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CDYL2

Chromodomain Y-like protein 2 · UniProt Q8N8U2

Length
506 aa
Mass
56.5 kDa
Annotated
2026-06-09
18 papers in source corpus 10 papers cited in narrative 10 extracted findings
Cross-family judge faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CDYL2 is a chromodomain-containing epigenetic reader that couples recognition of methylated histone marks to chromatin-based gene repression and mitotic genome stability (PMID:18450745, PMID:36658409). Its chromodomain binds multiple lysine-methylated ARK(S/T) motifs with comparatively low selectivity relative to CDY, and structural analysis shows a binding preference for H3tK27me3 over H3K27me3 (PMID:18450745, PMID:32470319). At pericentromeres, CDYL2 is recruited in an H3K9me3-dependent manner and, through a central non-conserved region, acts as an adaptor linking this mark to the mitotic regulators CHAMP1 and POGZ; both the chromodomain and the CHAMP1-POGZ-interacting region are required and together sufficient for CDYL2's role in mitotic fidelity, and its depletion causes loss of pericentromeric CHAMP1, nuclear aberrations, and mitotic errors (PMID:36658409). In a transcriptional repression role, CDYL2 co-immunoprecipitates with the histone methyltransferases G9a/EHMT2 and GLP/EHMT1 and modulates chromatin enrichment of G9a and EZH2 to silence MIR124, and it also represses SLC7A6 by reducing promoter H3K4me3, thereby restraining amino acid transport and mTORC1/S6K signaling (PMID:32450513, PMID:35314791). CDYL2 produces functionally distinct isoforms: CDYL2a localizes to SC35-positive nuclear speckles and promotes exon-skipping alternative splicing of FIP1L1, NKTR, and ADD3, while CDYL2b associates with heterochromatin to repress metastasis-promoting genes (HPSE, HLA-F, SELL) and forms complexes with JMJD2B that antagonize its transcriptional output (PMID:32373210, PMID:40812719).

Mechanistic history

Synthesis pass · year-by-year structured walk · 7 steps
  1. 2008 High

    Established the biochemical reader logic of the CDYL2 chromodomain, showing it binds a broad set of methylated ARK(S/T) histone motifs rather than discriminating among them as CDY does, explaining its variable chromatin distribution.

    Evidence In vitro methyllysine binding assays, point mutagenesis, and in vivo chromatin localization

    PMID:18450745

    Open questions at the time
    • Did not define which physiological mark dominates recruitment in vivo
    • No structural basis for the binding breadth
  2. 2020 High

    Provided the structural basis for CDYL2 mark selectivity, distinguishing it from CDY1 by preferential recognition of H3tK27me3 over H3K27me3.

    Evidence Crystal structure determination with selective chemical probe (UNC4850) validation

    PMID:32470319

    Open questions at the time
    • Physiological relevance of testis-specific H3tK27me3 binding not established
    • Does not address H3K9me3-dependent recruitment seen elsewhere
  3. 2020 Medium

    Connected CDYL2 to active gene repression by showing it partners with G9a/GLP and controls G9a/EZH2 occupancy at MIR124, linking the reader to a transcriptional silencing program driving breast cancer cell plasticity.

    Evidence Reciprocal Co-IP, ChIP-qPCR, and RNAi with migration/invasion/EMT readouts

    PMID:32450513

    Open questions at the time
    • Direct vs indirect recruitment of G9a/EZH2 not resolved
    • Single-lab functional model
  4. 2020 High

    Revealed isoform-specific functional partitioning, with CDYL2a driving alternative splicing at nuclear speckles and CDYL2b mediating heterochromatic repression of metastasis genes.

    Evidence Immunofluorescence, RNA-seq, ATAC-seq, ChIP-qPCR, and RNAi-rescue functional assays

    PMID:32373210

    Open questions at the time
    • Mechanism by which CDYL2a influences splicing machinery unknown
    • Roles of CDYL2c/CDYL2d not characterized
  5. 2022 Medium

    Extended CDYL2's repressive reach to metabolic control, showing it lowers SLC7A6 promoter H3K4me3 to suppress amino acid transport and mTORC1/S6K signaling, and identified STAT5A as its upstream transcriptional activator.

    Evidence ChIP-qPCR, gain/loss-of-function, and in vitro/in vivo functional assays

    PMID:35314791

    Open questions at the time
    • Mechanism of H3K4me3 reduction (demethylase recruitment) not defined
    • Single-lab evidence
  6. 2023 High

    Defined CDYL2 as a pericentromeric adaptor coupling H3K9me3 to the mitotic regulators CHAMP1 and POGZ, establishing a direct role in mitotic fidelity and genome stability.

    Evidence Mass spectrometry of interactors, RNAi rescue with domain mutants, and immunofluorescence of pericentromeric localization

    PMID:36658409

    Open questions at the time
    • How CHAMP1/POGZ enforce mitotic fidelity downstream not detailed
    • Interaction not structurally resolved
  7. 2025 Medium

    Showed CDYL2 isoforms oligomerize and that CDYL2b suppresses prostate cancer growth, with JMJD2B forming a complex that antagonizes CDYL2b-driven HES7 activation, while JMJD2A/B repress CDYL2 transcription.

    Evidence Co-IP, overexpression/knockdown with in vitro/in vivo assays, RNA-seq, and chromatin fractionation

    PMID:40812719

    Open questions at the time
    • Stoichiometry and structure of CDYL2b-JMJD2B complex unknown
    • Direct vs indirect HES7 regulation not resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How CDYL2's distinct activities — pericentromeric mitotic adaptor, HMT-coupled transcriptional repressor, and speckle-associated splicing factor — are coordinated and selected within a cell remains unresolved.
  • No unified model linking isoform choice to function
  • Endogenous mark-specific recruitment determinants undefined
  • Physiological role in spermatogenesis suggested only by expression data

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 4 GO:0042393 histone binding 2 GO:0060090 molecular adaptor activity 1
Localization
GO:0000228 nuclear chromosome 2 GO:0005634 nucleus 2 GO:0005654 nucleoplasm 1
Pathway
R-HSA-4839726 Chromatin organization 3 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-1640170 Cell Cycle 1 R-HSA-8953854 Metabolism of RNA 1
Partners
CHAMP1EHMT1EHMT2JMJD2BPOGZ

Evidence

Reading pass · 10 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2008 The CDYL2 chromodomain binds with comparable strength to multiple lysine-methylated ARK(S/T) motifs (including H3K9me3 and related marks), in contrast to CDY which shows discriminatory binding; full-length CDYL2 shows corresponding variability in chromatin localization. Point mutations in the CDYL chromodomain can rescue binding to these motifs. In vitro methyllysine binding assays, in vivo chromatin localization experiments, point mutagenesis The Journal of biological chemistry High 18450745
2020 Crystal/structural analysis revealed that CDYL2 chromodomain preferentially binds H3tK27me3 over H3K27me3, providing a structural basis for its binding selectivity distinct from CDY1 (which selectively binds H3K9me3). The CDYL1/2-selective compound UNC4850 provided further mechanistic insight into CDYL2 binding specificity. Crystal structure determination, structural analysis, compound binding studies Cell chemical biology High 32470319
2020 CDYL2 co-immunoprecipitates with G9a/EHMT2 and GLP/EHMT1, and regulates chromatin enrichment of G9a and EZH2 at MIR124 gene loci, resulting in epigenetic repression of MIR124 and downstream activation of NF-κB and STAT3 signaling, promoting breast cancer cell plasticity, migration, invasion, and EMT. Co-immunoprecipitation, ChIP-qPCR, RNAi knockdown with functional assays (migration, invasion, EMT markers) iScience Medium 32450513
2020 CDYL2 generates four transcript variants (CDYL2a–CDYL2d). CDYL2a localizes to SC35-positive nuclear speckles and promotes alternative splicing (exon skipping) of target genes FIP1L1, NKTR, and ADD3, promoting cell proliferation. CDYL2b localizes to heterochromatin and transcriptionally represses metastasis-promoting genes HPSE, HLA-F, and SELL, suppressing breast cancer cell migration and invasion. Immunofluorescent staining, RNA-seq, ATAC-seq, ChIP-qPCR, RNAi knockdown with rescue experiments, in vitro and in vivo functional assays Theranostics High 32373210
2022 CDYL2 down-regulates SLC7A6 expression by decreasing H3K4me3 enrichment at the SLC7A6 promoter, thereby suppressing amino acid transport and inhibiting the mTORC1/S6K pathway. STAT5A was identified as a direct positive transcriptional regulator of CDYL2. ChIP-qPCR (H3K4me3 at SLC7A6 promoter), gain- and loss-of-function experiments, in vitro and in vivo functional assays Oncogene Medium 35314791
2023 CDYL2 is recruited to pericentromeres in an H3K9me3-dependent manner, where it interacts (via a central non-conserved region) with mitotic regulators CHAMP1 and POGZ, identified by mass spectrometry. Both the CDYL2 chromodomain and the CHAMP1-POGZ interacting region are required and together sufficient for CDYL2's role in mitotic fidelity and genome stability. CDYL2 RNAi caused loss of CHAMP1 at pericentromeres, nuclear aberrations, and mitotic errors. Mass spectrometry of CDYL2-interacting proteins, RNAi knockdown, RNAi rescue assays with domain mutants, immunofluorescence (pericentromere localization, CHAMP1 localization) Cellular and molecular life sciences : CMLS High 36658409
2011 Knockdown of Cdyl2 in mouse embryonic stem cells leads to only modest proviral reactivation of ERVs (class I and II), indicating that Cdyl2 is largely dispensable for SETDB1/H3K9me3-dependent retroviral silencing. shRNA knockdown of Cdyl2 in mESCs with ERV reporter constructs; retroviral reactivation assay Epigenetics & chromatin Medium 21774827
2016 The PRC1 chemical probe UNC3866 shows submicromolar off-target affinity toward CDYL2 and CDYL chromodomains; an optimized analogue UNC4991 maintains submicromolar affinity toward CDYL chromodomains while displaying a distinct selectivity profile. In vitro pull-down experiments from HeLa nuclear lysates confirmed the selectivity of UNC4991 for CDYL proteins. Biochemical binding assays, combinatorial peptide library screening, in vitro pull-down from HeLa nuclear lysates ACS chemical biology Medium 27356154
2025 CDYL2 isoforms can form homo- and heteromers. CDYL2b is tightly associated with chromatin in prostate cancer cells, and overexpression of CDYL2b suppresses prostate cancer cell growth in vitro and tumor expansion in vivo. JMJD2B (but not JMJD2A) forms complexes with CDYL2b and antagonizes CDYL2b in upregulating HES7 transcription. JMJD2A and JMJD2B suppress CDYL2 transcription. Co-immunoprecipitation (JMJD2B–CDYL2b complex), overexpression and knockdown with in vitro and in vivo functional assays, RNA sequencing, chromatin fractionation Cancer letters Medium 40812719
2008 Bovine CDYL2 (bCDYL2) is expressed ubiquitously across tissues, and in situ hybridization of bovine testis shows bCDYL2 transcripts are found mainly in spermatids, supporting a role in spermatogenesis. RT-PCR expression analysis, in situ hybridization of bovine testis Animal genetics Low 18371128

Source papers

Stage 0 corpus · 18 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 Specificity of the chromodomain Y chromosome family of chromodomains for lysine-methylated ARK(S/T) motifs. The Journal of biological chemistry 86 18450745
2020 G9a regulates tumorigenicity and stemness through genome-wide DNA methylation reprogramming in non-small cell lung cancer. Clinical epigenetics 39 32552834
2016 Chromodomain Ligand Optimization via Target-Class Directed Combinatorial Repurposing. ACS chemical biology 39 27356154
2011 H3K9me3-binding proteins are dispensable for SETDB1/H3K9me3-dependent retroviral silencing. Epigenetics & chromatin 37 21774827
2020 CDYL2 Epigenetically Regulates MIR124 to Control NF-κB/STAT3-Dependent Breast Cancer Cell Plasticity. iScience 27 32450513
2022 STAT5A modulates CDYL2/SLC7A6 pathway to inhibit the proliferation and invasion of hepatocellular carcinoma by targeting to mTORC1. Oncogene 17 35314791
2020 Structural Basis for the Binding Selectivity of Human CDY Chromodomains. Cell chemical biology 16 32470319
2019 Integrative analysis reveals key mRNAs and lncRNAs in monocytes of osteoporotic patients. Mathematical biosciences and engineering : MBE 15 31499747
2020 Discrete functional and mechanistic roles of chromodomain Y-like 2 (CDYL2) transcript variants in breast cancer growth and metastasis. Theranostics 14 32373210
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
2019 An exome-wide rare variant analysis of Korean men identifies three novel genes predisposing to prostate cancer. Scientific reports 10 31748686
2023 Cdyl2-60aa encoded by CircCDYL2 accelerates cardiomyocyte death by blocking APAF1 ubiquitination in rats. Experimental & molecular medicine 9 37009805
2022 Discovery of hit compounds for methyl-lysine reader proteins from a target class DNA-encoded library. SLAS discovery : advancing life sciences R & D 9 36272689
2008 Molecular characterization of the bovine chromodomain Y-like genes. Animal genetics 9 18371128
2023 Chromodomain on Y-like 2 (CDYL2) implicated in mitosis and genome stability regulation via interaction with CHAMP1 and POGZ. Cellular and molecular life sciences : CMLS 4 36658409
2025 Anti-tumor activity of CDYL2b in prostate cancer. Cancer letters 2 40812719
2025 Identification of sus-PSMB7_0001 as a potential pro-angiogenic circular RNA in neonatal pig hearts. Journal of molecular and cellular cardiology 1 40744287
2025 Genetic markers for knee osteoarthritis presence are not associated with disease progression - data from the IMI-APPROACH cohort. PloS one 0 40554537

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