{"gene":"SMARCD2","run_date":"2026-06-10T07:46:35","timeline":{"discoveries":[{"year":2017,"finding":"SMARCD2 directly interacts with the transcription factor CEBPɛ and controls expression of neutrophil proteins stored in specific granules; loss-of-function mutations in SMARCD2 identified in patients with specific granule deficiency abolish this interaction with SWI/SNF and thereby secondary granule gene expression.","method":"Co-immunoprecipitation, in vitro interaction assays, chromatin immunoprecipitation, patient mutation analysis","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal interaction shown, replicated independently in two simultaneous papers (PMIDs 28369036 and 28369034) with multiple orthogonal methods including ChIP, Co-IP, and patient mutations","pmids":["28369036","28369034"],"is_preprint":false},{"year":2017,"finding":"SMARCD2-containing SWI/SNF complexes are required for CEBPɛ transcription factor recruitment to the promoter of neutrophilic secondary granule genes during granulocyte differentiation; SMARCD2 controls early steps in differentiation of myeloid-erythroid progenitor cells.","method":"Smarcd2-deficient mouse model, chromatin immunoprecipitation (ChIP) at secondary granule gene promoters, gene expression profiling","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — loss-of-function genetic model with defined molecular phenotype (loss of CEBPɛ recruitment by ChIP), replicated across two independent labs and multiple model organisms","pmids":["28369034","28369036"],"is_preprint":false},{"year":2017,"finding":"The functional specificity of SMARCD2 in granulocyte development (which cannot be replaced by the 63%-identical paralog SMARCD1) is conferred by its divergent coiled-coil 1 and SWIB domains.","method":"Domain swap experiments, Smarcd2-deficient mouse rescue assays with SMARCD1 substitution","journal":"Nature genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain-swap functional rescue experiment in single lab, but with clear negative control (SMARCD1 cannot substitute)","pmids":["28369034"],"is_preprint":false},{"year":2010,"finding":"BAF60b (SMARCD2) is ubiquitinated through a Rac GTPase-dependent signalling process mediated by the mammalian RING finger protein Unkempt, which binds BAF60b and promotes its degradative ubiquitination; this process occurs in the nuclear compartment.","method":"Two-hybrid cloning, Co-immunoprecipitation, ubiquitination assay, proteasome inhibitor (MG132) treatment, immunofluorescence","journal":"The FEBS journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (yeast two-hybrid, Co-IP, ubiquitination assay, MG132 rescue) in single lab","pmids":["20148946"],"is_preprint":false},{"year":2017,"finding":"Baf60b (SMARCD2) links chromatin opening to ATM activation during lineage conversion by facilitating ATM recruitment to open chromatin regions at hepatic gene loci, activating the ATM-p53 pathway independently of DNA damage to block cell identity conversion.","method":"Chromatin immunoprecipitation, ATM recruitment assay, loss-of-function knockdown in fibroblast-to-hepatocyte conversion model","journal":"Cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-based ATM recruitment assay plus functional loss-of-function in single lab with defined pathway placement","pmids":["28303890"],"is_preprint":false},{"year":2015,"finding":"SMARCD2 is selectively required for leukaemic cell expansion and self-renewal in MLL-rearranged leukaemia, where it regulates expression of haematopoietic stem cell-associated genes; however, unlike mouse data, it is not required for c-MYC-regulated gene expression in human cells.","method":"shRNA knockdown, gene expression profiling (RNA-seq), in vitro and in vivo leukaemia expansion assays","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean knockdown with gene expression profiling and functional leukaemia expansion assay in single lab","pmids":["26571505"],"is_preprint":false},{"year":2024,"finding":"BAF60b (SMARCD2) interacts with transcription factor RUNX1 to promote CCR9 expression on regulatory T cells, facilitating their migration to inflammatory tissues and suppressing inflammation in EAE and colitis models.","method":"Co-immunoprecipitation, transcriptome analysis, ATAC-seq (genome-wide chromatin landscape), conditional knockout mouse models","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP plus ATAC-seq and functional in vivo models, single lab","pmids":["38996070"],"is_preprint":false},{"year":2024,"finding":"Hepatic BAF60b (SMARCD2) interacts with transcription factor C/EBPβ to suppress Pparγ gene expression, thereby controlling hepatic lipid accumulation; BAF60b deficiency promotes HFD-induced liver steatosis while transgenic overexpression attenuates NAFLD.","method":"Co-immunoprecipitation, ATAC-seq motif analysis, liver-specific knockout and transgenic mouse models, gene expression analysis","journal":"Diabetes","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP interaction, ATAC-seq, and genetic gain/loss-of-function models in single lab with multiple orthogonal methods","pmids":["39046829"],"is_preprint":false}],"current_model":"SMARCD2 (BAF60b) is a context-specific subunit of SWI/SNF (BAF) chromatin-remodeling complexes that recruits transcription factors—including CEBPɛ (for granulopoiesis), RUNX1 (for Treg migration), and C/EBPβ (for hepatic lipid metabolism)—to specific genomic loci to remodel chromatin and activate or repress target gene programs; its functional specificity relative to paralogs is encoded by its divergent coiled-coil 1 and SWIB domains, and its protein levels are regulated by Rac GTPase-dependent, Unkempt-mediated degradative ubiquitination."},"narrative":{"mechanistic_narrative":"SMARCD2 (BAF60b) is a context-specific subunit of SWI/SNF (BAF) chromatin-remodeling complexes that bridges lineage-specifying transcription factors to chromatin to direct cell-type-specific gene programs [PMID:28369036, PMID:28369034]. In granulopoiesis it physically interacts with CEBPɛ and is required for CEBPɛ recruitment to the promoters of neutrophil secondary granule genes, and loss-of-function mutations in patients with specific granule deficiency abolish the SMARCD2–SWI/SNF interaction and secondary granule gene expression [PMID:28369036, PMID:28369034]. This developmental role extends to early myeloid-erythroid progenitor differentiation [PMID:28369034, PMID:28369036], to leukaemic self-renewal in MLL-rearranged leukaemia where SMARCD2 regulates haematopoietic stem cell-associated genes [PMID:26571505], to RUNX1-dependent CCR9 expression governing regulatory T cell migration and inflammation [PMID:38996070], and to a C/EBPβ-dependent program in liver that suppresses Pparγ and limits hepatic lipid accumulation [PMID:39046829]. Its functional specificity—which cannot be supplied by the 63%-identical paralog SMARCD1—is encoded by its divergent coiled-coil 1 and SWIB domains [PMID:28369034]. SMARCD2 also couples chromatin opening to ATM–p53 activation independently of DNA damage during attempted lineage conversion [PMID:28303890], and its protein levels are controlled by Rac-GTPase-dependent, Unkempt-mediated degradative ubiquitination in the nucleus [PMID:20148946].","teleology":[{"year":2010,"claim":"Established the first regulatory input on SMARCD2 abundance, showing its levels are controlled post-translationally rather than only transcriptionally.","evidence":"Yeast two-hybrid, Co-IP, ubiquitination assay, and MG132 rescue in mammalian cells linking BAF60b to Unkempt-mediated, Rac-dependent ubiquitination","pmids":["20148946"],"confidence":"Medium","gaps":["Single lab; the physiological signals that trigger Rac/Unkempt-dependent turnover are not defined","Does not connect degradation to a specific chromatin-remodeling output"]},{"year":2015,"claim":"Showed SMARCD2 is a selective dependency in a malignant context, distinguishing its requirement from general SWI/SNF housekeeping function.","evidence":"shRNA knockdown with RNA-seq and in vitro/in vivo leukaemia expansion assays in MLL-rearranged leukaemia","pmids":["26571505"],"confidence":"Medium","gaps":["Human cells did not reproduce the mouse c-MYC dependency, leaving species-specific target programs unresolved","Direct transcription-factor partners in leukaemia not identified"]},{"year":2017,"claim":"Defined the core molecular mechanism: SMARCD2 within SWI/SNF recruits CEBPɛ to drive a specific gene program, and human disease mutations validate this axis.","evidence":"Co-IP, in vitro interaction, ChIP at secondary granule promoters, Smarcd2-deficient mouse, and patient mutation analysis (two independent papers)","pmids":["28369036","28369034"],"confidence":"High","gaps":["Structure of the SMARCD2–CEBPɛ interface not resolved","Whether the same recruitment logic generalizes to other transcription factors was not tested here"]},{"year":2017,"claim":"Explained the basis of paralog non-redundancy, attributing SMARCD2's unique granulopoietic function to specific protein domains.","evidence":"Domain-swap and SMARCD1-substitution rescue experiments in Smarcd2-deficient cells","pmids":["28369034"],"confidence":"Medium","gaps":["Single lab; the binding partner(s) discriminated by the coiled-coil 1/SWIB domains not mapped biochemically","Domain contributions in non-myeloid contexts untested"]},{"year":2017,"claim":"Revealed a chromatin-to-signalling link, showing SMARCD2-driven chromatin opening can activate ATM-p53 to enforce cell identity.","evidence":"ChIP and ATM recruitment assays with knockdown in a fibroblast-to-hepatocyte conversion model","pmids":["28303890"],"confidence":"Medium","gaps":["Mechanism by which open chromatin recruits ATM independent of DNA damage not defined","Single lab and a specialized lineage-conversion system"]},{"year":2024,"claim":"Extended the transcription-factor-recruitment paradigm to immune regulation via RUNX1, linking SMARCD2 to Treg trafficking.","evidence":"Reciprocal Co-IP, ATAC-seq, transcriptome analysis, and conditional knockout mice in EAE and colitis models","pmids":["38996070"],"confidence":"Medium","gaps":["Direct genomic co-occupancy of SMARCD2 and RUNX1 at the CCR9 locus not shown by ChIP","Single lab"]},{"year":2024,"claim":"Generalized SMARCD2's TF-partnering role to metabolism, showing a C/EBPβ-dependent repression of Pparγ that constrains hepatic steatosis.","evidence":"Co-IP, ATAC-seq motif analysis, and liver-specific knockout/transgenic mouse models","pmids":["39046829"],"confidence":"Medium","gaps":["Whether C/EBPβ recruitment depends on the same domains as CEBPɛ recruitment untested","Single lab"]},{"year":null,"claim":"How a single SWI/SNF subunit selects among distinct transcription-factor partners (CEBPɛ, RUNX1, C/EBPβ) across tissues remains unresolved at structural and biochemical resolution.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of any SMARCD2–transcription-factor interface","Rules linking domain identity to partner choice not established","Genome-wide direct SMARCD2 occupancy maps lacking"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,1,6,7]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1,6,7]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[3]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[0,1]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,1,6,7]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[1,4]}],"complexes":["SWI/SNF (BAF)"],"partners":["CEBPE","RUNX1","CEBPB","UNK"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q92925","full_name":"SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily D member 2","aliases":["60 kDa BRG-1/Brm-associated factor subunit B","BRG1-associated factor 60B","BAF60B"],"length_aa":531,"mass_kda":58.9,"function":"Involved in transcriptional activation and repression of select genes by chromatin remodeling (alteration of DNA-nucleosome topology). Component of SWI/SNF chromatin remodeling complexes that carry out key enzymatic activities, changing chromatin structure by altering DNA-histone contacts within a nucleosome in an ATP-dependent manner (PubMed:22952240, PubMed:26601204). Critical regulator of myeloid differentiation, controlling granulocytopoiesis and the expression of genes involved in neutrophil granule formation (PubMed:28369036)","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q92925/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SMARCD2","classification":"Not Classified","n_dependent_lines":64,"n_total_lines":1208,"dependency_fraction":0.052980132450331126},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000108604","cell_line_id":"CID001680","localizations":[{"compartment":"nucleoplasm","grade":3},{"compartment":"chromatin","grade":2}],"interactors":[{"gene":"ARID1A","stoichiometry":10.0},{"gene":"SMARCA4","stoichiometry":10.0},{"gene":"SMARCB1","stoichiometry":10.0},{"gene":"SMARCC1","stoichiometry":10.0},{"gene":"SMARCC2","stoichiometry":10.0},{"gene":"SMARCE1","stoichiometry":10.0},{"gene":"DPF2","stoichiometry":10.0},{"gene":"ACTL6A","stoichiometry":10.0},{"gene":"BCL7A","stoichiometry":4.0},{"gene":"BRD7","stoichiometry":4.0}],"url":"https://opencell.sf.czbiohub.org/target/CID001680","total_profiled":1310},"omim":[{"mim_id":"617475","title":"SPECIFIC GRANULE DEFICIENCY 2; SGD2","url":"https://www.omim.org/entry/617475"},{"mim_id":"617463","title":"UNKEMPT FAMILY-LIKE ZINC FINGER; UNKL","url":"https://www.omim.org/entry/617463"},{"mim_id":"612756","title":"TESTICULAR CELL ADHESION MOLECULE 1; TCAM1","url":"https://www.omim.org/entry/612756"},{"mim_id":"601736","title":"SWI/SNF-RELATED, MATRIX-ASSOCIATED, ACTIN-DEPENDENT REGULATOR OF CHROMATIN, SUBFAMILY D, MEMBER 2; SMARCD2","url":"https://www.omim.org/entry/601736"},{"mim_id":"245480","title":"SPECIFIC GRANULE DEFICIENCY 1; SGD1","url":"https://www.omim.org/entry/245480"}],"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/SMARCD2"},"hgnc":{"alias_symbol":["BAF60B","Rsc6p","CRACD2","PRO2451"],"prev_symbol":[]},"alphafold":{"accession":"Q92925","domains":[{"cath_id":"2.60.40.1970","chopping":"189-203_227-306_384-413","consensus_level":"medium","plddt":90.4597,"start":189,"end":413},{"cath_id":"1.10.245.10","chopping":"309-383","consensus_level":"medium","plddt":93.9155,"start":309,"end":383},{"cath_id":"1.20.5","chopping":"142-188","consensus_level":"medium","plddt":90.8136,"start":142,"end":188}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q92925","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q92925-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q92925-F1-predicted_aligned_error_v6.png","plddt_mean":76.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SMARCD2","jax_strain_url":"https://www.jax.org/strain/search?query=SMARCD2"},"sequence":{"accession":"Q92925","fasta_url":"https://rest.uniprot.org/uniprotkb/Q92925.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q92925/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q92925"}},"corpus_meta":[{"pmid":"28369036","id":"PMC_28369036","title":"Chromatin-remodeling factor SMARCD2 regulates transcriptional networks controlling differentiation of neutrophil granulocytes.","date":"2017","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/28369036","citation_count":84,"is_preprint":false},{"pmid":"28369034","id":"PMC_28369034","title":"SMARCD2 subunit of SWI/SNF chromatin-remodeling complexes mediates granulopoiesis through a CEBPɛ dependent mechanism.","date":"2017","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/28369034","citation_count":63,"is_preprint":false},{"pmid":"26571505","id":"PMC_26571505","title":"SWI/SNF Subunits SMARCA4, SMARCD2 and DPF2 Collaborate in MLL-Rearranged Leukaemia Maintenance.","date":"2015","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/26571505","citation_count":23,"is_preprint":false},{"pmid":"20148946","id":"PMC_20148946","title":"The SWI/SNF protein BAF60b is ubiquitinated through a signalling process involving Rac GTPase and the RING finger protein Unkempt.","date":"2010","source":"The FEBS journal","url":"https://pubmed.ncbi.nlm.nih.gov/20148946","citation_count":21,"is_preprint":false},{"pmid":"28303890","id":"PMC_28303890","title":"Baf60b-mediated ATM-p53 activation blocks cell identity conversion by sensing chromatin opening.","date":"2017","source":"Cell research","url":"https://pubmed.ncbi.nlm.nih.gov/28303890","citation_count":21,"is_preprint":false},{"pmid":"9427560","id":"PMC_9427560","title":"Gene structure of rat BAF60b, a component of mammalian SW1/SNF complexes, and its physical linkage to the growth hormone gene and transcription factor SUG/proteasome p45 gene.","date":"1997","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/9427560","citation_count":12,"is_preprint":false},{"pmid":"33279574","id":"PMC_33279574","title":"Defective neutrophil development and specific granule deficiency caused by a homozygous splice-site mutation in SMARCD2.","date":"2020","source":"The Journal of allergy and clinical immunology","url":"https://pubmed.ncbi.nlm.nih.gov/33279574","citation_count":11,"is_preprint":false},{"pmid":"33025377","id":"PMC_33025377","title":"Novel Frameshift Autosomal Recessive Loss-of-Function Mutation in SMARCD2 Encoding a Chromatin Remodeling Factor Mediates Granulopoiesis.","date":"2020","source":"Journal of clinical immunology","url":"https://pubmed.ncbi.nlm.nih.gov/33025377","citation_count":10,"is_preprint":false},{"pmid":"9889334","id":"PMC_9889334","title":"Gene structure of rat testicular cell adhesion molecule 1 (TCAM-1), and its physical linkage to genes coding for the growth hormone and BAF60b, a component of SWI/SNF complexes.","date":"1999","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/9889334","citation_count":10,"is_preprint":false},{"pmid":"28442792","id":"PMC_28442792","title":"A SMARCD2-containing mSWI/SNF complex is required for granulopoiesis.","date":"2017","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/28442792","citation_count":10,"is_preprint":false},{"pmid":"38996070","id":"PMC_38996070","title":"SWI/SNF chromatin remodeling factor BAF60b restrains inflammatory diseases by affecting regulatory T cell migration.","date":"2024","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/38996070","citation_count":9,"is_preprint":false},{"pmid":"39046829","id":"PMC_39046829","title":"Identification of BAF60b as a Chromatin-Remodeling Checkpoint of Diet-Induced Fatty Liver Disease.","date":"2024","source":"Diabetes","url":"https://pubmed.ncbi.nlm.nih.gov/39046829","citation_count":5,"is_preprint":false},{"pmid":"37712719","id":"PMC_37712719","title":"Clinical and transcriptomic characteristics of a novel SMARCD2 mutation that disrupts neutrophil maturation and function.","date":"2023","source":"Pediatric blood & cancer","url":"https://pubmed.ncbi.nlm.nih.gov/37712719","citation_count":5,"is_preprint":false},{"pmid":"10382302","id":"PMC_10382302","title":"Evidence for evolutionary conservation of a physical linkage between the human BAF60b, a subunit of SWI/SNF complex, and thyroid hormone receptor interacting protein-1 genes on chromosome 17.","date":"1999","source":"Genome","url":"https://pubmed.ncbi.nlm.nih.gov/10382302","citation_count":5,"is_preprint":false},{"pmid":"35320004","id":"PMC_35320004","title":"Specific Granule Deficiency Due To Novel Homozygote SMARCD2 Variant.","date":"2022","source":"Pediatric allergy, immunology, and pulmonology","url":"https://pubmed.ncbi.nlm.nih.gov/35320004","citation_count":3,"is_preprint":false},{"pmid":"36135322","id":"PMC_36135322","title":"Congenital Neutropenia with Specific Granulocyte Deficiency Caused by Novel Double Heterozygous SMARCD2 Mutations.","date":"2022","source":"Hematology reports","url":"https://pubmed.ncbi.nlm.nih.gov/36135322","citation_count":2,"is_preprint":false},{"pmid":"41321749","id":"PMC_41321749","title":"Novel Nonsense Mutation in SMARCD2 Gene Results in Dysplasia of All Myeloid Cell Lines.","date":"2025","source":"EJHaem","url":"https://pubmed.ncbi.nlm.nih.gov/41321749","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":9451,"output_tokens":1905,"usd":0.028464,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8870,"output_tokens":2835,"usd":0.057612,"stage2_stop_reason":"end_turn"},"total_usd":0.086076,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2017,\n      \"finding\": \"SMARCD2 directly interacts with the transcription factor CEBPɛ and controls expression of neutrophil proteins stored in specific granules; loss-of-function mutations in SMARCD2 identified in patients with specific granule deficiency abolish this interaction with SWI/SNF and thereby secondary granule gene expression.\",\n      \"method\": \"Co-immunoprecipitation, in vitro interaction assays, chromatin immunoprecipitation, patient mutation analysis\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal interaction shown, replicated independently in two simultaneous papers (PMIDs 28369036 and 28369034) with multiple orthogonal methods including ChIP, Co-IP, and patient mutations\",\n      \"pmids\": [\"28369036\", \"28369034\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SMARCD2-containing SWI/SNF complexes are required for CEBPɛ transcription factor recruitment to the promoter of neutrophilic secondary granule genes during granulocyte differentiation; SMARCD2 controls early steps in differentiation of myeloid-erythroid progenitor cells.\",\n      \"method\": \"Smarcd2-deficient mouse model, chromatin immunoprecipitation (ChIP) at secondary granule gene promoters, gene expression profiling\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — loss-of-function genetic model with defined molecular phenotype (loss of CEBPɛ recruitment by ChIP), replicated across two independent labs and multiple model organisms\",\n      \"pmids\": [\"28369034\", \"28369036\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"The functional specificity of SMARCD2 in granulocyte development (which cannot be replaced by the 63%-identical paralog SMARCD1) is conferred by its divergent coiled-coil 1 and SWIB domains.\",\n      \"method\": \"Domain swap experiments, Smarcd2-deficient mouse rescue assays with SMARCD1 substitution\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain-swap functional rescue experiment in single lab, but with clear negative control (SMARCD1 cannot substitute)\",\n      \"pmids\": [\"28369034\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"BAF60b (SMARCD2) is ubiquitinated through a Rac GTPase-dependent signalling process mediated by the mammalian RING finger protein Unkempt, which binds BAF60b and promotes its degradative ubiquitination; this process occurs in the nuclear compartment.\",\n      \"method\": \"Two-hybrid cloning, Co-immunoprecipitation, ubiquitination assay, proteasome inhibitor (MG132) treatment, immunofluorescence\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (yeast two-hybrid, Co-IP, ubiquitination assay, MG132 rescue) in single lab\",\n      \"pmids\": [\"20148946\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Baf60b (SMARCD2) links chromatin opening to ATM activation during lineage conversion by facilitating ATM recruitment to open chromatin regions at hepatic gene loci, activating the ATM-p53 pathway independently of DNA damage to block cell identity conversion.\",\n      \"method\": \"Chromatin immunoprecipitation, ATM recruitment assay, loss-of-function knockdown in fibroblast-to-hepatocyte conversion model\",\n      \"journal\": \"Cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-based ATM recruitment assay plus functional loss-of-function in single lab with defined pathway placement\",\n      \"pmids\": [\"28303890\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"SMARCD2 is selectively required for leukaemic cell expansion and self-renewal in MLL-rearranged leukaemia, where it regulates expression of haematopoietic stem cell-associated genes; however, unlike mouse data, it is not required for c-MYC-regulated gene expression in human cells.\",\n      \"method\": \"shRNA knockdown, gene expression profiling (RNA-seq), in vitro and in vivo leukaemia expansion assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean knockdown with gene expression profiling and functional leukaemia expansion assay in single lab\",\n      \"pmids\": [\"26571505\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"BAF60b (SMARCD2) interacts with transcription factor RUNX1 to promote CCR9 expression on regulatory T cells, facilitating their migration to inflammatory tissues and suppressing inflammation in EAE and colitis models.\",\n      \"method\": \"Co-immunoprecipitation, transcriptome analysis, ATAC-seq (genome-wide chromatin landscape), conditional knockout mouse models\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP plus ATAC-seq and functional in vivo models, single lab\",\n      \"pmids\": [\"38996070\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Hepatic BAF60b (SMARCD2) interacts with transcription factor C/EBPβ to suppress Pparγ gene expression, thereby controlling hepatic lipid accumulation; BAF60b deficiency promotes HFD-induced liver steatosis while transgenic overexpression attenuates NAFLD.\",\n      \"method\": \"Co-immunoprecipitation, ATAC-seq motif analysis, liver-specific knockout and transgenic mouse models, gene expression analysis\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP interaction, ATAC-seq, and genetic gain/loss-of-function models in single lab with multiple orthogonal methods\",\n      \"pmids\": [\"39046829\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SMARCD2 (BAF60b) is a context-specific subunit of SWI/SNF (BAF) chromatin-remodeling complexes that recruits transcription factors—including CEBPɛ (for granulopoiesis), RUNX1 (for Treg migration), and C/EBPβ (for hepatic lipid metabolism)—to specific genomic loci to remodel chromatin and activate or repress target gene programs; its functional specificity relative to paralogs is encoded by its divergent coiled-coil 1 and SWIB domains, and its protein levels are regulated by Rac GTPase-dependent, Unkempt-mediated degradative ubiquitination.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SMARCD2 (BAF60b) is a context-specific subunit of SWI/SNF (BAF) chromatin-remodeling complexes that bridges lineage-specifying transcription factors to chromatin to direct cell-type-specific gene programs [#0, #1]. In granulopoiesis it physically interacts with CEBP\\u025b and is required for CEBP\\u025b recruitment to the promoters of neutrophil secondary granule genes, and loss-of-function mutations in patients with specific granule deficiency abolish the SMARCD2\\u2013SWI/SNF interaction and secondary granule gene expression [#0, #1]. This developmental role extends to early myeloid-erythroid progenitor differentiation [#1], to leukaemic self-renewal in MLL-rearranged leukaemia where SMARCD2 regulates haematopoietic stem cell-associated genes [#5], to RUNX1-dependent CCR9 expression governing regulatory T cell migration and inflammation [#6], and to a C/EBP\\u03b2-dependent program in liver that suppresses Ppar\\u03b3 and limits hepatic lipid accumulation [#7]. Its functional specificity\\u2014which cannot be supplied by the 63%-identical paralog SMARCD1\\u2014is encoded by its divergent coiled-coil 1 and SWIB domains [#2]. SMARCD2 also couples chromatin opening to ATM\\u2013p53 activation independently of DNA damage during attempted lineage conversion [#4], and its protein levels are controlled by Rac-GTPase-dependent, Unkempt-mediated degradative ubiquitination in the nucleus [#3].\",\n  \"teleology\": [\n    {\n      \"year\": 2010,\n      \"claim\": \"Established the first regulatory input on SMARCD2 abundance, showing its levels are controlled post-translationally rather than only transcriptionally.\",\n      \"evidence\": \"Yeast two-hybrid, Co-IP, ubiquitination assay, and MG132 rescue in mammalian cells linking BAF60b to Unkempt-mediated, Rac-dependent ubiquitination\",\n      \"pmids\": [\"20148946\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Single lab; the physiological signals that trigger Rac/Unkempt-dependent turnover are not defined\", \"Does not connect degradation to a specific chromatin-remodeling output\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Showed SMARCD2 is a selective dependency in a malignant context, distinguishing its requirement from general SWI/SNF housekeeping function.\",\n      \"evidence\": \"shRNA knockdown with RNA-seq and in vitro/in vivo leukaemia expansion assays in MLL-rearranged leukaemia\",\n      \"pmids\": [\"26571505\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Human cells did not reproduce the mouse c-MYC dependency, leaving species-specific target programs unresolved\", \"Direct transcription-factor partners in leukaemia not identified\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined the core molecular mechanism: SMARCD2 within SWI/SNF recruits CEBP\\u025b to drive a specific gene program, and human disease mutations validate this axis.\",\n      \"evidence\": \"Co-IP, in vitro interaction, ChIP at secondary granule promoters, Smarcd2-deficient mouse, and patient mutation analysis (two independent papers)\",\n      \"pmids\": [\"28369036\", \"28369034\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Structure of the SMARCD2\\u2013CEBP\\u025b interface not resolved\", \"Whether the same recruitment logic generalizes to other transcription factors was not tested here\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Explained the basis of paralog non-redundancy, attributing SMARCD2's unique granulopoietic function to specific protein domains.\",\n      \"evidence\": \"Domain-swap and SMARCD1-substitution rescue experiments in Smarcd2-deficient cells\",\n      \"pmids\": [\"28369034\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Single lab; the binding partner(s) discriminated by the coiled-coil 1/SWIB domains not mapped biochemically\", \"Domain contributions in non-myeloid contexts untested\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Revealed a chromatin-to-signalling link, showing SMARCD2-driven chromatin opening can activate ATM-p53 to enforce cell identity.\",\n      \"evidence\": \"ChIP and ATM recruitment assays with knockdown in a fibroblast-to-hepatocyte conversion model\",\n      \"pmids\": [\"28303890\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Mechanism by which open chromatin recruits ATM independent of DNA damage not defined\", \"Single lab and a specialized lineage-conversion system\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extended the transcription-factor-recruitment paradigm to immune regulation via RUNX1, linking SMARCD2 to Treg trafficking.\",\n      \"evidence\": \"Reciprocal Co-IP, ATAC-seq, transcriptome analysis, and conditional knockout mice in EAE and colitis models\",\n      \"pmids\": [\"38996070\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Direct genomic co-occupancy of SMARCD2 and RUNX1 at the CCR9 locus not shown by ChIP\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Generalized SMARCD2's TF-partnering role to metabolism, showing a C/EBP\\u03b2-dependent repression of Ppar\\u03b3 that constrains hepatic steatosis.\",\n      \"evidence\": \"Co-IP, ATAC-seq motif analysis, and liver-specific knockout/transgenic mouse models\",\n      \"pmids\": [\"39046829\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Whether C/EBP\\u03b2 recruitment depends on the same domains as CEBP\\u025b recruitment untested\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single SWI/SNF subunit selects among distinct transcription-factor partners (CEBP\\u025b, RUNX1, C/EBP\\u03b2) across tissues remains unresolved at structural and biochemical resolution.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"No structural model of any SMARCD2\\u2013transcription-factor interface\", \"Rules linking domain identity to partner choice not established\", \"Genome-wide direct SMARCD2 occupancy maps lacking\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 1, 6, 7]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1, 6, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 1, 6, 7]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [1, 4]}\n    ],\n    \"complexes\": [\"SWI/SNF (BAF)\"],\n    \"partners\": [\"CEBPE\", \"RUNX1\", \"CEBPB\", \"UNK\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}