{"gene":"CECR2","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":2005,"finding":"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.","method":"Biochemical isolation/co-purification, in vitro chromatin remodeling assay, ATPase activity assay","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution of chromatin remodeling activity, ATPase assay, biochemical co-purification; foundational study replicated by multiple subsequent labs","pmids":["15640247"],"is_preprint":false},{"year":2005,"finding":"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.","method":"Gene-trap mouse model, phenotypic analysis","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean loss-of-function mouse model with defined neural tube closure phenotype, replicated with additional alleles in subsequent papers","pmids":["15640247","20589882"],"is_preprint":false},{"year":2011,"finding":"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.","method":"Co-immunoprecipitation, Western blot","journal":"Journal of molecular biology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — reciprocal Co-IP in two cell types (testis and ES cells), single lab but consistent across contexts","pmids":["22154806"],"is_preprint":false},{"year":2011,"finding":"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.","method":"Cecr2 mutant mouse model, in vivo fertilization assays, histology, sperm functional assays","journal":"Journal of molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean loss-of-function with specific phenotypic readout, single lab","pmids":["22154806"],"is_preprint":false},{"year":2012,"finding":"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.","method":"Bromodomain screen (52 BRDs from 38 proteins), siRNA knockdown, γ-H2AX foci assay, dominant-negative bromodomain expression","journal":"Molecules and cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genome-wide BRD screen plus siRNA loss-of-function with defined molecular readout (γ-H2AX), single lab","pmids":["22699752"],"is_preprint":false},{"year":2010,"finding":"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.","method":"Microarray analysis, qRT-PCR validation in Cecr2 null embryos","journal":"Birth defects research. Part A, Clinical and molecular teratology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two alleles (hypomorphic and null) compared, qRT-PCR validation, single lab","pmids":["20589882"],"is_preprint":false},{"year":2021,"finding":"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.","method":"Mass spectrometry-based proteomics (co-IP/MS) of CECR2 complexes in ES cells and testis, validation by Co-IP","journal":"Biochemistry and cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP/MS in two tissue types with functional inference on LUZP1 stabilization, single lab","pmids":["34197713"],"is_preprint":false},{"year":2020,"finding":"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.","method":"OKS reprogramming assay, CECR2 overexpression/knockdown, domain deletion mutants (DTT domain), ChIP/promoter binding assay for SALL4","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain mutagenesis plus epistasis (SALL4→CECR2) with functional reprogramming readout, single lab","pmids":["33144328"],"is_preprint":false},{"year":2022,"finding":"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.","method":"ChIP-seq (chromatin accessibility/ATAC-seq), Co-IP of CECR2 and RELA, siRNA/shRNA knockdown, mouse metastasis models (immunocompetent and immunodeficient), bromodomain inhibitor treatment","journal":"Science translational medicine","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (ChIP-seq, Co-IP, KO mouse models, pharmacological inhibition), replicated across multiple model systems","pmids":["35108062"],"is_preprint":false},{"year":2020,"finding":"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.","method":"Chromatin fractionation, bromodomain inhibitor treatment, cell viability/apoptosis assays, CECR2 depletion rescue experiment","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct chromatin displacement assay plus CECR2 depletion rescue confirming on-target activity, single lab","pmids":["33004947"],"is_preprint":false},{"year":2024,"finding":"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.","method":"Isothermal titration calorimetry (ITC), NMR spectroscopy, high-throughput peptide assay, functional mutagenesis (N514, D464), nucleosome binding assays","journal":"bioRxiv (preprint)","confidence":"High","confidence_rationale":"Tier 1 / Moderate — multiple orthogonal biophysical methods (ITC, NMR, mutagenesis, peptide array) in a single rigorous study","pmids":["39713312"],"is_preprint":true},{"year":2017,"finding":"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.","method":"Structure-based drug design, X-ray crystallography (implied by structure-based design), biochemical BRD binding assays","journal":"ACS medicinal chemistry letters","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — structure-based design with selectivity profiling, single study; crystallography not explicitly confirmed in abstract","pmids":["28740608"],"is_preprint":false},{"year":2022,"finding":"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.","method":"RNA-seq of mutant vs. wild-type testes, immunostaining of staged seminiferous tubules, histology, in vivo fertilization assays","journal":"Reproduction (Cambridge, England)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA-seq plus immunolocalization with age-dependent functional phenotype, single lab","pmids":["34904570"],"is_preprint":false},{"year":2021,"finding":"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.","method":"Mutant mouse models (hypomorphic and null alleles), embryo counting at E5.5 and E10.5, artificial decidualization assay","journal":"Biology of reproduction","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two alleles with allele-severity correlation, defined implantation phenotype, single lab","pmids":["33354716"],"is_preprint":false},{"year":2025,"finding":"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.","method":"Molecular dynamics simulation, covalent docking, in vitro biochemical binding/inhibition assays, anti-proliferation assay in MDA-MB-231 cells","journal":"Acta pharmacologica Sinica","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — covalent docking validated by in vitro biochemical assay, single study with limited functional follow-up","pmids":["39833305"],"is_preprint":false},{"year":2024,"finding":"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.","method":"CECR2 overexpression/inhibitor treatment, CSF-1 ELISA/expression assays, macrophage polarization assays, in vivo breast cancer model","journal":"Biomaterials","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological and in vivo validation of CECR2-RELA-CSF1 axis, single lab, consistent with prior mechanistic work","pmids":["38615488"],"is_preprint":false}],"current_model":"CECR2 is a bromodomain- and DDT-domain-containing epigenetic reader that binds acetylated lysines on histones (preferring multi-acetylated H3/H4) and on non-histone proteins such as NF-κB RelA (K310ac), and assembles into tissue-specific ATP-dependent chromatin remodeling complexes (CERF) with ISWI ATPases SNF2L (SMARCA1) in neural/ES cells or SNF2H (SMARCA5) in testis, plus accessory subunits CCAR2 and LUZP1 in ES cells; through these complexes CECR2 remodels nucleosomes in vitro and in vivo to regulate transcription programs essential for neural tube closure, spermatogenesis, female implantation, DNA double-strand break repair, and NF-κB-driven metastatic gene expression in cancer."},"narrative":{"mechanistic_narrative":"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].","teleology":[{"year":2005,"claim":"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","pmids":["15640247"],"confidence":"High","gaps":["Did not define which nucleosome substrates or genomic loci are remodeled in vivo","Did not address tissue-specific partner choice"]},{"year":2005,"claim":"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","pmids":["15640247","20589882"],"confidence":"High","gaps":["Did not identify the transcriptional targets mediating the defect","Strain dependence not mechanistically explained"]},{"year":2010,"claim":"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","pmids":["20589882"],"confidence":"Medium","gaps":["Did not establish direct CECR2 occupancy at these gene loci","Whether regulation is via CERF remodeling at promoters untested"]},{"year":2011,"claim":"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","pmids":["22154806"],"confidence":"Medium","gaps":["Single lab","Functional consequence of ATPase choice not dissected"]},{"year":2011,"claim":"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","pmids":["22154806"],"confidence":"Medium","gaps":["Molecular basis of the fertilization defect unresolved","Did not link to specific gene expression changes"]},{"year":2012,"claim":"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","pmids":["22699752"],"confidence":"Medium","gaps":["Mechanism connecting CERF remodeling to γ-H2AX formation unclear","Single lab, not reconstituted"]},{"year":2020,"claim":"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","pmids":["33144328"],"confidence":"Medium","gaps":["Genome-wide CECR2 remodeling targets during reprogramming not mapped","Single lab"]},{"year":2020,"claim":"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","pmids":["33004947"],"confidence":"Medium","gaps":["Functional/transcriptional consequences of displacement limited","Single lab"]},{"year":2021,"claim":"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","pmids":["34197713"],"confidence":"Medium","gaps":["Structural arrangement of subunits unknown","Functional role of CCAR2 within CERF untested"]},{"year":2021,"claim":"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","pmids":["33354716"],"confidence":"Medium","gaps":["Target genes in decidual tissue not identified","Cell-autonomy in uterus versus embryo unresolved"]},{"year":2022,"claim":"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","pmids":["34904570"],"confidence":"Medium","gaps":["Direct role of CERF remodeling in MSCI not shown","Mechanistic link between spermatogonial expression and meiotic defect unclear"]},{"year":2022,"claim":"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","pmids":["35108062"],"confidence":"High","gaps":["Whether ISWI ATPase activity is required at RelA target genes not dissected","Acetylation-dependence of recruitment not yet defined at this stage"]},{"year":2024,"claim":"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)","pmids":["39713312"],"confidence":"High","gaps":["Acetyltransferases generating the read marks not identified","Cellular consequence of the dual histone/RelA reading mode untested in vivo"]},{"year":2024,"claim":"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","pmids":["38615488"],"confidence":"Medium","gaps":["Direct CECR2 occupancy at CSF1 not shown here","Single lab"]},{"year":2025,"claim":"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","pmids":["39833305"],"confidence":"Medium","gaps":["Limited functional/cellular follow-up","Selectivity over related bromodomains not fully established"]},{"year":null,"claim":"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.","evidence":"No single study links bromodomain reading specificity to genome-wide remodeling outcomes in vivo","pmids":[],"confidence":"Medium","gaps":["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":{"molecular_activity":[{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[10,9,4]},{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[0]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[8,5,7]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,6]}],"localization":[{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[9,8,0]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,6]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[0,6,8]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[5,8,15]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[1,5,7]},{"term_id":"R-HSA-1474165","term_label":"Reproduction","supporting_discovery_ids":[3,12,13]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[4]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[8,15]}],"complexes":["CERF (CECR2-containing remodeling factor)"],"partners":["SMARCA1","SMARCA5","CCAR2","LUZP1","RELA","SALL4"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9BXF3","full_name":"Chromatin remodeling regulator CECR2","aliases":["Cat eye syndrome critical region protein 2"],"length_aa":1484,"mass_kda":164.2,"function":"Regulatory subunit of the ATP-dependent CERF-1 and CERF-5 ISWI chromatin remodeling complexes, which form ordered nucleosome arrays on chromatin and facilitate access to DNA during DNA-templated processes such as DNA replication, transcription, and repair (PubMed:15640247, PubMed:22464331, PubMed:26365797, PubMed:28801535). The complexes do not have the ability to slide mononucleosomes to the center of a DNA template (PubMed:28801535). The CERF-1 ISWI chromatin remodeling complex has a lower ATP hydrolysis rate than the CERF-5 ISWI chromatin remodeling complex (PubMed:28801535). Plays a role in various processes during development: required during embryogenesis for neural tube closure and inner ear development. In adults, required for spermatogenesis, via the formation of ISWI-type chromatin complexes (By similarity). In histone-modifying complexes, CECR2 recognizes and binds acylated histones: binds histones that are acetylated and/or butyrylated (PubMed:22464331, PubMed:26365797). May also be involved through its interaction with LRPPRC in the integration of cytoskeletal network with vesicular trafficking, nucleocytosolic shuttling, transcription, chromosome remodeling and cytokinesis (PubMed:11827465)","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9BXF3/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CECR2","classification":"Not Classified","n_dependent_lines":30,"n_total_lines":77,"dependency_fraction":0.38961038961038963},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"SMARCA1","stoichiometry":10.0},{"gene":"NUCKS1","stoichiometry":0.2},{"gene":"PARP1","stoichiometry":0.2},{"gene":"SMARCA5","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/CECR2","total_profiled":1310},"omim":[{"mim_id":"607576","title":"CECR2 HISTONE ACETYL-LYSINE READER; CECR2","url":"https://www.omim.org/entry/607576"},{"mim_id":"607544","title":"LEUCINE-RICH PPR MOTIF-CONTAINING PROTEIN; LRPPRC","url":"https://www.omim.org/entry/607544"},{"mim_id":"300012","title":"SWI/SNF-RELATED, MATRIX-ASSOCIATED, ACTIN-DEPENDENT REGULATOR OF CHROMATIN, SUBFAMILY A, MEMBER 1; SMARCA1","url":"https://www.omim.org/entry/300012"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Vesicles","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":11.1},{"tissue":"retina","ntpm":11.8},{"tissue":"skeletal muscle","ntpm":18.3}],"url":"https://www.proteinatlas.org/search/CECR2"},"hgnc":{"alias_symbol":["KIAA1740"],"prev_symbol":[]},"alphafold":{"accession":"Q9BXF3","domains":[{"cath_id":"-","chopping":"145-171_241-302","consensus_level":"medium","plddt":81.8437,"start":145,"end":302},{"cath_id":"1.20.920.10","chopping":"432-543","consensus_level":"medium","plddt":91.1354,"start":432,"end":543},{"cath_id":"1.10.418","chopping":"10-138","consensus_level":"medium","plddt":89.7279,"start":10,"end":138}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BXF3","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BXF3-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BXF3-F1-predicted_aligned_error_v6.png","plddt_mean":48.84},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CECR2","jax_strain_url":"https://www.jax.org/strain/search?query=CECR2"},"sequence":{"accession":"Q9BXF3","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9BXF3.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9BXF3/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BXF3"}},"corpus_meta":[{"pmid":"15640247","id":"PMC_15640247","title":"CECR2, a protein involved in neurulation, forms a novel chromatin remodeling complex with SNF2L.","date":"2005","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/15640247","citation_count":122,"is_preprint":false},{"pmid":"35108062","id":"PMC_35108062","title":"CECR2 drives breast cancer metastasis by promoting NF-κB signaling and macrophage-mediated immune suppression.","date":"2022","source":"Science translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/35108062","citation_count":119,"is_preprint":false},{"pmid":"20589882","id":"PMC_20589882","title":"Cecr2 mutations causing exencephaly trigger misregulation of mesenchymal/ectodermal transcription factors.","date":"2010","source":"Birth defects research. Part A, Clinical and molecular teratology","url":"https://pubmed.ncbi.nlm.nih.gov/20589882","citation_count":35,"is_preprint":false},{"pmid":"22699752","id":"PMC_22699752","title":"Genome-wide screen of human bromodomain-containing proteins identifies Cecr2 as a novel DNA damage response protein.","date":"2012","source":"Molecules and cells","url":"https://pubmed.ncbi.nlm.nih.gov/22699752","citation_count":32,"is_preprint":false},{"pmid":"22154806","id":"PMC_22154806","title":"CECR2 is involved in spermatogenesis and forms a complex with SNF2H in the testis.","date":"2011","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/22154806","citation_count":26,"is_preprint":false},{"pmid":"21246654","id":"PMC_21246654","title":"Role of chromatin remodeling gene Cecr2 in neurulation and inner ear development.","date":"2011","source":"Developmental dynamics : an official publication of the American Association of 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letters","url":"https://pubmed.ncbi.nlm.nih.gov/28740608","citation_count":17,"is_preprint":false},{"pmid":"17623803","id":"PMC_17623803","title":"Modifier locus for exencephaly in Cecr2 mutant mice is syntenic to the 10q25.3 region associated with neural tube defects in humans.","date":"2007","source":"Physiological genomics","url":"https://pubmed.ncbi.nlm.nih.gov/17623803","citation_count":12,"is_preprint":false},{"pmid":"22045912","id":"PMC_22045912","title":"Strain-specific modifier genes of Cecr2-associated exencephaly in mice: genetic analysis and identification of differentially expressed candidate genes.","date":"2011","source":"Physiological genomics","url":"https://pubmed.ncbi.nlm.nih.gov/22045912","citation_count":11,"is_preprint":false},{"pmid":"34197713","id":"PMC_34197713","title":"Chromatin remodeling factor CECR2 forms tissue-specific complexes with CCAR2 and LUZP1.","date":"2021","source":"Biochemistry and cell biology = Biochimie et biologie 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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.\",\n      \"method\": \"Biochemical isolation/co-purification, in vitro chromatin remodeling assay, ATPase activity assay\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution of chromatin remodeling activity, ATPase assay, biochemical co-purification; foundational study replicated by multiple subsequent labs\",\n      \"pmids\": [\"15640247\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"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.\",\n      \"method\": \"Gene-trap mouse model, phenotypic analysis\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean loss-of-function mouse model with defined neural tube closure phenotype, replicated with additional alleles in subsequent papers\",\n      \"pmids\": [\"15640247\", \"20589882\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, Western blot\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — reciprocal Co-IP in two cell types (testis and ES cells), single lab but consistent across contexts\",\n      \"pmids\": [\"22154806\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"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.\",\n      \"method\": \"Cecr2 mutant mouse model, in vivo fertilization assays, histology, sperm functional assays\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean loss-of-function with specific phenotypic readout, single lab\",\n      \"pmids\": [\"22154806\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"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.\",\n      \"method\": \"Bromodomain screen (52 BRDs from 38 proteins), siRNA knockdown, γ-H2AX foci assay, dominant-negative bromodomain expression\",\n      \"journal\": \"Molecules and cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-wide BRD screen plus siRNA loss-of-function with defined molecular readout (γ-H2AX), single lab\",\n      \"pmids\": [\"22699752\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"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.\",\n      \"method\": \"Microarray analysis, qRT-PCR validation in Cecr2 null embryos\",\n      \"journal\": \"Birth defects research. Part A, Clinical and molecular teratology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two alleles (hypomorphic and null) compared, qRT-PCR validation, single lab\",\n      \"pmids\": [\"20589882\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"Mass spectrometry-based proteomics (co-IP/MS) of CECR2 complexes in ES cells and testis, validation by Co-IP\",\n      \"journal\": \"Biochemistry and cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP/MS in two tissue types with functional inference on LUZP1 stabilization, single lab\",\n      \"pmids\": [\"34197713\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"OKS reprogramming assay, CECR2 overexpression/knockdown, domain deletion mutants (DTT domain), ChIP/promoter binding assay for SALL4\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain mutagenesis plus epistasis (SALL4→CECR2) with functional reprogramming readout, single lab\",\n      \"pmids\": [\"33144328\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"ChIP-seq (chromatin accessibility/ATAC-seq), Co-IP of CECR2 and RELA, siRNA/shRNA knockdown, mouse metastasis models (immunocompetent and immunodeficient), bromodomain inhibitor treatment\",\n      \"journal\": \"Science translational medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (ChIP-seq, Co-IP, KO mouse models, pharmacological inhibition), replicated across multiple model systems\",\n      \"pmids\": [\"35108062\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"Chromatin fractionation, bromodomain inhibitor treatment, cell viability/apoptosis assays, CECR2 depletion rescue experiment\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct chromatin displacement assay plus CECR2 depletion rescue confirming on-target activity, single lab\",\n      \"pmids\": [\"33004947\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"Isothermal titration calorimetry (ITC), NMR spectroscopy, high-throughput peptide assay, functional mutagenesis (N514, D464), nucleosome binding assays\",\n      \"journal\": \"bioRxiv (preprint)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — multiple orthogonal biophysical methods (ITC, NMR, mutagenesis, peptide array) in a single rigorous study\",\n      \"pmids\": [\"39713312\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"Structure-based drug design, X-ray crystallography (implied by structure-based design), biochemical BRD binding assays\",\n      \"journal\": \"ACS medicinal chemistry letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — structure-based design with selectivity profiling, single study; crystallography not explicitly confirmed in abstract\",\n      \"pmids\": [\"28740608\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"RNA-seq of mutant vs. wild-type testes, immunostaining of staged seminiferous tubules, histology, in vivo fertilization assays\",\n      \"journal\": \"Reproduction (Cambridge, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA-seq plus immunolocalization with age-dependent functional phenotype, single lab\",\n      \"pmids\": [\"34904570\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"Mutant mouse models (hypomorphic and null alleles), embryo counting at E5.5 and E10.5, artificial decidualization assay\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two alleles with allele-severity correlation, defined implantation phenotype, single lab\",\n      \"pmids\": [\"33354716\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"Molecular dynamics simulation, covalent docking, in vitro biochemical binding/inhibition assays, anti-proliferation assay in MDA-MB-231 cells\",\n      \"journal\": \"Acta pharmacologica Sinica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — covalent docking validated by in vitro biochemical assay, single study with limited functional follow-up\",\n      \"pmids\": [\"39833305\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"CECR2 overexpression/inhibitor treatment, CSF-1 ELISA/expression assays, macrophage polarization assays, in vivo breast cancer model\",\n      \"journal\": \"Biomaterials\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological and in vivo validation of CECR2-RELA-CSF1 axis, single lab, consistent with prior mechanistic work\",\n      \"pmids\": [\"38615488\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CECR2 is a bromodomain- and DDT-domain-containing epigenetic reader that binds acetylated lysines on histones (preferring multi-acetylated H3/H4) and on non-histone proteins such as NF-κB RelA (K310ac), and assembles into tissue-specific ATP-dependent chromatin remodeling complexes (CERF) with ISWI ATPases SNF2L (SMARCA1) in neural/ES cells or SNF2H (SMARCA5) in testis, plus accessory subunits CCAR2 and LUZP1 in ES cells; through these complexes CECR2 remodels nucleosomes in vitro and in vivo to regulate transcription programs essential for neural tube closure, spermatogenesis, female implantation, DNA double-strand break repair, and NF-κB-driven metastatic gene expression in cancer.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"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 [#0, #6]. 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 [#2, #6]. The reconstituted complex hydrolyzes ATP in a nucleosome-stimulated manner and remodels chromatin in vitro [#0]. 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 [#10]; bromodomain inhibitors displace CECR2 from chromatin, confirming this dependency [#9]. 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 [#1, #5], for male fertility and meiotic sex chromosome inactivation in the testis [#3, #12], for female peri-implantation and decidualization [#13], for somatic cell reprogramming downstream of SALL4 in a DTT-domain-dependent manner [#7], and for γ-H2AX formation and DNA double-strand break repair [#4]. 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 [#8, #15]. The bromodomain acetyl-lysine pocket and a non-conserved allosteric Cys494 site are both druggable [#11, #14].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"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.\",\n      \"evidence\": \"Biochemical co-purification, in vitro chromatin remodeling and nucleosome-stimulated ATPase assays defining the CERF complex with SNF2L\",\n      \"pmids\": [\"15640247\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define which nucleosome substrates or genomic loci are remodeled in vivo\", \"Did not address tissue-specific partner choice\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Linked CECR2 to a developmental phenotype by showing its loss causes high-penetrance neural tube defects, establishing physiological essentiality for neurulation.\",\n      \"evidence\": \"Gene-trap mouse model with strain-dependent exencephaly phenotype\",\n      \"pmids\": [\"15640247\", \"20589882\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the transcriptional targets mediating the defect\", \"Strain dependence not mechanistically explained\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Connected the neural tube phenotype to specific transcriptional output by placing CECR2 upstream of mesenchymal/ectodermal transcription factors.\",\n      \"evidence\": \"Microarray and qRT-PCR in Cecr2 null embryonic heads showing downregulation of Alx1/Cart1, Dlx5, Eya1, Six1\",\n      \"pmids\": [\"20589882\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not establish direct CECR2 occupancy at these gene loci\", \"Whether regulation is via CERF remodeling at promoters untested\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Revealed that CECR2 selects its ISWI ATPase partner in a tissue-specific manner, expanding the CERF model beyond a single fixed complex.\",\n      \"evidence\": \"Reciprocal Co-IP showing SNF2H (SMARCA5) association in testis and ES cells versus SNF2L in neural contexts\",\n      \"pmids\": [\"22154806\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Functional consequence of ATPase choice not dissected\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Assigned a reproductive function to CECR2, localizing its requirement to sperm fertilization competence rather than gross spermatogenesis.\",\n      \"evidence\": \"Cecr2 mutant mouse fertilization assays, histology, and sperm functional analysis\",\n      \"pmids\": [\"22154806\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis of the fertilization defect unresolved\", \"Did not link to specific gene expression changes\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Implicated CECR2's bromodomain in the DNA damage response, broadening its role from transcription to genome maintenance.\",\n      \"evidence\": \"Bromodomain screen, siRNA knockdown and dominant-negative bromodomain expression with γ-H2AX foci and DSB repair readouts\",\n      \"pmids\": [\"22699752\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism connecting CERF remodeling to γ-H2AX formation unclear\", \"Single lab, not reconstituted\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Placed CECR2 in a defined regulatory pathway for pluripotency, showing a DTT-domain-dependent reprogramming function downstream of SALL4.\",\n      \"evidence\": \"OKS reprogramming assays, DTT domain deletion mutants, and SALL4 promoter ChIP/binding\",\n      \"pmids\": [\"33144328\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Genome-wide CECR2 remodeling targets during reprogramming not mapped\", \"Single lab\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Provided pharmacological proof that the bromodomain mediates CECR2's chromatin association, validating it as a tractable target.\",\n      \"evidence\": \"Chromatin fractionation with NVS-CECR2-1 inhibitor and CECR2-depletion rescue confirming on-target displacement\",\n      \"pmids\": [\"33004947\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional/transcriptional consequences of displacement limited\", \"Single lab\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined the full CERF subunit composition and its tissue specificity, identifying CCAR2 and LUZP1 as ES-cell-specific accessory subunits.\",\n      \"evidence\": \"Co-IP/MS of CECR2 complexes in ES cells and testis with validation of LUZP1 stabilizing role\",\n      \"pmids\": [\"34197713\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural arrangement of subunits unknown\", \"Functional role of CCAR2 within CERF untested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Extended CECR2's reproductive role to the female, localizing its requirement to peri-implantation and decidualization.\",\n      \"evidence\": \"Hypomorphic and null mutant dams with embryo counts and artificial decidualization assays\",\n      \"pmids\": [\"33354716\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Target genes in decidual tissue not identified\", \"Cell-autonomy in uterus versus embryo unresolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Refined the testis phenotype by linking CECR2 loss to failed meiotic sex chromosome inactivation, with expression mapped to spermatogonial stages.\",\n      \"evidence\": \"RNA-seq of mutant testes, staged immunostaining, and fertilization assays\",\n      \"pmids\": [\"34904570\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct role of CERF remodeling in MSCI not shown\", \"Mechanistic link between spermatogonial expression and meiotic defect unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"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.\",\n      \"evidence\": \"ChIP-seq/ATAC-seq, Co-IP of CECR2 and RELA, knockdown, mouse metastasis models, and bromodomain inhibitor treatment\",\n      \"pmids\": [\"35108062\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ISWI ATPase activity is required at RelA target genes not dissected\", \"Acetylation-dependence of recruitment not yet defined at this stage\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Resolved the molecular basis of CECR2 chromatin reading, defining bromodomain preference for multi-acetylated histones and a distinct mode for acetylated RelA.\",\n      \"evidence\": \"ITC, NMR, peptide arrays, mutagenesis (N514, D464), and nucleosome binding assays (preprint)\",\n      \"pmids\": [\"39713312\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Acetyltransferases generating the read marks not identified\", \"Cellular consequence of the dual histone/RelA reading mode untested in vivo\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Connected the CECR2-RelA axis to tumor microenvironment remodeling via CSF-1-driven macrophage polarization, reinforcing the cancer-immunology mechanism.\",\n      \"evidence\": \"CECR2 overexpression/inhibition, CSF-1 expression assays, macrophage polarization assays, and in vivo breast cancer model\",\n      \"pmids\": [\"38615488\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct CECR2 occupancy at CSF1 not shown here\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstrated a second druggable site by identifying an allosteric covalent pocket distinct from the acetyl-lysine binding site.\",\n      \"evidence\": \"Molecular dynamics, covalent docking, in vitro inhibition assays with BAY 11-7085/LC-CE-7 at Cys494, and anti-proliferation assays\",\n      \"pmids\": [\"39833305\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Limited functional/cellular follow-up\", \"Selectivity over related bromodomains not fully established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"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.\",\n      \"evidence\": \"No single study links bromodomain reading specificity to genome-wide remodeling outcomes in vivo\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"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\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [10, 9, 4]},\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [8, 5, 7]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [9, 8, 0]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [0, 6, 8]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [5, 8, 15]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [1, 5, 7]},\n      {\"term_id\": \"R-HSA-1474165\", \"supporting_discovery_ids\": [3, 12, 13]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [8, 15]}\n    ],\n    \"complexes\": [\"CERF (CECR2-containing remodeling factor)\"],\n    \"partners\": [\"SMARCA1\", \"SMARCA5\", \"CCAR2\", \"LUZP1\", \"RELA\", \"SALL4\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":7,"faith_pct":85.71428571428571}}