagation of H3K9me2 by anchoring EHMT2 (By similarity). Promotes EZH2 accumulation and H3K27me3 methylation at DNA double strand breaks (DSBs), thereby facilitating transcriptional repression at sites of DNA damage and homology-directed repair of DSBs (PubMed:29177481). Required for neuronal migration during brain development by repressing expression of RHOA (By similarity). By repressing the expression of SCN8A, contributes to the inhibition of intrinsic neuronal excitability and epileptogenesis (By similarity). In addition to acting as a chromatin reader, acts as a hydro-lyase (PubMed:28803779). Shows crotonyl-coA hydratase activity by mediating the conversion of crotonyl-CoA ((2E)-butenoyl-CoA) to beta-hydroxybutyryl-CoA (3-hydroxybutanoyl-CoA), thereby acting as a negative regulator of histone crotonylation (PubMed:28803779). Histone crotonylation is required during spermatogenesis; down-regulation of histone crotonylation by CDYL regulates the reactivation of sex chromosome-linked genes in round spermatids and histone replacement in elongating spermatids (By similarity). By regulating histone crotonylation and trimethylation of H3K27, may be involved in stress-induced depression-like behaviors, possibly by regulating VGF expression (By similarity) Not able to recognize and bind histone H3K9me3, histone H3K27me2 and histone H3K27me3, due to the presence of a N-terminal extension that inactivates the chromo domain (PubMed:19808672) Not able to recognize and bind histone H3K9me3, histone H3K27me2 and histone H3K27me3, due to the absence of the chromo domain (PubMed:19808672). Acts as a negative regulator of isoform 2 by displacing isoform 2 from chromatin","subcellular_location":"Nucleus; Chromosome","url":"https://www.uniprot.org/uniprotkb/Q9Y232/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CDYL","classification":"Not Classified","n_dependent_lines":40,"n_total_lines":1208,"dependency_fraction":0.033112582781456956},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CBX1","stoichiometry":0.2},{"gene":"CLNS1A","stoichiometry":0.2},{"gene":"CSNK2B","stoichiometry":0.2},{"gene":"HDAC2","stoichiometry":0.2},{"gene":"HIST2H2BE","stoichiometry":0.2},{"gene":"NUMA1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/CDYL","total_profiled":1310},"omim":[{"mim_id":"618816","title":"CDY-LIKE PROTEIN 2; CDYL2","url":"https://www.omim.org/entry/618816"},{"mim_id":"603778","title":"CDY-LIKE PROTEIN; CDYL","url":"https://www.omim.org/entry/603778"},{"mim_id":"400018","title":"CHROMODOMAIN PROTEIN, Y-LINKED, 2A; CDY2A","url":"https://www.omim.org/entry/400018"},{"mim_id":"400016","title":"CHROMODOMAIN PROTEIN, Y-LINKED, 1; CDY1","url":"https://www.omim.org/entry/400016"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nuclear speckles","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/CDYL"},"hgnc":{"alias_symbol":["DKFZP586C1622","CDYL1"],"prev_symbol":[]},"alphafold":{"accession":"Q9Y232","domains":[{"cath_id":"2.40.50.40","chopping":"64-117","consensus_level":"high","plddt":87.2343,"start":64,"end":117},{"cath_id":"3.90.226.10","chopping":"345-598","consensus_level":"high","plddt":95.4759,"start":345,"end":598}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y232","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y232-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y232-F1-predicted_aligned_error_v6.png","plddt_mean":67.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CDYL","jax_strain_url":"https://www.jax.org/strain/search?query=CDYL"},"sequence":{"accession":"Q9Y232","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9Y232.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9Y232/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y232"}},"corpus_meta":[{"pmid":"28803779","id":"PMC_28803779","title":"Chromodomain Protein CDYL Acts as a Crotonyl-CoA Hydratase to Regulate Histone Crotonylation and Spermatogenesis.","date":"2017","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/28803779","citation_count":197,"is_preprint":false},{"pmid":"31148183","id":"PMC_31148183","title":"A Noncoding Regulatory RNAs Network Driven by Circ-CDYL Acts Specifically in the Early Stages Hepatocellular Carcinoma.","date":"2019","source":"Hepatology (Baltimore, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/31148183","citation_count":182,"is_preprint":false},{"pmid":"19061646","id":"PMC_19061646","title":"CDYL bridges REST and histone methyltransferases for gene repression and suppression of cellular transformation.","date":"2008","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/19061646","citation_count":124,"is_preprint":false},{"pmid":"32201722","id":"PMC_32201722","title":"Global crotonylome reveals CDYL-regulated RPA1 crotonylation in homologous recombination-mediated DNA repair.","date":"2020","source":"Science advances","url":"https://pubmed.ncbi.nlm.nih.gov/32201722","citation_count":120,"is_preprint":false},{"pmid":"34547461","id":"PMC_34547461","title":"Circular RNA Cdyl promotes abdominal aortic aneurysm formation by inducing M1 macrophage polarization and M1-type inflammation.","date":"2021","source":"Molecular therapy : the journal of the American Society of Gene Therapy","url":"https://pubmed.ncbi.nlm.nih.gov/34547461","citation_count":106,"is_preprint":false},{"pmid":"12947414","id":"PMC_12947414","title":"Cdyl: a new transcriptional co-repressor.","date":"2003","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/12947414","citation_count":95,"is_preprint":false},{"pmid":"22009739","id":"PMC_22009739","title":"Corepressor protein CDYL functions as a molecular bridge between polycomb repressor complex 2 and repressive chromatin mark trimethylated histone lysine 27.","date":"2011","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/22009739","citation_count":67,"is_preprint":false},{"pmid":"24144980","id":"PMC_24144980","title":"Cdyl, a new partner of the inactive X chromosome and potential reader of H3K27me3 and H3K9me2.","date":"2013","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/24144980","citation_count":61,"is_preprint":false},{"pmid":"32522972","id":"PMC_32522972","title":"Circular RNA (circRNA) CDYL Induces Myocardial Regeneration by ceRNA After Myocardial Infarction.","date":"2020","source":"Medical science monitor : international medical journal of experimental and clinical research","url":"https://pubmed.ncbi.nlm.nih.gov/32522972","citation_count":55,"is_preprint":false},{"pmid":"29177481","id":"PMC_29177481","title":"CDYL1 fosters double-strand break-induced transcription silencing and promotes homology-directed repair.","date":"2018","source":"Journal of molecular cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/29177481","citation_count":54,"is_preprint":false},{"pmid":"28842554","id":"PMC_28842554","title":"CDYL suppresses epileptogenesis in mice through repression of axonal Nav1.6 sodium channel expression.","date":"2017","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/28842554","citation_count":49,"is_preprint":false},{"pmid":"24671995","id":"PMC_24671995","title":"Coordinated regulation of dendrite arborization by epigenetic factors CDYL and EZH2.","date":"2014","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/24671995","citation_count":47,"is_preprint":false},{"pmid":"31367252","id":"PMC_31367252","title":"CDYL promotes the chemoresistance of small cell lung cancer by regulating H3K27 trimethylation at the CDKN1C promoter.","date":"2019","source":"Theranostics","url":"https://pubmed.ncbi.nlm.nih.gov/31367252","citation_count":41,"is_preprint":false},{"pmid":"32321304","id":"PMC_32321304","title":"Circular RNA circ-CDYL sponges miR-1180 to elevate yes-associated protein in multiple myeloma.","date":"2020","source":"Experimental biology and medicine (Maywood, N.J.)","url":"https://pubmed.ncbi.nlm.nih.gov/32321304","citation_count":38,"is_preprint":false},{"pmid":"28402439","id":"PMC_28402439","title":"Chromodomain protein CDYL is required for transmission/restoration of repressive histone marks.","date":"2017","source":"Journal of molecular cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/28402439","citation_count":36,"is_preprint":false},{"pmid":"37852428","id":"PMC_37852428","title":"Hypoxia-induced circ-CDYL-EEF1A2 transcriptional complex drives lung metastasis of cancer stem cells from hepatocellular carcinoma.","date":"2023","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/37852428","citation_count":34,"is_preprint":false},{"pmid":"35918147","id":"PMC_35918147","title":"Nuclear Condensation of CDYL Links Histone Crotonylation and Cystogenesis in Autosomal Dominant Polycystic Kidney Disease.","date":"2022","source":"Journal of the American Society of Nephrology : JASN","url":"https://pubmed.ncbi.nlm.nih.gov/35918147","citation_count":30,"is_preprint":false},{"pmid":"35447080","id":"PMC_35447080","title":"CDYL1-dependent decrease in lysine crotonylation at DNA double-strand break sites functionally uncouples transcriptional silencing and repair.","date":"2022","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/35447080","citation_count":30,"is_preprint":false},{"pmid":"30850578","id":"PMC_30850578","title":"Germline deletion of Cdyl causes teratozoospermia and progressive infertility in male mice.","date":"2019","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/30850578","citation_count":23,"is_preprint":false},{"pmid":"32158757","id":"PMC_32158757","title":"Loss of CDYL Results in Suppression of CTNNB1 and Decreased Endometrial Receptivity.","date":"2020","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/32158757","citation_count":21,"is_preprint":false},{"pmid":"40250664","id":"PMC_40250664","title":"Circular RNA CDYL facilitates hepatocellular carcinoma stemness and PD-L1+ exosomes-mediated immunotherapy resistance via stabilizing hornerin protein by blocking synoviolin 1-mediated ubiquitination.","date":"2025","source":"International journal of biological macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/40250664","citation_count":15,"is_preprint":false},{"pmid":"23282990","id":"PMC_23282990","title":"Generation and neuronal differentiation of induced pluripotent stem cells in Cdyl-/- mice.","date":"2013","source":"Neuroreport","url":"https://pubmed.ncbi.nlm.nih.gov/23282990","citation_count":14,"is_preprint":false},{"pmid":"31494467","id":"PMC_31494467","title":"Identification and characterization of benzo[d]oxazol-2(3H)-one derivatives as the first potent and selective small-molecule inhibitors of chromodomain protein CDYL.","date":"2019","source":"European journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/31494467","citation_count":13,"is_preprint":false},{"pmid":"37302564","id":"PMC_37302564","title":"CDYL knockdown reduces glioma development through an antitumor immune response in the tumor microenvironment.","date":"2023","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/37302564","citation_count":12,"is_preprint":false},{"pmid":"35353073","id":"PMC_35353073","title":"Knockdown of circ_CDYL Contributes to Inhibit Angiotensin II-Induced Podocytes Apoptosis in Membranous Nephropathy via the miR-149-5p/TNFSF11 Pathway.","date":"2022","source":"Journal of cardiovascular pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/35353073","citation_count":10,"is_preprint":false},{"pmid":"34888944","id":"PMC_34888944","title":"Ubiquitin ligase TRIM32 promotes dendrite arborization by mediating degradation of the epigenetic factor CDYL.","date":"2022","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/34888944","citation_count":8,"is_preprint":false},{"pmid":"28681565","id":"PMC_28681565","title":"Tubulin acetylation: A novel functional avenue for CDYL in sperm.","date":"2017","source":"Cytoskeleton (Hoboken, N.J.)","url":"https://pubmed.ncbi.nlm.nih.gov/28681565","citation_count":8,"is_preprint":false},{"pmid":"37155872","id":"PMC_37155872","title":"CDYL reinforces male gonadal sex determination through epigenetically repressing Wnt4 transcription in mice.","date":"2023","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/37155872","citation_count":6,"is_preprint":false},{"pmid":"39378153","id":"PMC_39378153","title":"The chromodomain protein CDYL confers forebrain identity to human cortical organoids by inhibiting neuronatin.","date":"2024","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/39378153","citation_count":5,"is_preprint":false},{"pmid":"39043969","id":"PMC_39043969","title":"Chromodomain Y-like (CDYL) inhibition ameliorates acute kidney injury in mice by regulating tubular pyroptosis.","date":"2024","source":"Acta pharmacologica Sinica","url":"https://pubmed.ncbi.nlm.nih.gov/39043969","citation_count":2,"is_preprint":false},{"pmid":"38991463","id":"PMC_38991463","title":"CDYL loss promotes cervical cancer aggression by increasing PD-L1 expression via the suppression of IRF2BP2 transcription.","date":"2024","source":"Translational 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Association With hnRNPL Modulates CDYL Isoform Switching in Breast Cancer Cells.","date":"2025","source":"Cancer science","url":"https://pubmed.ncbi.nlm.nih.gov/40702809","citation_count":0,"is_preprint":false},{"pmid":"40965992","id":"PMC_40965992","title":"[Expression and function of CDYL-interacting protein MYH9 in mouse testis].","date":"2025","source":"Zhonghua nan ke xue = National journal of andrology","url":"https://pubmed.ncbi.nlm.nih.gov/40965992","citation_count":0,"is_preprint":false},{"pmid":"41912773","id":"PMC_41912773","title":"OTUB1/CDYL axis-mediated epigenetic repression of SOX18 facilitates lung cancer progression by inhibiting FDX1-dependent cuproptosis.","date":"2026","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/41912773","citation_count":0,"is_preprint":false},{"pmid":"41199761","id":"PMC_41199761","title":"Expression Significance of Serum Circular RNA CDYL and Circular RNA ROBO2 in Patients with Acute Myocardial Infarction and the Value of Their Combined Prediction for Major Adverse Cardiovascular Events.","date":"2025","source":"International journal of general medicine","url":"https://pubmed.ncbi.nlm.nih.gov/41199761","citation_count":0,"is_preprint":false},{"pmid":"42174416","id":"PMC_42174416","title":"Elevated CDYL expression in the peripheral blood of patients with rheumatoid arthritis.","date":"2026","source":"BMC immunology","url":"https://pubmed.ncbi.nlm.nih.gov/42174416","citation_count":0,"is_preprint":false},{"pmid":"41287335","id":"PMC_41287335","title":"[CDYL deficiency promotes vascular smooth muscle cell phenotypic switching through H3K18 crotonylation-mediated SGK1 transcriptional activation].","date":"2025","source":"Zhonghua yu fang yi xue za zhi [Chinese journal of preventive medicine]","url":"https://pubmed.ncbi.nlm.nih.gov/41287335","citation_count":0,"is_preprint":false},{"pmid":"41675054","id":"PMC_41675054","title":"CircRNA Cdyl promotes the proliferation and differentiation of neural stem cells via regulating miR-544-3p/Nr3c1 axis.","date":"2026","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/41675054","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.10.22.683908","title":"Automethylation of lysine methyltransferase SETDB1 on H3K9-like motifs regulates interactions with chromodomain proteins and controls its functions","date":"2025-10-22","source":"bioRxiv","url":"https://doi.org/10.1101/2025.10.22.683908","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":22734,"output_tokens":7205,"usd":0.088138,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":16425,"output_tokens":7815,"usd":0.13875,"stage2_stop_reason":"end_turn"},"total_usd":0.226888,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2017,\n      \"finding\": \"CDYL acts as a crotonyl-CoA hydratase, converting crotonyl-CoA to β-hydroxybutyryl-CoA, thereby negatively regulating histone lysine crotonylation (Kcr). This enzymatic activity is intrinsically linked to its transcription repression function and regulates reactivation of sex chromosome-linked genes and histone replacement in spermatids.\",\n      \"method\": \"Biochemical in vitro enzymatic assay; Cdyl transgenic mouse model with sperm phenotype readout; histone modification analysis\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstituted enzymatic activity in vitro, validated in transgenic mouse model with multiple orthogonal readouts\",\n      \"pmids\": [\"28803779\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"CDYL physically bridges the neuronal gene repressor REST and the histone methyltransferase G9a, forming a corepressor complex that represses transcription. RNAi knockdown of CDYL (along with REST and G9a) derepresses the proto-oncogene TrkC and induces oncogenic transformation of immortalized primary human cells.\",\n      \"method\": \"Co-immunoprecipitation; RNAi knockdown; oncogenic transformation assay in human cells\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP demonstrating bridging interaction, functional epistasis via RNAi knockdown with defined transformation phenotype, replicated across cell types\",\n      \"pmids\": [\"19061646\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"CDYL's C-terminal enoyl-CoA hydratase/isomerase-like domain binds CoA and histone deacetylases (HDAC1/2), and CDYL efficiently represses transcription. Binding of HDAC1 to CDYL prevents CoA binding, suggesting mutually exclusive interactions that distinguish CDYL's corepressor role from a potential metabolic role.\",\n      \"method\": \"CoA-binding assay; co-immunoprecipitation with HDACs; transcription repression assay\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple biochemical assays in a single lab establishing domain function and protein-protein interactions\",\n      \"pmids\": [\"12947414\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CDYL specifically recognizes di- and tri-methylated H3K27 (H3K27me2/3) via its chromodomain and directly interacts with EZH2, the catalytic subunit of PRC2. CDYL dramatically enhances PRC2 methyltransferase activity toward oligonucleosome substrates in vitro and is required for chromatin targeting and maximal enzymatic activity of PRC2 at common genomic targets, forming a positive feedback loop for H3K27me3 propagation.\",\n      \"method\": \"In vitro methyltransferase assay with oligonucleosome substrates; co-immunoprecipitation; ChIP-sequencing; chromodomain binding assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstituted in vitro enzymatic stimulation assay plus genome-wide ChIP-seq and co-IP, multiple orthogonal methods in one study\",\n      \"pmids\": [\"22009739\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Cdyl associates with the inactive X chromosome (Xi) through a requirement for H3K9me2 for general chromatin association in vivo, and requires both H3K9me2 and H3K27me3 for Xi-specific enrichment. Cdyl associates with the H3K9 methyltransferase G9a and MGA protein on Xi, and loss of PRC2/H3K27me3 reduces Cdyl and H3K9me2 enrichment on Xi.\",\n      \"method\": \"Mouse embryonic stem cell lines with mutated histone methyltransferases; ChIP; immunofluorescence; co-immunoprecipitation/mass spectrometry (SILAC)\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic loss-of-function in ESCs with defined histone mark requirements, multiple orthogonal localization and interaction methods\",\n      \"pmids\": [\"24144980\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CDYL negatively regulates dendrite morphogenesis in hippocampal neurons by interacting with EZH2 and recruiting H3K27 methyltransferase activity to the BDNF gene promoter, repressing BDNF expression. Neural activity increases dendritic complexity through degradation of CDYL protein, de-repressing BDNF.\",\n      \"method\": \"Gain- and loss-of-function in primary cultured rat neurons and in vivo; DNA microarray; ChIP; co-immunoprecipitation\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — epistasis established via CDYL/EZH2 co-knockdown, ChIP confirming promoter occupancy, in vitro and in vivo concordant phenotypes\",\n      \"pmids\": [\"24671995\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CDYL is required for the transmission and restoration of repressive histone marks during DNA replication. CDYL physically associates with chromatin assembly factor 1 (CAF-1) and the replicative helicase MCM complex, bridging them to facilitate histone deposition. CDYL recruits histone-modifying enzymes G9a, SETDB1, and EZH2 to replication forks, leading to addition of H3K9me2/3 and H3K27me2/3 on newly deposited histone H3. CDYL depletion impedes early S phase progression.\",\n      \"method\": \"Co-immunoprecipitation; chromatin fractionation; cell cycle analysis; ChIP\",\n      \"journal\": \"Journal of molecular cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP establishing multiprotein complex, ChIP at replication forks, cell cycle phenotype with CDYL depletion, multiple orthogonal methods\",\n      \"pmids\": [\"28402439\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CDYL binds to a regulatory element in intron 1 of SCN8A and recruits H3K27me3 activity to repress transcription of the Nav1.6 sodium channel gene. CDYL knockdown in hippocampal neurons augments Nav1.6 currents and lowers neuronal threshold, increasing seizure susceptibility, while CDYL transgenic overexpression reduces epileptogenesis.\",\n      \"method\": \"ChIP; electrophysiology; RNAi knockdown in neurons; transgenic mouse model; human brain tissue analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP confirming CDYL binding and H3K27me3 deposition at SCN8A locus, electrophysiological phenotype, gain- and loss-of-function mouse models\",\n      \"pmids\": [\"28842554\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CDYL1 is rapidly recruited to DNA double-strand breaks (DSBs) in a PARP1-dependent manner. The C-terminal ECH domain of CDYL1 binds poly(ADP-ribose) (PAR) moieties, mediating its accumulation at damage sites. CDYL1 promotes EZH2 recruitment, stimulates local H3K27me3, and fosters transcription silencing at DSBs. CDYL1 depletion causes persistent G2/M arrest and impairs homologous recombination (HR) repair. CDYL1-knockout cells show synthetic lethality with cisplatin.\",\n      \"method\": \"Live-cell imaging; ChIP; co-immunoprecipitation; 'traffic-light reporter' system for HR quantification; cell cycle analysis; domain-deletion mapping; PAR-binding assay\",\n      \"journal\": \"Journal of molecular cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods including PAR-binding domain mapping, functional HR reporter assay, genetic KO with defined cisplatin synthetic lethality phenotype\",\n      \"pmids\": [\"29177481\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CDYL promotes chemoresistance in small cell lung cancer by recruiting EZH2 to regulate H3K27me3 at the CDKN1C promoter, silencing CDKN1C transcription. The CDYL/EZH2/CDKN1C axis drives chemoresistance, and the EZH2 inhibitor GSK126 de-represses CDKN1C and decreases CDYL-induced resistance.\",\n      \"method\": \"ChIP-qPCR; co-immunoprecipitation; GST pull-down; gain- and loss-of-function assays; in vivo xenograft\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP confirming H3K27me3 deposition at CDKN1C promoter, reciprocal Co-IP and GST pulldown establishing CDYL-EZH2 interaction, in vitro and in vivo functional rescue\",\n      \"pmids\": [\"31367252\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CDYL negatively regulates protein crotonylation globally. Specifically, CDYL negatively regulates crotonylation of RPA1; mutation of the Kcr sites of RPA1 impairs its interaction with single-stranded DNA and with components of the DNA resection machinery, establishing a role for RPA1 crotonylation in homologous recombination DNA repair.\",\n      \"method\": \"Large-scale proteomics/mass spectrometry crotonylome analysis in CDYL-depleted HeLa cells; RPA1 Kcr site mutagenesis; ssDNA-binding assay; co-immunoprecipitation\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — large-scale proteomic mapping plus site-directed mutagenesis with functional validation of DNA binding, multiple orthogonal approaches\",\n      \"pmids\": [\"32201722\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CDYL1 crotonyl-CoA hydratase activity drives a local decrease in histone lysine crotonylation (Kcr) and H3K9cr at DNA double-strand break sites. This reduction in Kcr triggers eviction of the transcription elongation factor ENL and fosters DSB-induced transcriptional silencing. Genetic inhibition of CDYL1 hydratase activity blocks H3K9cr reduction and alleviates silencing without impairing HR efficiency, functionally uncoupling repair from DSB-induced silencing.\",\n      \"method\": \"CDYL1 hydratase active-site mutants; ChIP for Kcr and H3K9cr at AsiSI-induced DSBs; transcription reporter assay; HR repair assay\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — active-site mutagenesis combined with ChIP and functional silencing/repair assays, establishes causal mechanistic link\",\n      \"pmids\": [\"35447080\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CDYL assembles nuclear condensates through liquid-liquid phase separation in kidney epithelial cells and normal kidney tissues. The phase-separating capacity of CDYL is required for efficient suppression of locus-specific histone Kcr and of its target gene expression. CDYL overexpression reduces histone Kcr and slows cyst growth in Pkd1-knockout mice.\",\n      \"method\": \"Biochemical phase-separation assays; zebrafish model; Cdyl transgenic × Pkd1 KO mouse crosses; ChIP-seq; mass spectrometry histone acylation analysis\",\n      \"journal\": \"Journal of the American Society of Nephrology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — phase separation shown biochemically and in vivo, functional consequence demonstrated in two animal models, integrated cistromic and transcriptomic analysis\",\n      \"pmids\": [\"35918147\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Germline conditional knockout of Cdyl in mice causes defects in spermatogonia maintenance and spermatozoon morphogenesis (teratozoospermia), with extensive changes in histone methylation and acetylation patterns and a disturbed testicular transcriptome, demonstrating CDYL is required for spermatogenesis and male fertility.\",\n      \"method\": \"Germline conditional knockout mouse model; histology; histone modification analysis; transcriptome analysis\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional knockout with defined spermatogenesis and fertility phenotype and molecular characterization of histone modification changes\",\n      \"pmids\": [\"30850578\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TRIM32, an E3 ubiquitin ligase, promotes dendrite arborization by mediating ubiquitylation and proteasomal degradation of CDYL. TRIM32 interacts with CDYL in vivo and in vitro; TRIM32 overexpression decreases CDYL protein and increases dendritic complexity, while TRIM32 knockdown increases CDYL levels and decreases dendritic complexity. The E3 ligase RING domain is required for this regulation, and CDYL knockdown abolishes the effect of TRIM32 knockdown.\",\n      \"method\": \"Mass spectrometry; co-immunoprecipitation; ubiquitylation assay in vitro and in vivo; gain/loss-of-function in primary rat neurons; domain mutant (ΔRING)\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vitro and in vivo ubiquitylation assays, domain mutagenesis, epistasis rescue experiment, mass spectrometry identification of interaction\",\n      \"pmids\": [\"34888944\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CDYL co-localizes with acetylated α-tubulin in rat sperm flagella and is present in the sperm axonemal fraction. Recombinant CDYL and sperm-derived CDYL acetylate soluble tubulin and microtubules in vitro, and CDYL overexpression increases tubulin acetylation more than two-fold in cells, demonstrating CDYL functions as a tubulin acetyltransferase.\",\n      \"method\": \"Microscale thermophoresis (chromodomain–α-tubulin interaction); in vitro tubulin acetylation assay; co-localization in sperm; CDYL overexpression in cells\",\n      \"journal\": \"Cytoskeleton\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro acetyltransferase assay and binding confirmation, but single lab and limited mechanistic follow-up\",\n      \"pmids\": [\"28681565\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"A homozygous splicing mutation in CDYL (c.103+1G>A) causes aberrant alternative splicing, reducing tubulin acetylation in human spermatozoa. CDYL co-localizes with Ac-tubulin along the flagella of human spermatozoa, and CDYL loss results in thin mid-piece related flagella abnormalities, decreased sperm motility, and asthenoteratozoospermia.\",\n      \"method\": \"Whole-exome sequencing; minigene alternative splicing assay; immunofluorescence co-localization; sperm ultrastructural analysis (electron microscopy)\",\n      \"journal\": \"Andrology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — human genetic variant validated by minigene assay and co-localization, consistent with mouse knockout data, single-patient case\",\n      \"pmids\": [\"39823157\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CDYL directly binds to the Wnt4 promoter, maintains H3K27me3 levels at the Wnt4 locus, and represses Wnt4 transcription during the sex-determination period. Loss of CDYL in XY mice derepresses Wnt4, leading to repression of Sox9 and XY sex reversal. Wnt4 heterozygous deficiency restores SOX9 expression in Cdyl-deficient XY gonads.\",\n      \"method\": \"Cdyl conditional knockout mouse; ChIP (H3K27me3); genetic epistasis via Wnt4 heterozygous rescue; gene expression analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP confirming direct promoter binding and H3K27me3, genetic epistasis rescue experiment establishing pathway order\",\n      \"pmids\": [\"37155872\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CDK5 phosphorylates CDYL at Ser147 in response to neural activity. This phosphorylation facilitates TRIM32-mediated ubiquitination and proteasomal degradation of CDYL. An interfering peptide targeting CDYL Ser147 phosphorylation decreases contextual fear memory in mice. Ablation of CDYL in CaMKIIα+ excitatory neurons or hippocampus increases fear memory.\",\n      \"method\": \"In vitro and in vivo phosphorylation assays; mutagenesis at Ser147; co-immunoprecipitation; ubiquitination assay; interfering peptide in vivo; conditional KO mouse\",\n      \"journal\": \"Translational psychiatry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — site-specific phosphorylation mapped to Ser147 with mutagenesis, downstream ubiquitination cascade validated, in vivo functional consequence confirmed\",\n      \"pmids\": [\"40885707\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Small-molecule inhibitor D03 (benzo[d]oxazol-2(3H)-one derivative) selectively binds the chromodomain of CDYL (KD = 0.5 μM), perturbs CDYL recruitment onto chromatin, and causes transcriptional de-repression of CDYL target genes. D03 promotes neurodendrite development and branching in hippocampal neurons by inhibiting CDYL.\",\n      \"method\": \"SPR binding assay; structure-guided molecular docking; cellular target engagement assay; ChIP; neurite morphology analysis\",\n      \"journal\": \"European journal of medicinal chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — SPR confirmed binding and selectivity, ChIP confirmed chromatin displacement, neuronal phenotype observed; limited mechanistic depth beyond chromodomain blockade\",\n      \"pmids\": [\"31494467\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CDYL represses neuronatin (NNAT) expression in human cortical neural stem cells (NSCs). CDYL deficiency leads to a substantial increase in GABAergic neurons in cortical organoids, and abnormal NNAT expression influences fate commitment of cortical NSCs toward GABAergic identity.\",\n      \"method\": \"Human cortical organoids with CDYL knockout; RNA-seq; gain- and loss-of-function; cross-species comparison\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — organoid KO with defined cell-fate phenotype and identification of NNAT as downstream target; single lab\",\n      \"pmids\": [\"39378153\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CDYL knockdown in human endometrial Ishikawa cells reduces CTNNB1 (β-catenin) expression, impairs endometrial cell migration, and this impaired migration can be rescued by overexpression of either CDYL or CTNNB1, placing CTNNB1 downstream of CDYL in endometrial cell function.\",\n      \"method\": \"RNAi knockdown; overexpression rescue; cell migration assay; gene expression analysis in primary endometrial cells\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — functional rescue experiment establishes epistatic relationship, validated in primary cells as well as cell line\",\n      \"pmids\": [\"32158757\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CDYL interacts with MYH9 in murine testis, co-localizes with CDYL at the manchette structure in spermatids. Conditional deletion of Cdyl in spermatogenic cells causes transcriptional downregulation of Myh9, disorganization of the manchette, and abnormal MYH9 localization in spermatozoa.\",\n      \"method\": \"Co-immunoprecipitation with LC-MS/MS; immunofluorescence; Western blot; conditional knockout mouse; RT-qPCR\",\n      \"journal\": \"Zhonghua nan ke xue (National journal of andrology)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP confirmed CDYL-MYH9 interaction in testis, KO mouse with defined localization phenotype; single lab\",\n      \"pmids\": [\"40965992\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"OTUB1, a deubiquitinating enzyme, interacts with and stabilizes CDYL protein. CDYL, together with EZH2, deposits H3K27me3 at the SOX18 promoter to repress its transcription. SOX18 normally transcriptionally activates FDX1, a cuproptosis regulator, so CDYL-driven SOX18 repression suppresses FDX1 expression, enabling resistance to copper-induced cell death in lung cancer cells.\",\n      \"method\": \"Co-immunoprecipitation (OTUB1-CDYL); ChIP (H3K27me3 at SOX18 promoter); transcriptomic and epigenomic profiling; in vivo xenograft with copper chelator treatment\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and Co-IP establish CDYL–EZH2–SOX18 axis mechanistically; single lab study, preprint not required as peer-reviewed\",\n      \"pmids\": [\"41912773\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SETDB1 automethylation on H3K9-like motifs within its catalytic domain is required for interaction with CDYL (as well as SUV39H1 and HP1γ). Automethylation-deficient SETDB1 fails to interact with CDYL, impairing SETDB1 localization to target sites and H3K9me3 establishment.\",\n      \"method\": \"SETDB1 automethylation-deficient mutants; co-immunoprecipitation; ChIP; ESC growth assay\",\n      \"journal\": \"bioRxiv (preprint)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — preprint, single lab, Co-IP interaction but CDYL is one of several partners and mechanistic detail on CDYL side is limited\",\n      \"pmids\": [\"bio_10.1101_2025.10.22.683908\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CDYL deficiency in vascular smooth muscle cells (VSMCs) results in elevated H3K18 crotonylation, which transcriptionally activates SGK1. ChIP assays confirmed CDYL occupancy at the SGK1 locus and its regulation via H3K18cr. SGK1 upregulation promotes VSMC phenotypic switching.\",\n      \"method\": \"CDYL knockdown/overexpression in VSMCs; Western blot for H3K18cr; ChIP; RT-qPCR\",\n      \"journal\": \"Zhonghua yu fang yi xue za zhi\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP establishes CDYL-mediated H3K18cr regulation at SGK1 locus; single lab, limited methodological depth in abstract\",\n      \"pmids\": [\"41287335\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CDYL regulates tubular epithelial cell pyroptosis in acute kidney injury via FABP4-mediated reactive oxygen species production. CDYL overexpression aggravates tubular injury and pyroptosis in cisplatin-induced AKI, while pharmacological inhibition with compound D03 attenuates kidney dysfunction and tubular pyroptosis in mice.\",\n      \"method\": \"RNA sequencing; CDYL overexpression in AKI mouse model; compound D03 pharmacological inhibition; pyroptosis assays\",\n      \"journal\": \"Acta pharmacologica Sinica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo gain-of-function and pharmacological inhibition with defined pyroptosis phenotype; FABP4/ROS pathway identified by transcriptomics; single lab\",\n      \"pmids\": [\"39043969\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CDYL is a chromodomain-containing transcriptional corepressor that (1) enzymatically converts crotonyl-CoA to β-hydroxybutyryl-CoA (crotonyl-CoA hydratase activity), thereby negatively regulating histone and protein lysine crotonylation; (2) reads repressive histone marks H3K9me2/3 and H3K27me2/3 via its chromodomain to localize to heterochromatin and the inactive X chromosome; (3) scaffolds multiprotein repressive complexes by physically bridging REST and G9a, CAF-1 and MCM, and by binding and stimulating PRC2/EZH2 to deposit H3K27me3; (4) is recruited to DNA double-strand breaks via PAR binding, where its hydratase activity reduces local histone Kcr to silence transcription and promote homologous recombination repair; (5) undergoes CDK5-mediated phosphorylation at Ser147 followed by TRIM32-mediated ubiquitination and degradation in response to neural activity; and (6) controls spermatogenesis, neuronal dendrite morphogenesis, sex determination, and other developmental processes through these epigenetic mechanisms.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CDYL is a chromodomain-containing transcriptional corepressor that couples histone acylation metabolism to epigenetic gene silencing across spermatogenesis, neuronal development, sex determination, and DNA repair [#0, #3, #13]. Enzymatically, its C-terminal enoyl-CoA hydratase-like domain functions as a crotonyl-CoA hydratase that converts crotonyl-CoA to \\u03b2-hydroxybutyryl-CoA, depleting the substrate for lysine crotonylation and thereby negatively regulating histone and protein crotonylation genome-wide [#0, #10]; this same domain binds CoA and HDAC1/2, with HDAC binding excluding CoA binding [#2]. Its chromodomain reads the repressive marks H3K9me2/3 and H3K27me2/3, directing CDYL to heterochromatin and the inactive X chromosome, where H3K9me2 supports general chromatin association and combined H3K9me2/H3K27me3 drives Xi-specific enrichment [#4]. CDYL acts as a scaffold for repressive machinery: it bridges the neuronal repressor REST to the methyltransferase G9a [#1], links CAF-1 to the MCM helicase to restore repressive marks during replication by recruiting G9a, SETDB1, and EZH2 to forks [#6], and binds and stimulates PRC2/EZH2 to propagate H3K27me3 at target loci [#3]. Through CDYL-EZH2-directed H3K27me3 deposition, CDYL represses specific target promoters including BDNF in dendrite morphogenesis [#5], SCN8A/Nav1.6 in neuronal excitability [#7], Wnt4 during sex determination where its loss causes XY sex reversal [#17], and CDKN1C and SOX18 in cancer chemoresistance and copper-death evasion [#9, #23]. At DNA double-strand breaks, CDYL1 is recruited via PAR binding by its ECH domain, where it promotes EZH2-dependent H3K27me3 and hydratase-driven loss of histone crotonylation to evict ENL and enforce transcriptional silencing, supporting homologous recombination [#8, #11]. CDYL protein levels are controlled by CDK5-mediated phosphorylation at Ser147, which licenses TRIM32-mediated ubiquitination and proteasomal degradation in response to neural activity [#14, #18]. A homozygous CDYL splicing mutation causes asthenoteratozoospermia in humans [#16].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Established that CDYL is a corepressor whose conserved C-terminal hydratase-like domain binds both CoA and histone deacetylases, posing the question of whether CDYL is a metabolic enzyme or a chromatin regulator.\",\n      \"evidence\": \"CoA-binding and HDAC co-immunoprecipitation assays with transcription repression readout\",\n      \"pmids\": [\"12947414\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not resolve whether CoA binding reflects catalytic activity\", \"No in vivo target genes identified\", \"Functional consequence of mutually exclusive CoA/HDAC binding untested\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Showed CDYL physically bridges REST and G9a into a corepressor complex, defining a scaffolding role linking a sequence-specific repressor to a methyltransferase and connecting CDYL loss to oncogenic transformation.\",\n      \"evidence\": \"Reciprocal Co-IP and RNAi knockdown with oncogenic transformation assay in human cells\",\n      \"pmids\": [\"19061646\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not map the chromatin marks deposited by this complex\", \"Genome-wide targets of the REST-CDYL-G9a complex undefined\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Demonstrated that CDYL's chromodomain reads H3K27me2/3 and that CDYL binds and stimulates PRC2/EZH2, establishing a positive-feedback loop for H3K27me3 propagation rather than a passive reader role.\",\n      \"evidence\": \"In vitro methyltransferase assay on oligonucleosomes, ChIP-seq, chromodomain binding assays\",\n      \"pmids\": [\"22009739\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of PRC2 stimulation not resolved\", \"Did not address how CDYL is initially recruited to nucleate the loop\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined the histone-mark requirements for CDYL chromatin association, showing H3K9me2 supports general localization while combined H3K9me2 and H3K27me3 drive inactive-X enrichment, integrating CDYL into both major repressive mark systems.\",\n      \"evidence\": \"ESC lines with mutated histone methyltransferases, ChIP, immunofluorescence, SILAC Co-IP/MS\",\n      \"pmids\": [\"24144980\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of CDYL on Xi gene silencing not directly tested\", \"Hierarchy between H3K9me2 and H3K27me3 recruitment unresolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Connected CDYL to neuronal plasticity by showing it recruits EZH2/H3K27me3 to the BDNF promoter to restrain dendrite morphogenesis, and that activity-induced CDYL degradation de-represses BDNF.\",\n      \"evidence\": \"Gain/loss-of-function in rat neurons and in vivo, microarray, ChIP, Co-IP\",\n      \"pmids\": [\"24671995\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of activity-induced CDYL degradation not identified at this stage\", \"Other neuronal CDYL targets unmapped\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Resolved the metabolic-versus-epigenetic question by demonstrating CDYL is a crotonyl-CoA hydratase that negatively regulates histone crotonylation, linking its enzymatic activity directly to repression of sex-linked genes and histone replacement in spermatids.\",\n      \"evidence\": \"Reconstituted in vitro enzymatic assay plus Cdyl transgenic mouse with sperm phenotype and histone modification analysis\",\n      \"pmids\": [\"28803779\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of hydratase versus scaffolding activity to phenotypes not parsed\", \"Substrate range beyond histones unaddressed at this point\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Extended CDYL function to S-phase by showing it bridges CAF-1 and the MCM helicase and recruits G9a/SETDB1/EZH2 to replication forks, providing a mechanism for inheritance of repressive marks on newly deposited histones.\",\n      \"evidence\": \"Reciprocal Co-IP, chromatin fractionation, ChIP at forks, cell cycle analysis\",\n      \"pmids\": [\"28402439\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct demonstration of mark transmission to daughter chromatin not shown\", \"How CDYL is targeted specifically to forks unresolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showed CDYL represses the Nav1.6 sodium channel gene SCN8A via H3K27me3, defining a causal epigenetic control of neuronal excitability and seizure susceptibility.\",\n      \"evidence\": \"ChIP, electrophysiology, RNAi, transgenic mouse, human brain tissue\",\n      \"pmids\": [\"28842554\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether hydratase activity contributes to SCN8A silencing not tested\", \"Broader epilepsy-relevant CDYL targets undefined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Reported a distinct CDYL activity as a tubulin acetyltransferase in sperm flagella, suggesting a cytoplasmic, microtubule-directed function separate from chromatin repression.\",\n      \"evidence\": \"Microscale thermophoresis, in vitro tubulin acetylation assay, sperm co-localization, cellular overexpression\",\n      \"pmids\": [\"28681565\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab finding without independent confirmation\", \"Catalytic mechanism for acetyltransferase activity unresolved\", \"Relationship to the established hydratase/repressor functions unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Placed CDYL1 in the DNA damage response by showing its ECH domain binds PAR for PARP1-dependent recruitment to double-strand breaks, where it promotes EZH2/H3K27me3, transcriptional silencing, and homologous recombination.\",\n      \"evidence\": \"Live-cell imaging, ChIP, Co-IP, HR traffic-light reporter, domain mapping, PAR-binding assay, KO with cisplatin synthetic lethality\",\n      \"pmids\": [\"29177481\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not separate the silencing function from HR repair\", \"Role of hydratase activity at breaks not yet addressed\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrated CDYL is required for spermatogonia maintenance and spermatozoon morphogenesis in vivo, establishing male fertility as a core physiological output of CDYL-dependent histone modification control.\",\n      \"evidence\": \"Germline conditional knockout mouse, histology, histone modification and transcriptome analysis\",\n      \"pmids\": [\"30850578\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific target genes driving the sperm phenotype not pinpointed\", \"Contribution of individual CDYL activities not dissected\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified CDYL as a chemoresistance driver in small cell lung cancer via the CDYL/EZH2/CDKN1C axis, providing a pharmacologically tractable EZH2-dependent vulnerability.\",\n      \"evidence\": \"ChIP-qPCR, Co-IP, GST pull-down, gain/loss-of-function, xenograft with GSK126\",\n      \"pmids\": [\"31367252\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether crotonylation contributes to CDKN1C silencing not tested\", \"Generality across cancer types unaddressed\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Provided a chemical-biology tool by developing D03, a chromodomain-binding small-molecule inhibitor that displaces CDYL from chromatin and de-represses targets, validating the chromodomain as a druggable module.\",\n      \"evidence\": \"SPR, structure-guided docking, cellular target engagement, ChIP, neurite morphology\",\n      \"pmids\": [\"31494467\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Selectivity against other chromodomain proteins limited in scope\", \"Does not affect hydratase activity directly\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Generalized CDYL's anti-crotonylation function beyond histones by showing it controls RPA1 crotonylation, where Kcr sites govern ssDNA and resection-machinery binding, linking protein crotonylation to homologous recombination.\",\n      \"evidence\": \"Crotonylome proteomics in CDYL-depleted cells, RPA1 Kcr site mutagenesis, ssDNA-binding and Co-IP assays\",\n      \"pmids\": [\"32201722\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full set of CDYL-regulated non-histone crotonylation substrates unknown\", \"Direct CDYL action on RPA1 versus indirect crotonyl-CoA depletion not separated\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Linked CDYL to endometrial cell migration through CTNNB1, placing \\u03b2-catenin downstream of CDYL in a non-neuronal epithelial context.\",\n      \"evidence\": \"RNAi knockdown, overexpression rescue, migration assay in primary endometrial cells\",\n      \"pmids\": [\"32158757\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which CDYL regulates CTNNB1 not defined\", \"Whether chromatin or enzymatic activity is involved untested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Causally uncoupled CDYL's two DSB functions by showing its hydratase activity drives local Kcr/H3K9cr loss and ENL eviction to enforce silencing, while being dispensable for HR efficiency.\",\n      \"evidence\": \"Hydratase active-site mutants, ChIP for Kcr/H3K9cr at AsiSI breaks, transcription reporter and HR assays\",\n      \"pmids\": [\"35447080\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological importance of DSB-induced silencing per se unclear\", \"Interplay with the PAR-recruitment/EZH2 arm not fully integrated\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Revealed that CDYL forms liquid-liquid phase-separated nuclear condensates required for locus-specific Kcr suppression, and that this activity slows cyst growth in a polycystic kidney model, adding a biophysical layer to its repressive function.\",\n      \"evidence\": \"Phase-separation assays, zebrafish, Cdyl x Pkd1 KO mouse crosses, ChIP-seq, histone acylation MS\",\n      \"pmids\": [\"35918147\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Condensate composition and regulation in vivo incompletely defined\", \"Relationship between phase separation and scaffolding/enzymatic activities unresolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified TRIM32 as the E3 ligase that ubiquitinates and degrades CDYL to promote dendrite arborization, providing the long-sought mechanism for activity-coupled CDYL turnover.\",\n      \"evidence\": \"Mass spectrometry, Co-IP, in vitro/in vivo ubiquitylation, \\u0394RING mutant, neuron epistasis rescue\",\n      \"pmids\": [\"34888944\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signal triggering TRIM32-CDYL targeting not defined at this stage\", \"Whether degradation is locus-selective unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established CDYL as a determinant of sex determination by showing it represses Wnt4 via H3K27me3 to permit Sox9 expression, with its loss causing XY sex reversal rescuable by Wnt4 haploinsufficiency.\",\n      \"evidence\": \"Cdyl conditional KO mouse, H3K27me3 ChIP, Wnt4 heterozygous genetic epistasis\",\n      \"pmids\": [\"37155872\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream regulator targeting CDYL to the Wnt4 locus unknown\", \"Timing window restricting this function not mechanistically defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Connected CDYL to cortical neural cell-fate decisions by showing it represses NNAT and that CDYL loss biases human cortical NSCs toward GABAergic identity.\",\n      \"evidence\": \"Human cortical organoid KO, RNA-seq, gain/loss-of-function, cross-species comparison\",\n      \"pmids\": [\"39378153\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct chromatin mechanism at NNAT not fully established\", \"Single-lab organoid model\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Implicated CDYL in acute kidney injury by showing it regulates tubular epithelial pyroptosis via FABP4/ROS, with pharmacological D03 inhibition protective in mice.\",\n      \"evidence\": \"RNA-seq, CDYL overexpression in AKI model, D03 inhibition, pyroptosis assays\",\n      \"pmids\": [\"39043969\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct chromatin link between CDYL and FABP4 not demonstrated\", \"Single-lab in vivo study\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Completed the activity-dependent regulatory circuit by showing CDK5 phosphorylates CDYL at Ser147 to license TRIM32-mediated degradation, with functional consequences for contextual fear memory.\",\n      \"evidence\": \"In vitro/in vivo phosphorylation, Ser147 mutagenesis, ubiquitination assay, interfering peptide, conditional KO mouse\",\n      \"pmids\": [\"40885707\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How CDK5 is activated to target CDYL in specific neurons unclear\", \"Locus selectivity of the degraded CDYL pool undefined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Provided human genetic evidence that a CDYL splicing mutation reducing flagellar tubulin acetylation causes asthenoteratozoospermia, translating the sperm phenotype to human male infertility.\",\n      \"evidence\": \"Whole-exome sequencing, minigene splicing assay, IF co-localization, sperm electron microscopy\",\n      \"pmids\": [\"39823157\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-patient case\", \"Whether the defect reflects loss of acetyltransferase versus chromatin function not resolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Extended CDYL's repressive scaffolding to vascular biology and cancer copper-death, showing CDYL controls H3K18cr at SGK1 in VSMCs and, stabilized by OTUB1, represses SOX18 to suppress FDX1 and confer cuproptosis resistance.\",\n      \"evidence\": \"CDYL knockdown/overexpression with ChIP in VSMCs; OTUB1-CDYL Co-IP, SOX18 H3K27me3 ChIP, xenograft with copper chelator\",\n      \"pmids\": [\"41287335\", \"41912773\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Both are single-lab studies\", \"Integration of crotonylation and H3K27me3 arms at these loci unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified CDYL as a testis-specific partner of MYH9 at the spermatid manchette, linking CDYL to cytoskeletal organization during spermiogenesis.\",\n      \"evidence\": \"Co-IP/LC-MS/MS, immunofluorescence, conditional KO mouse, RT-qPCR\",\n      \"pmids\": [\"40965992\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether interaction is direct not established\", \"Single-lab study\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CDYL's distinct activities \\u2014 crotonyl-CoA hydratase, methyl-mark reader/PRC2 scaffold, tubulin acetyltransferase, and phase-separation \\u2014 are coordinated, switched, and targeted to specific loci within a given cell context remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model partitioning hydratase versus scaffolding contributions per phenotype\", \"Structural basis for chromodomain mark discrimination and PRC2 stimulation incomplete\", \"Tubulin acetyltransferase activity not independently confirmed or mechanistically explained\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016853\", \"supporting_discovery_ids\": [0, 10, 11]},\n      {\"term_id\": \"GO:0016829\", \"supporting_discovery_ids\": [0, 11]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [3, 4]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [1, 2, 5, 7, 17]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 6]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [7, 17]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [15]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [15, 22]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [3, 4, 12]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [3, 6, 8]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [15, 22]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [3, 4, 6]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [1, 5, 7, 17]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [8, 10, 11]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [13, 17, 20]},\n      {\"term_id\": \"R-HSA-69306\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 10]}\n    ],\n    \"complexes\": [\n      \"REST-CDYL-G9a corepressor complex\",\n      \"CDYL-PRC2/EZH2\",\n      \"CDYL-CAF-1-MCM replication complex\"\n    ],\n    \"partners\": [\n      \"EZH2\",\n      \"G9a\",\n      \"REST\",\n      \"SETDB1\",\n      \"CAF-1\",\n      \"TRIM32\",\n      \"OTUB1\",\n      \"MYH9\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}