Affinage

CDYL

Chromodomain Y-like protein · UniProt Q9Y232

Length
598 aa
Mass
66.5 kDa
Annotated
2026-06-09
41 papers in source corpus 27 papers cited in narrative 27 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 25 steps
  1. 2003 Medium

    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

    PMID:12947414

    Open questions at the time
    • Did not resolve whether CoA binding reflects catalytic activity
    • No in vivo target genes identified
    • Functional consequence of mutually exclusive CoA/HDAC binding untested
  2. 2008 High

    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

    PMID:19061646

    Open questions at the time
    • Did not map the chromatin marks deposited by this complex
    • Genome-wide targets of the REST-CDYL-G9a complex undefined
  3. 2011 High

    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

    PMID:22009739

    Open questions at the time
    • Structural basis of PRC2 stimulation not resolved
    • Did not address how CDYL is initially recruited to nucleate the loop
  4. 2013 High

    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

    PMID:24144980

    Open questions at the time
    • Functional consequence of CDYL on Xi gene silencing not directly tested
    • Hierarchy between H3K9me2 and H3K27me3 recruitment unresolved
  5. 2014 High

    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

    PMID:24671995

    Open questions at the time
    • Mechanism of activity-induced CDYL degradation not identified at this stage
    • Other neuronal CDYL targets unmapped
  6. 2017 High

    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

    PMID:28803779

    Open questions at the time
    • Relative contribution of hydratase versus scaffolding activity to phenotypes not parsed
    • Substrate range beyond histones unaddressed at this point
  7. 2017 High

    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

    PMID:28402439

    Open questions at the time
    • Direct demonstration of mark transmission to daughter chromatin not shown
    • How CDYL is targeted specifically to forks unresolved
  8. 2017 High

    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

    PMID:28842554

    Open questions at the time
    • Whether hydratase activity contributes to SCN8A silencing not tested
    • Broader epilepsy-relevant CDYL targets undefined
  9. 2017 Medium

    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

    PMID:28681565

    Open questions at the time
    • Single-lab finding without independent confirmation
    • Catalytic mechanism for acetyltransferase activity unresolved
    • Relationship to the established hydratase/repressor functions unclear
  10. 2018 High

    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

    PMID:29177481

    Open questions at the time
    • Did not separate the silencing function from HR repair
    • Role of hydratase activity at breaks not yet addressed
  11. 2019 High

    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

    PMID:30850578

    Open questions at the time
    • Specific target genes driving the sperm phenotype not pinpointed
    • Contribution of individual CDYL activities not dissected
  12. 2019 High

    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

    PMID:31367252

    Open questions at the time
    • Whether crotonylation contributes to CDKN1C silencing not tested
    • Generality across cancer types unaddressed
  13. 2019 Medium

    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

    PMID:31494467

    Open questions at the time
    • Selectivity against other chromodomain proteins limited in scope
    • Does not affect hydratase activity directly
  14. 2020 High

    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

    PMID:32201722

    Open questions at the time
    • Full set of CDYL-regulated non-histone crotonylation substrates unknown
    • Direct CDYL action on RPA1 versus indirect crotonyl-CoA depletion not separated
  15. 2020 Medium

    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

    PMID:32158757

    Open questions at the time
    • Mechanism by which CDYL regulates CTNNB1 not defined
    • Whether chromatin or enzymatic activity is involved untested
  16. 2022 High

    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

    PMID:35447080

    Open questions at the time
    • Physiological importance of DSB-induced silencing per se unclear
    • Interplay with the PAR-recruitment/EZH2 arm not fully integrated
  17. 2022 High

    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

    PMID:35918147

    Open questions at the time
    • Condensate composition and regulation in vivo incompletely defined
    • Relationship between phase separation and scaffolding/enzymatic activities unresolved
  18. 2022 High

    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

    PMID:34888944

    Open questions at the time
    • Signal triggering TRIM32-CDYL targeting not defined at this stage
    • Whether degradation is locus-selective unknown
  19. 2023 High

    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

    PMID:37155872

    Open questions at the time
    • Upstream regulator targeting CDYL to the Wnt4 locus unknown
    • Timing window restricting this function not mechanistically defined
  20. 2024 Medium

    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

    PMID:39378153

    Open questions at the time
    • Direct chromatin mechanism at NNAT not fully established
    • Single-lab organoid model
  21. 2024 Medium

    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

    PMID:39043969

    Open questions at the time
    • Direct chromatin link between CDYL and FABP4 not demonstrated
    • Single-lab in vivo study
  22. 2025 High

    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

    PMID:40885707

    Open questions at the time
    • How CDK5 is activated to target CDYL in specific neurons unclear
    • Locus selectivity of the degraded CDYL pool undefined
  23. 2025 Medium

    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

    PMID:39823157

    Open questions at the time
    • Single-patient case
    • Whether the defect reflects loss of acetyltransferase versus chromatin function not resolved
  24. 2025 Medium

    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

    PMID:41287335 PMID:41912773

    Open questions at the time
    • Both are single-lab studies
    • Integration of crotonylation and H3K27me3 arms at these loci unresolved
  25. 2025 Medium

    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

    PMID:40965992

    Open questions at the time
    • Whether interaction is direct not established
    • Single-lab study

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 5 GO:0016853 isomerase activity 3 GO:0003677 DNA binding 2 GO:0008092 cytoskeletal protein binding 2 GO:0016829 lyase activity 2 GO:0042393 histone binding 2 GO:0060090 molecular adaptor activity 2 GO:0016740 transferase activity 1 GO:0098772 molecular function regulator activity 1
Localization
GO:0005634 nucleus 3 GO:0005694 chromosome 3 GO:0005856 cytoskeleton 2 GO:0000228 nuclear chromosome 1
Pathway
R-HSA-74160 Gene expression (Transcription) 4 R-HSA-1266738 Developmental Biology 3 R-HSA-4839726 Chromatin organization 3 R-HSA-73894 DNA Repair 3 R-HSA-1430728 Metabolism 2 R-HSA-69306 DNA Replication 1
Partners
CAF-1EZH2G9AMYH9OTUB1RESTSETDB1TRIM32
Complex memberships
CDYL-CAF-1-MCM replication complexCDYL-PRC2/EZH2REST-CDYL-G9a corepressor complex

Evidence

Reading pass · 27 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2017 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. Biochemical in vitro enzymatic assay; Cdyl transgenic mouse model with sperm phenotype readout; histone modification analysis Molecular cell High 28803779
2008 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. Co-immunoprecipitation; RNAi knockdown; oncogenic transformation assay in human cells Molecular cell High 19061646
2003 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. CoA-binding assay; co-immunoprecipitation with HDACs; transcription repression assay EMBO reports Medium 12947414
2011 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. In vitro methyltransferase assay with oligonucleosome substrates; co-immunoprecipitation; ChIP-sequencing; chromodomain binding assays The Journal of biological chemistry High 22009739
2013 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. Mouse embryonic stem cell lines with mutated histone methyltransferases; ChIP; immunofluorescence; co-immunoprecipitation/mass spectrometry (SILAC) Molecular and cellular biology High 24144980
2014 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. Gain- and loss-of-function in primary cultured rat neurons and in vivo; DNA microarray; ChIP; co-immunoprecipitation The Journal of neuroscience High 24671995
2017 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. Co-immunoprecipitation; chromatin fractionation; cell cycle analysis; ChIP Journal of molecular cell biology High 28402439
2017 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. ChIP; electrophysiology; RNAi knockdown in neurons; transgenic mouse model; human brain tissue analysis Nature communications High 28842554
2018 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. Live-cell imaging; ChIP; co-immunoprecipitation; 'traffic-light reporter' system for HR quantification; cell cycle analysis; domain-deletion mapping; PAR-binding assay Journal of molecular cell biology High 29177481
2019 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. ChIP-qPCR; co-immunoprecipitation; GST pull-down; gain- and loss-of-function assays; in vivo xenograft Theranostics High 31367252
2020 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. Large-scale proteomics/mass spectrometry crotonylome analysis in CDYL-depleted HeLa cells; RPA1 Kcr site mutagenesis; ssDNA-binding assay; co-immunoprecipitation Science advances High 32201722
2022 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. CDYL1 hydratase active-site mutants; ChIP for Kcr and H3K9cr at AsiSI-induced DSBs; transcription reporter assay; HR repair assay Molecular cell High 35447080
2022 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. Biochemical phase-separation assays; zebrafish model; Cdyl transgenic × Pkd1 KO mouse crosses; ChIP-seq; mass spectrometry histone acylation analysis Journal of the American Society of Nephrology High 35918147
2019 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. Germline conditional knockout mouse model; histology; histone modification analysis; transcriptome analysis Cell death & disease High 30850578
2022 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. Mass spectrometry; co-immunoprecipitation; ubiquitylation assay in vitro and in vivo; gain/loss-of-function in primary rat neurons; domain mutant (ΔRING) FASEB journal High 34888944
2017 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. Microscale thermophoresis (chromodomain–α-tubulin interaction); in vitro tubulin acetylation assay; co-localization in sperm; CDYL overexpression in cells Cytoskeleton Medium 28681565
2025 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. Whole-exome sequencing; minigene alternative splicing assay; immunofluorescence co-localization; sperm ultrastructural analysis (electron microscopy) Andrology Medium 39823157
2023 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. Cdyl conditional knockout mouse; ChIP (H3K27me3); genetic epistasis via Wnt4 heterozygous rescue; gene expression analysis Proceedings of the National Academy of Sciences High 37155872
2025 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. In vitro and in vivo phosphorylation assays; mutagenesis at Ser147; co-immunoprecipitation; ubiquitination assay; interfering peptide in vivo; conditional KO mouse Translational psychiatry High 40885707
2019 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. SPR binding assay; structure-guided molecular docking; cellular target engagement assay; ChIP; neurite morphology analysis European journal of medicinal chemistry Medium 31494467
2024 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. Human cortical organoids with CDYL knockout; RNA-seq; gain- and loss-of-function; cross-species comparison Cell reports Medium 39378153
2020 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. RNAi knockdown; overexpression rescue; cell migration assay; gene expression analysis in primary endometrial cells Frontiers in cell and developmental biology Medium 32158757
2025 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. Co-immunoprecipitation with LC-MS/MS; immunofluorescence; Western blot; conditional knockout mouse; RT-qPCR Zhonghua nan ke xue (National journal of andrology) Medium 40965992
2026 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. Co-immunoprecipitation (OTUB1-CDYL); ChIP (H3K27me3 at SOX18 promoter); transcriptomic and epigenomic profiling; in vivo xenograft with copper chelator treatment Oncogene Medium 41912773
2025 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. SETDB1 automethylation-deficient mutants; co-immunoprecipitation; ChIP; ESC growth assay bioRxiv (preprint)preprint Low bio_10.1101_2025.10.22.683908
2025 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. CDYL knockdown/overexpression in VSMCs; Western blot for H3K18cr; ChIP; RT-qPCR Zhonghua yu fang yi xue za zhi Medium 41287335
2024 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. RNA sequencing; CDYL overexpression in AKI mouse model; compound D03 pharmacological inhibition; pyroptosis assays Acta pharmacologica Sinica Medium 39043969

Source papers

Stage 0 corpus · 41 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2017 Chromodomain Protein CDYL Acts as a Crotonyl-CoA Hydratase to Regulate Histone Crotonylation and Spermatogenesis. Molecular cell 197 28803779
2019 A Noncoding Regulatory RNAs Network Driven by Circ-CDYL Acts Specifically in the Early Stages Hepatocellular Carcinoma. Hepatology (Baltimore, Md.) 182 31148183
2008 CDYL bridges REST and histone methyltransferases for gene repression and suppression of cellular transformation. Molecular cell 124 19061646
2020 Global crotonylome reveals CDYL-regulated RPA1 crotonylation in homologous recombination-mediated DNA repair. Science advances 120 32201722
2021 Circular RNA Cdyl promotes abdominal aortic aneurysm formation by inducing M1 macrophage polarization and M1-type inflammation. Molecular therapy : the journal of the American Society of Gene Therapy 106 34547461
2003 Cdyl: a new transcriptional co-repressor. EMBO reports 95 12947414
2011 Corepressor protein CDYL functions as a molecular bridge between polycomb repressor complex 2 and repressive chromatin mark trimethylated histone lysine 27. The Journal of biological chemistry 67 22009739
2013 Cdyl, a new partner of the inactive X chromosome and potential reader of H3K27me3 and H3K9me2. Molecular and cellular biology 61 24144980
2020 Circular RNA (circRNA) CDYL Induces Myocardial Regeneration by ceRNA After Myocardial Infarction. Medical science monitor : international medical journal of experimental and clinical research 55 32522972
2018 CDYL1 fosters double-strand break-induced transcription silencing and promotes homology-directed repair. Journal of molecular cell biology 54 29177481
2017 CDYL suppresses epileptogenesis in mice through repression of axonal Nav1.6 sodium channel expression. Nature communications 49 28842554
2014 Coordinated regulation of dendrite arborization by epigenetic factors CDYL and EZH2. The Journal of neuroscience : the official journal of the Society for Neuroscience 47 24671995
2019 CDYL promotes the chemoresistance of small cell lung cancer by regulating H3K27 trimethylation at the CDKN1C promoter. Theranostics 41 31367252
2020 Circular RNA circ-CDYL sponges miR-1180 to elevate yes-associated protein in multiple myeloma. Experimental biology and medicine (Maywood, N.J.) 38 32321304
2017 Chromodomain protein CDYL is required for transmission/restoration of repressive histone marks. Journal of molecular cell biology 36 28402439
2023 Hypoxia-induced circ-CDYL-EEF1A2 transcriptional complex drives lung metastasis of cancer stem cells from hepatocellular carcinoma. Cancer letters 34 37852428
2022 CDYL1-dependent decrease in lysine crotonylation at DNA double-strand break sites functionally uncouples transcriptional silencing and repair. Molecular cell 30 35447080
2022 Nuclear Condensation of CDYL Links Histone Crotonylation and Cystogenesis in Autosomal Dominant Polycystic Kidney Disease. Journal of the American Society of Nephrology : JASN 30 35918147
2019 Germline deletion of Cdyl causes teratozoospermia and progressive infertility in male mice. Cell death & disease 23 30850578
2020 Loss of CDYL Results in Suppression of CTNNB1 and Decreased Endometrial Receptivity. Frontiers in cell and developmental biology 21 32158757
2025 Circular RNA CDYL facilitates hepatocellular carcinoma stemness and PD-L1+ exosomes-mediated immunotherapy resistance via stabilizing hornerin protein by blocking synoviolin 1-mediated ubiquitination. International journal of biological macromolecules 15 40250664
2013 Generation and neuronal differentiation of induced pluripotent stem cells in Cdyl-/- mice. Neuroreport 14 23282990
2019 Identification and characterization of benzo[d]oxazol-2(3H)-one derivatives as the first potent and selective small-molecule inhibitors of chromodomain protein CDYL. European journal of medicinal chemistry 13 31494467
2023 CDYL knockdown reduces glioma development through an antitumor immune response in the tumor microenvironment. Cancer letters 12 37302564
2022 Knockdown of circ_CDYL Contributes to Inhibit Angiotensin II-Induced Podocytes Apoptosis in Membranous Nephropathy via the miR-149-5p/TNFSF11 Pathway. Journal of cardiovascular pharmacology 10 35353073
2022 Ubiquitin ligase TRIM32 promotes dendrite arborization by mediating degradation of the epigenetic factor CDYL. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 8 34888944
2017 Tubulin acetylation: A novel functional avenue for CDYL in sperm. Cytoskeleton (Hoboken, N.J.) 8 28681565
2023 CDYL reinforces male gonadal sex determination through epigenetically repressing Wnt4 transcription in mice. Proceedings of the National Academy of Sciences of the United States of America 6 37155872
2024 The chromodomain protein CDYL confers forebrain identity to human cortical organoids by inhibiting neuronatin. Cell reports 5 39378153
2024 CDYL loss promotes cervical cancer aggression by increasing PD-L1 expression via the suppression of IRF2BP2 transcription. Translational oncology 2 38991463
2024 Chromodomain Y-like (CDYL) inhibition ameliorates acute kidney injury in mice by regulating tubular pyroptosis. Acta pharmacologica Sinica 2 39043969
2025 Aberrant acetylation caused by a CDYL splicing mutation contributes to thin mid-piece related asthenoteratozoospermia and male infertility. Andrology 1 39823157
2022 Disruption of Cdyl gene impairs mouse lung epithelium differentiation and maturation. Gene 1 36464171
2026 CircRNA Cdyl promotes the proliferation and differentiation of neural stem cells via regulating miR-544-3p/Nr3c1 axis. iScience 0 41675054
2026 OTUB1/CDYL axis-mediated epigenetic repression of SOX18 facilitates lung cancer progression by inhibiting FDX1-dependent cuproptosis. Oncogene 0 41912773
2026 Elevated CDYL expression in the peripheral blood of patients with rheumatoid arthritis. BMC immunology 0 42174416
2025 CircCDYL Association With hnRNPL Modulates CDYL Isoform Switching in Breast Cancer Cells. Cancer science 0 40702809
2025 Activity-dependent phosphorylation of CDYL by CDK5 regulates fear memory in mice. Translational psychiatry 0 40885707
2025 [Expression and function of CDYL-interacting protein MYH9 in mouse testis]. Zhonghua nan ke xue = National journal of andrology 0 40965992
2025 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. International journal of general medicine 0 41199761
2025 [CDYL deficiency promotes vascular smooth muscle cell phenotypic switching through H3K18 crotonylation-mediated SGK1 transcriptional activation]. Zhonghua yu fang yi xue za zhi [Chinese journal of preventive medicine] 0 41287335

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