{"gene":"GATAD2A","run_date":"2026-06-10T01:55:21","timeline":{"discoveries":[{"year":2011,"finding":"GATAD2A (p66α) forms a coiled-coil interaction with MBD2 that is required to recruit Mi-2 (CHD4) to the MBD2-NuRD complex; enforced expression of the isolated p66α coiled-coil domain disrupts this interaction and relieves MBD2-mediated globin gene silencing.","method":"Structural/biophysical characterization of coiled-coil interaction, enforced expression of dominant-negative p66α coiled-coil peptide, globin gene silencing assays in erythroid cells","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — structural determination combined with functional mutagenesis and in vivo gene silencing assays, independently foundational for the field","pmids":["21490301"],"is_preprint":false},{"year":2006,"finding":"GATAD2A (p66α) mediates interaction between MBD2 and histone tails within the Mi-2/NuRD complex; mutation of a single amino acid abolishes MBD2 binding and MBD2-mediated repression, changes subnuclear localization from speckled to diffuse, and acetylation of histone tails interferes with p66α binding. The conserved region 2 (CR2) of p66α is required for histone tail interaction.","method":"In vitro binding assays with histone tails, point mutagenesis of p66α, in vivo co-immunoprecipitation, knockdown of p66α/p66β, subnuclear localization by microscopy","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (mutagenesis, in vitro histone binding, Co-IP, localization, knockdown functional assay) in a single study with clear mechanistic outcomes","pmids":["16415179"],"is_preprint":false},{"year":2012,"finding":"The GATAD2A (p66α)–MBD2 coiled-coil forms an anti-parallel heterodimeric complex; individual peptides remain monomeric in isolation, and heterodimeric specificity is driven by complementary electrostatic surface potentials and inherent helical content. Binding affinity hierarchy: p66α binds MBD2 ≈ MBD3 > MBD3L1 ≈ MBD3L2.","method":"Analytical ultracentrifugation, circular dichroism, biophysical binding analyses with MBD2/MBD3/MBD3L1/MBD3L2 and charge-altering mutants","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — rigorous biophysical reconstitution and mutagenesis in a single focused study establishing structural basis of heterodimer specificity","pmids":["23239876"],"is_preprint":false},{"year":2016,"finding":"The MYND domain of ZMYND8 directly interacts with PPPLΦ motifs in GATAD2A, bridging NuRD to zinc finger DNA-binding proteins. GATAD2A and GATAD2B form exclusive homodimers defining mutually exclusive NuRD subcomplexes. ZMYND8 facilitates rapid, poly(ADP-ribose)-dependent recruitment of GATAD2A/NuRD to DNA damage sites to promote homologous recombination repair.","method":"Co-immunoprecipitation, genome-wide ChIP-seq, ZMYND8 depletion, live-cell imaging of DNA damage recruitment, MYND domain interaction mapping","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, genome-wide occupancy, functional DNA damage repair assay, and domain-level interaction mapping in a single study","pmids":["27732854"],"is_preprint":false},{"year":2018,"finding":"GATAD2A is a NuRD-specific subunit whose complete deletion specifically disrupts Mbd3/NuRD repressive activity on the pluripotency circuitry during iPSC reprogramming and differentiation; GATAD2A defines a distinct molecular axis (Gatad2a-Chd4-Mbd3) within Mbd3/NuRD critical for blocking re-establishment of naive pluripotency.","method":"Genetic knockout of Gatad2a in mouse cells, iPSC reprogramming assays, NuRD complex assembly analysis, post-translational modification analysis of Mbd3/NuRD","journal":"Cell stem cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic KO with defined molecular and cellular phenotypes, pathway placement via epistasis, and complex assembly analysis","pmids":["30122475"],"is_preprint":false},{"year":2007,"finding":"Mouse Gatad2a (mp66α) is essential for early embryonic development; homozygous mutant embryos die around embryonic day 10, consistent with a role in methylated DNA-dependent gene silencing.","method":"Loss-of-function mouse genetics (knockout), embryonic phenotype analysis, gene expression profiling in mutants","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean genetic KO with clear developmental phenotype, but mechanistic pathway placement inferred rather than directly demonstrated","pmids":["17565372"],"is_preprint":false},{"year":2021,"finding":"Heterozygous knockout of GATAD2A impairs recruitment of CHD4 to the MBD2-containing NuRD complex in erythroid progenitors, leading to reactivation of fetal hemoglobin (γ-globin); a patient-derived GATAD2A mutation causing haploinsufficiency elevated HbF and ameliorated β-thalassemia severity.","method":"Targeted next-generation sequencing, CRISPR knockout in HUDEP-2 and CD34+ erythroid progenitors, HbF quantification, Co-immunoprecipitation of NuRD complex components","journal":"British journal of haematology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP showing impaired CHD4 recruitment combined with functional HbF assay in relevant cell types, single lab","pmids":["33997955"],"is_preprint":false},{"year":2021,"finding":"GATAD2A (p66α) functions as a co-activator of p53 independently of its NuRD role; it binds the DNA-binding domain of p53 predominantly via its CR2 domain (identified by co-immunoprecipitation), promotes p53 binding at target gene promoters, and its depletion reduces p53 target gene expression in breast cancer cells.","method":"Co-immunoprecipitation, domain-mapping with CR2 mutants, ChIP, p53 target gene expression analysis upon p66α depletion and overexpression","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — reciprocal Co-IP with domain mapping and ChIP functional validation, single lab with two orthogonal methods","pmids":["34944103"],"is_preprint":false},{"year":2023,"finding":"De novo dominant GATAD2A missense variants disrupt interactions of GATAD2A with CHD3, CHD4, and CHD5 (NuRD chromatin remodeling subunits), linking GATAD2A to a neurodevelopmental disorder (NuRDopathy).","method":"Identification of de novo variants in affected individuals, interaction assays showing disruption of GATAD2A binding to CHD3/CHD4/CHD5","journal":"HGG advances","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — interaction disruption shown for specific missense variants, but methods described at abstract level without full reconstitution detail","pmids":["37181331"],"is_preprint":false},{"year":2026,"finding":"ZMYND8 recruits GATAD2A to the MAPT213 lncRNA internal regulatory region via direct interaction of the ZMYND8 MYND domain with proline-rich motifs in GATAD2A's central region, suppressing MAPT213 transcription; crystal structure of the ZMYND8 coiled-coil MYND domain reveals a homodimeric architecture and the molecular basis for GATAD2A recognition.","method":"Crystal structure determination of ZMYND8 MYND domain, ChIP, MYND domain binding assays with GATAD2A proline-rich motifs, structure-function mutagenesis, quantitative binding measurements","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure combined with ChIP and mutagenesis of binding interface in a single focused study, single lab","pmids":["41999894"],"is_preprint":false}],"current_model":"GATAD2A (p66α) is a core NuRD complex subunit that bridges MBD2 to CHD4/Mi-2 via an anti-parallel heterodimeric coiled-coil interaction, simultaneously engaging histone tails through its CR2 domain to mediate DNA methylation-dependent gene silencing; it forms exclusive homodimers defining distinct NuRD subcomplexes, is recruited to DNA damage sites via ZMYND8 MYND-domain recognition of its PPPLΦ motifs to promote homologous recombination, suppresses pluripotency gene networks as part of a Gatad2a-Chd4-Mbd3 axis, and can additionally act as a p53 co-activator through direct binding to p53's DNA-binding domain via CR2."},"narrative":{"mechanistic_narrative":"GATAD2A (p66α) is a core subunit of the Mi-2/NuRD chromatin-remodeling complex that couples DNA methylation reading to gene silencing by physically bridging the methyl-CpG-binding protein MBD2 to the CHD4/Mi-2 remodeler [PMID:21490301]. It engages MBD2 through an anti-parallel heterodimeric coiled-coil whose specificity is set by complementary electrostatic surfaces, with comparable affinity for MBD2 and MBD3 [PMID:23239876]; disrupting this coiled-coil relieves MBD2-mediated globin gene silencing [PMID:21490301]. In parallel, the conserved CR2 region of GATAD2A contacts histone tails, an interaction abolished by point mutation and antagonized by histone acetylation, that is required for MBD2-dependent repression and proper subnuclear localization [PMID:16415179]. GATAD2A and its paralog GATAD2B form mutually exclusive homodimers that define distinct NuRD subcomplexes, and the ZMYND8 MYND domain directly recognizes PPPLΦ/proline-rich motifs in GATAD2A's central region to recruit NuRD to chromatin—both to poly(ADP-ribose)-marked DNA damage sites to promote homologous recombination [PMID:27732854] and to repress specific transcriptional targets [PMID:41999894]. Functionally, GATAD2A defines a Gatad2a-Chd4-Mbd3 axis within Mbd3/NuRD that suppresses the pluripotency circuitry during reprogramming and differentiation [PMID:30122475], and it is essential for early mouse embryonic development [PMID:17565372]. Beyond NuRD, GATAD2A acts as a p53 co-activator, binding the p53 DNA-binding domain via CR2 to promote p53 occupancy at target promoters [PMID:34944103]. In erythroid progenitors GATAD2A haploinsufficiency impairs CHD4 recruitment to MBD2-NuRD and reactivates fetal hemoglobin, ameliorating β-thalassemia [PMID:33997955], and de novo dominant missense variants that disrupt GATAD2A binding to CHD3/CHD4/CHD5 cause a NuRD-related neurodevelopmental disorder [PMID:37181331].","teleology":[{"year":2006,"claim":"Established that GATAD2A is not merely a scaffold but directly reads chromatin, linking MBD2 to histone tails through its CR2 region to enable repression.","evidence":"In vitro histone-tail binding, point mutagenesis, Co-IP, knockdown, and subnuclear localization microscopy","pmids":["16415179"],"confidence":"High","gaps":["Does not resolve which specific histone residues or modification states beyond acetylation govern binding","Structural basis of the CR2-histone interaction not determined"]},{"year":2007,"claim":"Showed GATAD2A is physiologically essential, establishing organismal relevance for methylated-DNA-dependent silencing.","evidence":"Gatad2a knockout mouse with embryonic lethality and expression profiling","pmids":["17565372"],"confidence":"Medium","gaps":["Causative molecular lesion underlying lethality inferred, not directly demonstrated","Tissue-specific requirements not separated from global silencing role"]},{"year":2011,"claim":"Identified the GATAD2A coiled-coil as the bridge that recruits CHD4 to MBD2-NuRD, defining a targetable node controlling globin silencing.","evidence":"Coiled-coil structural/biophysical characterization with dominant-negative peptide and globin silencing assays in erythroid cells","pmids":["21490301"],"confidence":"High","gaps":["Did not establish stoichiometry of CHD4 within the assembled complex","Generality beyond globin loci not tested"]},{"year":2012,"claim":"Resolved how GATAD2A selects its partner, defining the antiparallel heterodimer architecture and affinity hierarchy across MBD2/MBD3 family members.","evidence":"Analytical ultracentrifugation, circular dichroism, and biophysical binding with charge-altering mutants","pmids":["23239876"],"confidence":"High","gaps":["In vitro peptide system does not capture full-complex context","Functional consequence of MBD2 vs MBD3 preference in cells not addressed"]},{"year":2016,"claim":"Connected GATAD2A to genome maintenance, showing ZMYND8-mediated recruitment of NuRD to DNA damage and defining paralog-exclusive subcomplexes.","evidence":"Co-IP, genome-wide ChIP-seq, ZMYND8 depletion, live-cell DNA damage imaging, and MYND domain mapping","pmids":["27732854"],"confidence":"High","gaps":["Mechanism by which NuRD promotes homologous recombination at the chromatin level not fully resolved","Whether GATAD2A and GATAD2B subcomplexes have distinct functional outputs not established"]},{"year":2018,"claim":"Placed GATAD2A in the pluripotency-suppressing arm of Mbd3/NuRD, defining a Gatad2a-Chd4-Mbd3 axis required to block naive pluripotency.","evidence":"Gatad2a knockout in mouse cells with iPSC reprogramming assays and complex assembly analysis","pmids":["30122475"],"confidence":"High","gaps":["Direct target loci of the axis during reprogramming not enumerated","Relationship to GATAD2A's DNA-damage role not integrated"]},{"year":2021,"claim":"Revealed a NuRD-independent activity, with GATAD2A acting as a p53 co-activator via CR2 binding to the p53 DNA-binding domain.","evidence":"Co-IP, CR2 domain mapping, ChIP, and p53 target expression upon depletion/overexpression in breast cancer cells","pmids":["34944103"],"confidence":"Medium","gaps":["Single-lab evidence not independently replicated","How GATAD2A reconciles repressive NuRD and activating p53 roles is unexplained"]},{"year":2021,"claim":"Demonstrated therapeutic relevance: GATAD2A haploinsufficiency reactivates fetal hemoglobin by impairing CHD4 recruitment to MBD2-NuRD.","evidence":"Patient sequencing, CRISPR knockout in HUDEP-2/CD34+ progenitors, HbF quantification, and NuRD Co-IP","pmids":["33997955"],"confidence":"Medium","gaps":["Single-lab functional data","Dose-response of GATAD2A levels on HbF not fully mapped"]},{"year":2023,"claim":"Linked GATAD2A directly to human disease, showing de novo missense variants disrupt binding to CHD3/CHD4/CHD5 and cause a NuRDopathy.","evidence":"De novo variant identification in affected individuals and interaction-disruption assays","pmids":["37181331"],"confidence":"Medium","gaps":["Methods described at abstract level without full reconstitution detail","Genotype-phenotype correlation and cellular consequences not delineated"]},{"year":2026,"claim":"Provided the structural basis for ZMYND8 recognition of GATAD2A and showed this recruitment drives transcriptional repression of a specific lncRNA target.","evidence":"Crystal structure of the ZMYND8 coiled-coil MYND domain, ChIP, binding assays with GATAD2A proline-rich motifs, and structure-function mutagenesis","pmids":["41999894"],"confidence":"High","gaps":["Breadth of ZMYND8-GATAD2A-regulated loci beyond MAPT213 not defined","Relationship to the DNA-damage recruitment role not unified"]},{"year":null,"claim":"How GATAD2A's distinct roles—NuRD-dependent repression, p53 co-activation, DNA-damage recruitment, and developmental silencing—are partitioned and regulated within a cell remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No model integrating repressive NuRD and activating p53 functions","Determinants selecting GATAD2A vs GATAD2B subcomplexes for specific tasks unknown","Genome-wide map of direct GATAD2A targets across contexts incomplete"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,2,3]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[1]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[4,7,9]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[3]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[0,1,4]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[3]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[4,7,9]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[4,5]}],"complexes":["NuRD complex","MBD2-NuRD complex","Mbd3/NuRD complex"],"partners":["MBD2","CHD4","MBD3","ZMYND8","CHD3","CHD5","TP53","GATAD2B"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q86YP4","full_name":"Transcriptional repressor p66-alpha","aliases":["GATA zinc finger domain-containing protein 2A"],"length_aa":633,"mass_kda":68.1,"function":"Transcriptional repressor (PubMed:12183469, PubMed:16415179). Acts as a component of the histone deacetylase NuRD complex which participates in the remodeling of chromatin (PubMed:16428440, PubMed:28977666). Enhances MBD2-mediated repression (PubMed:12183469, PubMed:16415179). Efficient repression requires the presence of GATAD2B (PubMed:16415179)","subcellular_location":"Nucleus speckle; Nucleus; Chromosome","url":"https://www.uniprot.org/uniprotkb/Q86YP4/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/GATAD2A","classification":"Not Classified","n_dependent_lines":370,"n_total_lines":1208,"dependency_fraction":0.30629139072847683},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"HDAC2","stoichiometry":10.0},{"gene":"CSNK2B","stoichiometry":0.2},{"gene":"H2AFZ","stoichiometry":0.2},{"gene":"HDAC1","stoichiometry":0.2},{"gene":"HIST2H2BE","stoichiometry":0.2},{"gene":"PARP1","stoichiometry":0.2},{"gene":"RBBP4","stoichiometry":0.2},{"gene":"SSRP1","stoichiometry":0.2},{"gene":"SYVN1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/GATAD2A","total_profiled":1310},"omim":[{"mim_id":"614998","title":"GATA ZINC FINGER DOMAIN-CONTAINING PROTEIN 2B; GATAD2B","url":"https://www.omim.org/entry/614998"},{"mim_id":"614997","title":"GATA ZINC FINGER DOMAIN-CONTAINING PROTEIN 2A; GATAD2A","url":"https://www.omim.org/entry/614997"},{"mim_id":"603547","title":"METHYL-CpG-BINDING DOMAIN PROTEIN 2; MBD2","url":"https://www.omim.org/entry/603547"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoplasm","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/GATAD2A"},"hgnc":{"alias_symbol":["p66alpha"],"prev_symbol":[]},"alphafold":{"accession":"Q86YP4","domains":[{"cath_id":"1.20.5","chopping":"138-171","consensus_level":"medium","plddt":91.7885,"start":138,"end":171},{"cath_id":"1.20.5","chopping":"377-412","consensus_level":"medium","plddt":75.6153,"start":377,"end":412}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q86YP4","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q86YP4-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q86YP4-F1-predicted_aligned_error_v6.png","plddt_mean":56.41},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=GATAD2A","jax_strain_url":"https://www.jax.org/strain/search?query=GATAD2A"},"sequence":{"accession":"Q86YP4","fasta_url":"https://rest.uniprot.org/uniprotkb/Q86YP4.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q86YP4/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q86YP4"}},"corpus_meta":[{"pmid":"21490301","id":"PMC_21490301","title":"p66Alpha-MBD2 coiled-coil interaction and recruitment of Mi-2 are critical for globin gene silencing by the MBD2-NuRD complex.","date":"2011","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/21490301","citation_count":122,"is_preprint":false},{"pmid":"31324198","id":"PMC_31324198","title":"Hsa_circ_0058124 promotes papillary thyroid cancer tumorigenesis and invasiveness through the NOTCH3/GATAD2A axis.","date":"2019","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/31324198","citation_count":120,"is_preprint":false},{"pmid":"27732854","id":"PMC_27732854","title":"ZMYND8 Co-localizes with NuRD on Target Genes and Regulates Poly(ADP-Ribose)-Dependent Recruitment of GATAD2A/NuRD to Sites of DNA Damage.","date":"2016","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/27732854","citation_count":98,"is_preprint":false},{"pmid":"16415179","id":"PMC_16415179","title":"p66alpha and p66beta of the Mi-2/NuRD complex mediate MBD2 and histone interaction.","date":"2006","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/16415179","citation_count":67,"is_preprint":false},{"pmid":"30122475","id":"PMC_30122475","title":"Neutralizing Gatad2a-Chd4-Mbd3/NuRD Complex Facilitates Deterministic Induction of Naive Pluripotency.","date":"2018","source":"Cell stem cell","url":"https://pubmed.ncbi.nlm.nih.gov/30122475","citation_count":63,"is_preprint":false},{"pmid":"30955816","id":"PMC_30955816","title":"Circular RNA GATAD2A promotes H1N1 replication through inhibiting autophagy.","date":"2019","source":"Veterinary microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/30955816","citation_count":59,"is_preprint":false},{"pmid":"23239876","id":"PMC_23239876","title":"Unique features of the anti-parallel, heterodimeric coiled-coil interaction between methyl-cytosine binding domain 2 (MBD2) homologues and GATA zinc finger domain containing 2A (GATAD2A/p66α).","date":"2012","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/23239876","citation_count":32,"is_preprint":false},{"pmid":"17565372","id":"PMC_17565372","title":"Mutants in the mouse NuRD/Mi2 component P66alpha are embryonic lethal.","date":"2007","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/17565372","citation_count":24,"is_preprint":false},{"pmid":"28260108","id":"PMC_28260108","title":"Knockdown of GATAD2A suppresses cell proliferation in thyroid cancer in vitro.","date":"2017","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/28260108","citation_count":17,"is_preprint":false},{"pmid":"33997955","id":"PMC_33997955","title":"GATA zinc finger domain-containing protein 2A (GATAD2A) deficiency reactivates fetal haemoglobin in patients with β-thalassaemia through impaired formation of methyl-binding domain protein 2 (MBD2)-containing nucleosome remodelling and deacetylation (NuRD) complex.","date":"2021","source":"British journal of haematology","url":"https://pubmed.ncbi.nlm.nih.gov/33997955","citation_count":15,"is_preprint":false},{"pmid":"35904180","id":"PMC_35904180","title":"lncKRT16P6 promotes tongue squamous cell carcinoma progression by sponging miR‑3180 and regulating GATAD2A expression.","date":"2022","source":"International journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/35904180","citation_count":7,"is_preprint":false},{"pmid":"34944103","id":"PMC_34944103","title":"p66α Suppresses Breast Cancer Cell Growth and Migration by Acting as Co-Activator of p53.","date":"2021","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/34944103","citation_count":5,"is_preprint":false},{"pmid":"33963205","id":"PMC_33963205","title":"Germinal GLT8D1, GATAD2A and SLC25A39 mutations in a patient with a 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in<i>SAMM50</i>,<i>SUGP1</i>,<i>MAU2</i>, and<i>GATAD2A</i>and liver fat in individuals with normal weight","date":"2024-11-05","source":"bioRxiv","url":"https://doi.org/10.1101/2024.11.05.24316758","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":10035,"output_tokens":2720,"usd":0.035452,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10000,"output_tokens":3663,"usd":0.070788,"stage2_stop_reason":"end_turn"},"total_usd":0.10624,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2011,\n      \"finding\": \"GATAD2A (p66α) forms a coiled-coil interaction with MBD2 that is required to recruit Mi-2 (CHD4) to the MBD2-NuRD complex; enforced expression of the isolated p66α coiled-coil domain disrupts this interaction and relieves MBD2-mediated globin gene silencing.\",\n      \"method\": \"Structural/biophysical characterization of coiled-coil interaction, enforced expression of dominant-negative p66α coiled-coil peptide, globin gene silencing assays in erythroid cells\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — structural determination combined with functional mutagenesis and in vivo gene silencing assays, independently foundational for the field\",\n      \"pmids\": [\"21490301\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"GATAD2A (p66α) mediates interaction between MBD2 and histone tails within the Mi-2/NuRD complex; mutation of a single amino acid abolishes MBD2 binding and MBD2-mediated repression, changes subnuclear localization from speckled to diffuse, and acetylation of histone tails interferes with p66α binding. The conserved region 2 (CR2) of p66α is required for histone tail interaction.\",\n      \"method\": \"In vitro binding assays with histone tails, point mutagenesis of p66α, in vivo co-immunoprecipitation, knockdown of p66α/p66β, subnuclear localization by microscopy\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (mutagenesis, in vitro histone binding, Co-IP, localization, knockdown functional assay) in a single study with clear mechanistic outcomes\",\n      \"pmids\": [\"16415179\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"The GATAD2A (p66α)–MBD2 coiled-coil forms an anti-parallel heterodimeric complex; individual peptides remain monomeric in isolation, and heterodimeric specificity is driven by complementary electrostatic surface potentials and inherent helical content. Binding affinity hierarchy: p66α binds MBD2 ≈ MBD3 > MBD3L1 ≈ MBD3L2.\",\n      \"method\": \"Analytical ultracentrifugation, circular dichroism, biophysical binding analyses with MBD2/MBD3/MBD3L1/MBD3L2 and charge-altering mutants\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — rigorous biophysical reconstitution and mutagenesis in a single focused study establishing structural basis of heterodimer specificity\",\n      \"pmids\": [\"23239876\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"The MYND domain of ZMYND8 directly interacts with PPPLΦ motifs in GATAD2A, bridging NuRD to zinc finger DNA-binding proteins. GATAD2A and GATAD2B form exclusive homodimers defining mutually exclusive NuRD subcomplexes. ZMYND8 facilitates rapid, poly(ADP-ribose)-dependent recruitment of GATAD2A/NuRD to DNA damage sites to promote homologous recombination repair.\",\n      \"method\": \"Co-immunoprecipitation, genome-wide ChIP-seq, ZMYND8 depletion, live-cell imaging of DNA damage recruitment, MYND domain interaction mapping\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, genome-wide occupancy, functional DNA damage repair assay, and domain-level interaction mapping in a single study\",\n      \"pmids\": [\"27732854\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"GATAD2A is a NuRD-specific subunit whose complete deletion specifically disrupts Mbd3/NuRD repressive activity on the pluripotency circuitry during iPSC reprogramming and differentiation; GATAD2A defines a distinct molecular axis (Gatad2a-Chd4-Mbd3) within Mbd3/NuRD critical for blocking re-establishment of naive pluripotency.\",\n      \"method\": \"Genetic knockout of Gatad2a in mouse cells, iPSC reprogramming assays, NuRD complex assembly analysis, post-translational modification analysis of Mbd3/NuRD\",\n      \"journal\": \"Cell stem cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic KO with defined molecular and cellular phenotypes, pathway placement via epistasis, and complex assembly analysis\",\n      \"pmids\": [\"30122475\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Mouse Gatad2a (mp66α) is essential for early embryonic development; homozygous mutant embryos die around embryonic day 10, consistent with a role in methylated DNA-dependent gene silencing.\",\n      \"method\": \"Loss-of-function mouse genetics (knockout), embryonic phenotype analysis, gene expression profiling in mutants\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean genetic KO with clear developmental phenotype, but mechanistic pathway placement inferred rather than directly demonstrated\",\n      \"pmids\": [\"17565372\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Heterozygous knockout of GATAD2A impairs recruitment of CHD4 to the MBD2-containing NuRD complex in erythroid progenitors, leading to reactivation of fetal hemoglobin (γ-globin); a patient-derived GATAD2A mutation causing haploinsufficiency elevated HbF and ameliorated β-thalassemia severity.\",\n      \"method\": \"Targeted next-generation sequencing, CRISPR knockout in HUDEP-2 and CD34+ erythroid progenitors, HbF quantification, Co-immunoprecipitation of NuRD complex components\",\n      \"journal\": \"British journal of haematology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP showing impaired CHD4 recruitment combined with functional HbF assay in relevant cell types, single lab\",\n      \"pmids\": [\"33997955\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"GATAD2A (p66α) functions as a co-activator of p53 independently of its NuRD role; it binds the DNA-binding domain of p53 predominantly via its CR2 domain (identified by co-immunoprecipitation), promotes p53 binding at target gene promoters, and its depletion reduces p53 target gene expression in breast cancer cells.\",\n      \"method\": \"Co-immunoprecipitation, domain-mapping with CR2 mutants, ChIP, p53 target gene expression analysis upon p66α depletion and overexpression\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — reciprocal Co-IP with domain mapping and ChIP functional validation, single lab with two orthogonal methods\",\n      \"pmids\": [\"34944103\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"De novo dominant GATAD2A missense variants disrupt interactions of GATAD2A with CHD3, CHD4, and CHD5 (NuRD chromatin remodeling subunits), linking GATAD2A to a neurodevelopmental disorder (NuRDopathy).\",\n      \"method\": \"Identification of de novo variants in affected individuals, interaction assays showing disruption of GATAD2A binding to CHD3/CHD4/CHD5\",\n      \"journal\": \"HGG advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — interaction disruption shown for specific missense variants, but methods described at abstract level without full reconstitution detail\",\n      \"pmids\": [\"37181331\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"ZMYND8 recruits GATAD2A to the MAPT213 lncRNA internal regulatory region via direct interaction of the ZMYND8 MYND domain with proline-rich motifs in GATAD2A's central region, suppressing MAPT213 transcription; crystal structure of the ZMYND8 coiled-coil MYND domain reveals a homodimeric architecture and the molecular basis for GATAD2A recognition.\",\n      \"method\": \"Crystal structure determination of ZMYND8 MYND domain, ChIP, MYND domain binding assays with GATAD2A proline-rich motifs, structure-function mutagenesis, quantitative binding measurements\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure combined with ChIP and mutagenesis of binding interface in a single focused study, single lab\",\n      \"pmids\": [\"41999894\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"GATAD2A (p66α) is a core NuRD complex subunit that bridges MBD2 to CHD4/Mi-2 via an anti-parallel heterodimeric coiled-coil interaction, simultaneously engaging histone tails through its CR2 domain to mediate DNA methylation-dependent gene silencing; it forms exclusive homodimers defining distinct NuRD subcomplexes, is recruited to DNA damage sites via ZMYND8 MYND-domain recognition of its PPPLΦ motifs to promote homologous recombination, suppresses pluripotency gene networks as part of a Gatad2a-Chd4-Mbd3 axis, and can additionally act as a p53 co-activator through direct binding to p53's DNA-binding domain via CR2.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"GATAD2A (p66\\u03b1) is a core subunit of the Mi-2/NuRD chromatin-remodeling complex that couples DNA methylation reading to gene silencing by physically bridging the methyl-CpG-binding protein MBD2 to the CHD4/Mi-2 remodeler [#0]. It engages MBD2 through an anti-parallel heterodimeric coiled-coil whose specificity is set by complementary electrostatic surfaces, with comparable affinity for MBD2 and MBD3 [#2]; disrupting this coiled-coil relieves MBD2-mediated globin gene silencing [#0]. In parallel, the conserved CR2 region of GATAD2A contacts histone tails, an interaction abolished by point mutation and antagonized by histone acetylation, that is required for MBD2-dependent repression and proper subnuclear localization [#1]. GATAD2A and its paralog GATAD2B form mutually exclusive homodimers that define distinct NuRD subcomplexes, and the ZMYND8 MYND domain directly recognizes PPPL\\u03a6/proline-rich motifs in GATAD2A's central region to recruit NuRD to chromatin\\u2014both to poly(ADP-ribose)-marked DNA damage sites to promote homologous recombination [#3] and to repress specific transcriptional targets [#9]. Functionally, GATAD2A defines a Gatad2a-Chd4-Mbd3 axis within Mbd3/NuRD that suppresses the pluripotency circuitry during reprogramming and differentiation [#4], and it is essential for early mouse embryonic development [#5]. Beyond NuRD, GATAD2A acts as a p53 co-activator, binding the p53 DNA-binding domain via CR2 to promote p53 occupancy at target promoters [#7]. In erythroid progenitors GATAD2A haploinsufficiency impairs CHD4 recruitment to MBD2-NuRD and reactivates fetal hemoglobin, ameliorating \\u03b2-thalassemia [#6], and de novo dominant missense variants that disrupt GATAD2A binding to CHD3/CHD4/CHD5 cause a NuRD-related neurodevelopmental disorder [#8].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Established that GATAD2A is not merely a scaffold but directly reads chromatin, linking MBD2 to histone tails through its CR2 region to enable repression.\",\n      \"evidence\": \"In vitro histone-tail binding, point mutagenesis, Co-IP, knockdown, and subnuclear localization microscopy\",\n      \"pmids\": [\"16415179\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not resolve which specific histone residues or modification states beyond acetylation govern binding\", \"Structural basis of the CR2-histone interaction not determined\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Showed GATAD2A is physiologically essential, establishing organismal relevance for methylated-DNA-dependent silencing.\",\n      \"evidence\": \"Gatad2a knockout mouse with embryonic lethality and expression profiling\",\n      \"pmids\": [\"17565372\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causative molecular lesion underlying lethality inferred, not directly demonstrated\", \"Tissue-specific requirements not separated from global silencing role\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identified the GATAD2A coiled-coil as the bridge that recruits CHD4 to MBD2-NuRD, defining a targetable node controlling globin silencing.\",\n      \"evidence\": \"Coiled-coil structural/biophysical characterization with dominant-negative peptide and globin silencing assays in erythroid cells\",\n      \"pmids\": [\"21490301\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish stoichiometry of CHD4 within the assembled complex\", \"Generality beyond globin loci not tested\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Resolved how GATAD2A selects its partner, defining the antiparallel heterodimer architecture and affinity hierarchy across MBD2/MBD3 family members.\",\n      \"evidence\": \"Analytical ultracentrifugation, circular dichroism, and biophysical binding with charge-altering mutants\",\n      \"pmids\": [\"23239876\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vitro peptide system does not capture full-complex context\", \"Functional consequence of MBD2 vs MBD3 preference in cells not addressed\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Connected GATAD2A to genome maintenance, showing ZMYND8-mediated recruitment of NuRD to DNA damage and defining paralog-exclusive subcomplexes.\",\n      \"evidence\": \"Co-IP, genome-wide ChIP-seq, ZMYND8 depletion, live-cell DNA damage imaging, and MYND domain mapping\",\n      \"pmids\": [\"27732854\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which NuRD promotes homologous recombination at the chromatin level not fully resolved\", \"Whether GATAD2A and GATAD2B subcomplexes have distinct functional outputs not established\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Placed GATAD2A in the pluripotency-suppressing arm of Mbd3/NuRD, defining a Gatad2a-Chd4-Mbd3 axis required to block naive pluripotency.\",\n      \"evidence\": \"Gatad2a knockout in mouse cells with iPSC reprogramming assays and complex assembly analysis\",\n      \"pmids\": [\"30122475\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct target loci of the axis during reprogramming not enumerated\", \"Relationship to GATAD2A's DNA-damage role not integrated\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Revealed a NuRD-independent activity, with GATAD2A acting as a p53 co-activator via CR2 binding to the p53 DNA-binding domain.\",\n      \"evidence\": \"Co-IP, CR2 domain mapping, ChIP, and p53 target expression upon depletion/overexpression in breast cancer cells\",\n      \"pmids\": [\"34944103\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab evidence not independently replicated\", \"How GATAD2A reconciles repressive NuRD and activating p53 roles is unexplained\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrated therapeutic relevance: GATAD2A haploinsufficiency reactivates fetal hemoglobin by impairing CHD4 recruitment to MBD2-NuRD.\",\n      \"evidence\": \"Patient sequencing, CRISPR knockout in HUDEP-2/CD34+ progenitors, HbF quantification, and NuRD Co-IP\",\n      \"pmids\": [\"33997955\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab functional data\", \"Dose-response of GATAD2A levels on HbF not fully mapped\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Linked GATAD2A directly to human disease, showing de novo missense variants disrupt binding to CHD3/CHD4/CHD5 and cause a NuRDopathy.\",\n      \"evidence\": \"De novo variant identification in affected individuals and interaction-disruption assays\",\n      \"pmids\": [\"37181331\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Methods described at abstract level without full reconstitution detail\", \"Genotype-phenotype correlation and cellular consequences not delineated\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Provided the structural basis for ZMYND8 recognition of GATAD2A and showed this recruitment drives transcriptional repression of a specific lncRNA target.\",\n      \"evidence\": \"Crystal structure of the ZMYND8 coiled-coil MYND domain, ChIP, binding assays with GATAD2A proline-rich motifs, and structure-function mutagenesis\",\n      \"pmids\": [\"41999894\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Breadth of ZMYND8-GATAD2A-regulated loci beyond MAPT213 not defined\", \"Relationship to the DNA-damage recruitment role not unified\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How GATAD2A's distinct roles\\u2014NuRD-dependent repression, p53 co-activation, DNA-damage recruitment, and developmental silencing\\u2014are partitioned and regulated within a cell remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No model integrating repressive NuRD and activating p53 functions\", \"Determinants selecting GATAD2A vs GATAD2B subcomplexes for specific tasks unknown\", \"Genome-wide map of direct GATAD2A targets across contexts incomplete\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 2, 3]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [4, 7, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [0, 1, 4]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [4, 7, 9]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [4, 5]}\n    ],\n    \"complexes\": [\"NuRD complex\", \"MBD2-NuRD complex\", \"Mbd3/NuRD complex\"],\n    \"partners\": [\"MBD2\", \"CHD4\", \"MBD3\", \"ZMYND8\", \"CHD3\", \"CHD5\", \"TP53\", \"GATAD2B\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}