Affinage

CECR2

Chromatin remodeling regulator CECR2 · UniProt Q9BXF3

Length
1484 aa
Mass
164.2 kDa
Annotated
2026-06-09
26 papers in source corpus 14 papers cited in narrative 16 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/7 claims corpus-supported (86%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CECR2 is a bromodomain- and DDT/DTT-domain-containing chromatin protein that nucleates an ATP-dependent nucleosome remodeling complex (CERF) by pairing with mammalian ISWI ATPases, and through this activity controls transcriptional programs in development, reproduction, genome maintenance, and cancer (PMID:15640247, PMID:34197713). It assembles in a tissue-specific manner: with SNF2L (SMARCA1) and with SNF2H (SMARCA5) plus accessory subunits CCAR2 and LUZP1 in embryonic stem cells, but a more minimal SMARCA5/SMARCA1 complex lacking CCAR2 and LUZP1 in testis, with LUZP1 stabilizing the ES-cell complex (PMID:22154806, PMID:34197713). The reconstituted complex hydrolyzes ATP in a nucleosome-stimulated manner and remodels chromatin in vitro (PMID:15640247). CECR2 is targeted to chromatin through its bromodomain, which selectively reads multi-acetylated histone H3 and H4 (highest affinity for tetra-acetylated H4) and also recognizes acetylated RelA (K310ac) via a distinct binding mode, with Asn514 and Asp464 governing ligand specificity (PMID:39713312); bromodomain inhibitors displace CECR2 from chromatin, confirming this dependency (PMID:33004947). Through these activities CECR2 is essential for neural tube closure, where its loss causes exencephaly and downregulation of the transcription factors Alx1/Cart1, Dlx5, Eya1, and Six1 (PMID:15640247, PMID:20589882), for male fertility and meiotic sex chromosome inactivation in the testis (PMID:22154806, PMID:34904570), for female peri-implantation and decidualization (PMID:33354716), for somatic cell reprogramming downstream of SALL4 in a DTT-domain-dependent manner (PMID:33144328), and for γ-H2AX formation and DNA double-strand break repair (PMID:22699752). In breast cancer, CECR2 is recruited by NF-κB RelA to increase chromatin accessibility and activate metastasis-promoting (TNC, MMP2, VEGFA) and immunosuppressive cytokine genes (CSF1, CXCL1), and bromodomain inhibition blocks NF-κB-driven immune suppression, M2 macrophage polarization, and metastasis (PMID:35108062, PMID:38615488). The bromodomain acetyl-lysine pocket and a non-conserved allosteric Cys494 site are both druggable (PMID:28740608, PMID:39833305).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 2005 High

    Established that CECR2 is not merely a chromatin-associated protein but the targeting subunit of a bona fide ATP-dependent remodeling complex, defining its core biochemical activity.

    Evidence Biochemical co-purification, in vitro chromatin remodeling and nucleosome-stimulated ATPase assays defining the CERF complex with SNF2L

    PMID:15640247

    Open questions at the time
    • Did not define which nucleosome substrates or genomic loci are remodeled in vivo
    • Did not address tissue-specific partner choice
  2. 2005 High

    Linked CECR2 to a developmental phenotype by showing its loss causes high-penetrance neural tube defects, establishing physiological essentiality for neurulation.

    Evidence Gene-trap mouse model with strain-dependent exencephaly phenotype

    PMID:15640247 PMID:20589882

    Open questions at the time
    • Did not identify the transcriptional targets mediating the defect
    • Strain dependence not mechanistically explained
  3. 2010 Medium

    Connected the neural tube phenotype to specific transcriptional output by placing CECR2 upstream of mesenchymal/ectodermal transcription factors.

    Evidence Microarray and qRT-PCR in Cecr2 null embryonic heads showing downregulation of Alx1/Cart1, Dlx5, Eya1, Six1

    PMID:20589882

    Open questions at the time
    • Did not establish direct CECR2 occupancy at these gene loci
    • Whether regulation is via CERF remodeling at promoters untested
  4. 2011 Medium

    Revealed that CECR2 selects its ISWI ATPase partner in a tissue-specific manner, expanding the CERF model beyond a single fixed complex.

    Evidence Reciprocal Co-IP showing SNF2H (SMARCA5) association in testis and ES cells versus SNF2L in neural contexts

    PMID:22154806

    Open questions at the time
    • Single lab
    • Functional consequence of ATPase choice not dissected
  5. 2011 Medium

    Assigned a reproductive function to CECR2, localizing its requirement to sperm fertilization competence rather than gross spermatogenesis.

    Evidence Cecr2 mutant mouse fertilization assays, histology, and sperm functional analysis

    PMID:22154806

    Open questions at the time
    • Molecular basis of the fertilization defect unresolved
    • Did not link to specific gene expression changes
  6. 2012 Medium

    Implicated CECR2's bromodomain in the DNA damage response, broadening its role from transcription to genome maintenance.

    Evidence Bromodomain screen, siRNA knockdown and dominant-negative bromodomain expression with γ-H2AX foci and DSB repair readouts

    PMID:22699752

    Open questions at the time
    • Mechanism connecting CERF remodeling to γ-H2AX formation unclear
    • Single lab, not reconstituted
  7. 2020 Medium

    Placed CECR2 in a defined regulatory pathway for pluripotency, showing a DTT-domain-dependent reprogramming function downstream of SALL4.

    Evidence OKS reprogramming assays, DTT domain deletion mutants, and SALL4 promoter ChIP/binding

    PMID:33144328

    Open questions at the time
    • Genome-wide CECR2 remodeling targets during reprogramming not mapped
    • Single lab
  8. 2020 Medium

    Provided pharmacological proof that the bromodomain mediates CECR2's chromatin association, validating it as a tractable target.

    Evidence Chromatin fractionation with NVS-CECR2-1 inhibitor and CECR2-depletion rescue confirming on-target displacement

    PMID:33004947

    Open questions at the time
    • Functional/transcriptional consequences of displacement limited
    • Single lab
  9. 2021 Medium

    Defined the full CERF subunit composition and its tissue specificity, identifying CCAR2 and LUZP1 as ES-cell-specific accessory subunits.

    Evidence Co-IP/MS of CECR2 complexes in ES cells and testis with validation of LUZP1 stabilizing role

    PMID:34197713

    Open questions at the time
    • Structural arrangement of subunits unknown
    • Functional role of CCAR2 within CERF untested
  10. 2021 Medium

    Extended CECR2's reproductive role to the female, localizing its requirement to peri-implantation and decidualization.

    Evidence Hypomorphic and null mutant dams with embryo counts and artificial decidualization assays

    PMID:33354716

    Open questions at the time
    • Target genes in decidual tissue not identified
    • Cell-autonomy in uterus versus embryo unresolved
  11. 2022 Medium

    Refined the testis phenotype by linking CECR2 loss to failed meiotic sex chromosome inactivation, with expression mapped to spermatogonial stages.

    Evidence RNA-seq of mutant testes, staged immunostaining, and fertilization assays

    PMID:34904570

    Open questions at the time
    • Direct role of CERF remodeling in MSCI not shown
    • Mechanistic link between spermatogonial expression and meiotic defect unclear
  12. 2022 High

    Established a cancer mechanism in which CECR2 is recruited by NF-κB RelA to open chromatin and drive metastatic and immunosuppressive gene programs, making it a therapeutic target.

    Evidence ChIP-seq/ATAC-seq, Co-IP of CECR2 and RELA, knockdown, mouse metastasis models, and bromodomain inhibitor treatment

    PMID:35108062

    Open questions at the time
    • Whether ISWI ATPase activity is required at RelA target genes not dissected
    • Acetylation-dependence of recruitment not yet defined at this stage
  13. 2024 High

    Resolved the molecular basis of CECR2 chromatin reading, defining bromodomain preference for multi-acetylated histones and a distinct mode for acetylated RelA.

    Evidence ITC, NMR, peptide arrays, mutagenesis (N514, D464), and nucleosome binding assays (preprint)

    PMID:39713312

    Open questions at the time
    • Acetyltransferases generating the read marks not identified
    • Cellular consequence of the dual histone/RelA reading mode untested in vivo
  14. 2024 Medium

    Connected the CECR2-RelA axis to tumor microenvironment remodeling via CSF-1-driven macrophage polarization, reinforcing the cancer-immunology mechanism.

    Evidence CECR2 overexpression/inhibition, CSF-1 expression assays, macrophage polarization assays, and in vivo breast cancer model

    PMID:38615488

    Open questions at the time
    • Direct CECR2 occupancy at CSF1 not shown here
    • Single lab
  15. 2025 Medium

    Demonstrated a second druggable site by identifying an allosteric covalent pocket distinct from the acetyl-lysine binding site.

    Evidence Molecular dynamics, covalent docking, in vitro inhibition assays with BAY 11-7085/LC-CE-7 at Cys494, and anti-proliferation assays

    PMID:39833305

    Open questions at the time
    • Limited functional/cellular follow-up
    • Selectivity over related bromodomains not fully established

Open questions

Synthesis pass · forward-looking unresolved questions
  • How CERF remodeling activity, histone-acetylation reading, and RelA recognition are mechanistically integrated at specific target loci across the diverse developmental, reproductive, and oncogenic contexts remains unresolved.
  • No structure of the assembled CERF complex on a nucleosome
  • Upstream acetyltransferases setting CECR2 recruitment marks unidentified
  • Whether ATPase remodeling is required for each phenotype untested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0042393 histone binding 3 GO:0140110 transcription regulator activity 3 GO:0060090 molecular adaptor activity 2 GO:0140657 ATP-dependent activity 1
Localization
GO:0000228 nuclear chromosome 3 GO:0005634 nucleus 2
Pathway
R-HSA-1266738 Developmental Biology 3 R-HSA-1474165 Reproduction 3 R-HSA-4839726 Chromatin organization 3 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-1643685 Disease 2 R-HSA-73894 DNA Repair 1
Partners
CCAR2LUZP1RELASALL4SMARCA1SMARCA5
Complex memberships
CERF (CECR2-containing remodeling factor)

Evidence

Reading pass · 16 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2005 CECR2 forms a novel heterodimeric chromatin remodeling complex called CERF (CECR2-containing remodeling factor) with the ATP-dependent chromatin remodeler SNF2L (a mammalian ISWI ortholog). CERF is capable of remodeling chromatin in vitro and displays ATP hydrolyzing activity stimulated by nucleosomes. Biochemical isolation/co-purification, in vitro chromatin remodeling assay, ATPase activity assay Human molecular genetics High 15640247
2005 Loss-of-function mutation of Cecr2 in mice (gene-trap) causes high-penetrance exencephaly (neural tube defect) in a strain-dependent manner, establishing CECR2 as essential for neurulation. Gene-trap mouse model, phenotypic analysis Human molecular genetics High 15640247 20589882
2011 In the testis, CECR2 forms a complex with SNF2H (SMARCA5), the other mammalian ISWI ATPase, rather than SNF2L, demonstrating cell-type-specific choice of ISWI binding partner. This interaction was also observed in embryonic stem cells. Co-immunoprecipitation, Western blot Journal of molecular biology Medium 22154806
2011 Cecr2 mutant males exhibit subfertility with compromised sperm fertilization ability despite normal seminiferous epithelium, sperm count, motility, and morphology, placing CECR2 function at the step of oocyte fertilization during spermatogenesis. Cecr2 mutant mouse model, in vivo fertilization assays, histology, sperm functional assays Journal of molecular biology Medium 22154806
2012 The bromodomain of CECR2 exhibits γ-H2AX inhibition activity dependent on its chromatin-binding affinity. siRNA knockdown of CECR2 impairs γ-H2AX formation and DNA double-strand break (DSB) repair, identifying CECR2 as a DNA damage response protein. Bromodomain screen (52 BRDs from 38 proteins), siRNA knockdown, γ-H2AX foci assay, dominant-negative bromodomain expression Molecules and cells Medium 22699752
2010 Cecr2 null mutation causes downregulation of transcription factors Alx1/Cart1, Dlx5, Eya1, and Six1 in developing mouse heads, placing CECR2 upstream of mesenchymal/ectodermal transcription factor expression during neural tube closure. Microarray analysis, qRT-PCR validation in Cecr2 null embryos Birth defects research. Part A, Clinical and molecular teratology Medium 20589882
2021 CECR2 forms tissue-specific complexes: in embryonic stem cells, CERF contains SMARCA5, SMARCA1, CCAR2, and LUZP1; in testis, CERF contains SMARCA5 and SMARCA1 but not CCAR2 or LUZP1. LUZP1 appears to stabilize the CERF complex in ES cells. Mass spectrometry-based proteomics (co-IP/MS) of CECR2 complexes in ES cells and testis, validation by Co-IP Biochemistry and cell biology Medium 34197713
2020 CECR2 promotes somatic cell reprogramming to pluripotency by forming a chromatin remodeling complex containing SMARCA1. This activity requires CECR2's DTT domain. SALL4 activates Cecr2 expression by directly binding to its promoter region, placing CECR2 downstream of SALL4 in the reprogramming pathway. OKS reprogramming assay, CECR2 overexpression/knockdown, domain deletion mutants (DTT domain), ChIP/promoter binding assay for SALL4 The Journal of biological chemistry Medium 33144328
2022 CECR2 is recruited by the NF-κB subunit RELA to increase chromatin accessibility and activate transcription of metastasis-promoting genes (TNC, MMP2, VEGFA) and immunosuppressive cytokine genes (CSF1, CXCL1) in breast cancer. Pharmacological inhibition of the CECR2 bromodomain impedes NF-κB-mediated immune suppression and inhibits metastasis. ChIP-seq (chromatin accessibility/ATAC-seq), Co-IP of CECR2 and RELA, siRNA/shRNA knockdown, mouse metastasis models (immunocompetent and immunodeficient), bromodomain inhibitor treatment Science translational medicine High 35108062
2020 The bromodomain inhibitor NVS-CECR2-1 inhibits chromatin binding of CECR2's bromodomain and displaces CECR2 from chromatin within cells, confirming that the bromodomain mediates CECR2's chromatin association. Chromatin fractionation, bromodomain inhibitor treatment, cell viability/apoptosis assays, CECR2 depletion rescue experiment Scientific reports Medium 33004947
2024 The CECR2 bromodomain (CECR2-BRD) selectively binds acetylated histone H3 and H4 ligands with preference for multi-acetylated over mono-acetylated targets (highest affinity for tetra-acetylated H4). It also binds acetylated RelA (K310ac) of NF-κB using a distinct binding mode. Key residues Asn514 and Asp464 are critical for ligand specificity. CECR2-BRD remains monomeric in solution and exclusively interacts with nucleosomes containing multi-acetylated histones. Isothermal titration calorimetry (ITC), NMR spectroscopy, high-throughput peptide assay, functional mutagenesis (N514, D464), nucleosome binding assays bioRxiv (preprint)preprint High 39713312
2017 Crystal structure-guided drug design of GNE-886 identified the CECR2 bromodomain acetyl-lysine binding pocket as a druggable site, enabling structure-based inhibitor development. Structure-based drug design, X-ray crystallography (implied by structure-based design), biochemical BRD binding assays ACS medicinal chemistry letters Medium 28740608
2022 Cecr2 mutant males show age-dependent subfertility with inappropriate expression of X-chromosome genes in juvenile testes (P24), consistent with a failure of meiotic sex chromosome inactivation. CECR2 protein is expressed in type A, intermediate, and B spermatogonia and less in spermatocytes. RNA-seq of mutant vs. wild-type testes, immunostaining of staged seminiferous tubules, histology, in vivo fertilization assays Reproduction (Cambridge, England) Medium 34904570
2021 Female mice mutant for Cecr2 are subfertile due to peri-implantation defects: Cecr2GT/GT dams show normal implantation at E5.5 but embryo loss by E10.5; Cecr2GT/Del dams show reduced implantation sites at E5.5 and premature decidual tissue loss after artificial decidualization, placing CECR2 function at peri-implantation/decidualization. Mutant mouse models (hypomorphic and null alleles), embryo counting at E5.5 and E10.5, artificial decidualization assay Biology of reproduction Medium 33354716
2025 A non-conserved allosteric pocket containing Cys494 was identified in the CECR2 bromodomain. The compound BAY 11-7085 and the optimized derivative LC-CE-7 covalently bind C494 at this allosteric site to inhibit CECR2 BRD activity, demonstrating that allosteric covalent inhibition of CECR2 is achievable at a site distinct from the acetyl-lysine binding pocket. Molecular dynamics simulation, covalent docking, in vitro biochemical binding/inhibition assays, anti-proliferation assay in MDA-MB-231 cells Acta pharmacologica Sinica Medium 39833305
2024 CECR2 recognizes RELA (RelA/NF-κB) and activates NF-κB-driven CSF-1 expression; competitive pharmacological inhibition of the CECR2 bromodomain by bromosporine downregulates CSF-1, thereby inhibiting M2-type tumor-associated macrophage polarization. CECR2 overexpression/inhibitor treatment, CSF-1 ELISA/expression assays, macrophage polarization assays, in vivo breast cancer model Biomaterials Medium 38615488

Source papers

Stage 0 corpus · 26 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 CECR2, a protein involved in neurulation, forms a novel chromatin remodeling complex with SNF2L. Human molecular genetics 122 15640247
2022 CECR2 drives breast cancer metastasis by promoting NF-κB signaling and macrophage-mediated immune suppression. Science translational medicine 119 35108062
2010 Cecr2 mutations causing exencephaly trigger misregulation of mesenchymal/ectodermal transcription factors. Birth defects research. Part A, Clinical and molecular teratology 35 20589882
2012 Genome-wide screen of human bromodomain-containing proteins identifies Cecr2 as a novel DNA damage response protein. Molecules and cells 32 22699752
2011 CECR2 is involved in spermatogenesis and forms a complex with SNF2H in the testis. Journal of molecular biology 26 22154806
2011 Role of chromatin remodeling gene Cecr2 in neurulation and inner ear development. Developmental dynamics : an official publication of the American Association of Anatomists 22 21246654
2020 Cytotoxic activity of bromodomain inhibitor NVS-CECR2-1 on human cancer cells. Scientific reports 20 33004947
2020 Optimization of Potent ATAD2 and CECR2 Bromodomain Inhibitors with an Atypical Binding Mode. Journal of medicinal chemistry 17 32321240
2017 GNE-886: A Potent and Selective Inhibitor of the Cat Eye Syndrome Chromosome Region Candidate 2 Bromodomain (CECR2). ACS medicinal chemistry letters 17 28740608
2007 Modifier locus for exencephaly in Cecr2 mutant mice is syntenic to the 10q25.3 region associated with neural tube defects in humans. Physiological genomics 12 17623803
2011 Strain-specific modifier genes of Cecr2-associated exencephaly in mice: genetic analysis and identification of differentially expressed candidate genes. Physiological genomics 11 22045912
2021 Chromatin remodeling factor CECR2 forms tissue-specific complexes with CCAR2 and LUZP1. Biochemistry and cell biology = Biochimie et biologie cellulaire 8 34197713
2022 Discovery of a highly potent CECR2 bromodomain inhibitor with 7H-pyrrolo[2,3-d] pyrimidine scaffold. Bioorganic chemistry 7 35378372
2021 Cecr2 mutant mice as a model for human cat eye syndrome. Scientific reports 7 33542446
2020 The nuclear factor CECR2 promotes somatic cell reprogramming by reorganizing the chromatin structure. The Journal of biological chemistry 7 33144328
2024 Optical controlled and nuclear targeted CECR2 competitor to downregulate CSF-1 for metastatic breast cancer immunotherapy. Biomaterials 5 38615488
2021 A novel tumor suppressor CECR2 down regulation links glutamine metabolism contributes tumor growth in laryngeal squamous cell carcinoma. Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico 5 33826083
2010 Molecular cloning of chicken Cecr2 and its expression during chicken embryo development. The International journal of developmental biology 5 20336606
2022 Subfertility in young male mice mutant for chromatin remodeller CECR2. Reproduction (Cambridge, England) 3 34904570
2021 Implantation failure and embryo loss contribute to subfertility in female mice mutant for chromatin remodeler Cecr2†. Biology of reproduction 3 33354716
2023 Double whammy: the genetic variants in CECR2 and high Hcy on the development of neural tube defects. Frontiers in genetics 2 37424722
2025 Identifying a non-conserved site for achieving allosteric covalent inhibition of CECR2. Acta pharmacologica Sinica 1 39833305
2024 The CECR2 bromodomain displays distinct binding modes to select for acetylated histone proteins versus non-histone ligands. bioRxiv : the preprint server for biology 1 39713312
2007 Mutation analysis of Drosophila dikar/CG32394, homologue of the chromatin-remodelling gene CECR2. Genome 1 17893736
2026 Heterozygous CECR2 variants support a distinct neurodevelopmental syndrome with features overlapping cat eye syndrome. HGG advances 0 41964217
2025 Cat Eye Syndrome Chromosome Region Candidate 2 (CECR2) in chromatin remodeling and cancer: A review. International journal of biological macromolecules 0 41106749

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