{"gene":"KANSL2","run_date":"2026-06-10T01:55:23","timeline":{"discoveries":[{"year":2014,"finding":"KANSL2 directly binds WDR5 via a conserved linear motif, and WDR5 in turn binds KANSL1, forming a KANSL1/WDR5/KANSL2 subcomplex within the NSL complex. Crystal structure analysis revealed that WDR5 is required for efficient assembly of the NSL complex and its recruitment to target promoters. The interactions of WDR5 with the NSL complex and MLL/COMPASS are mutually exclusive.","method":"Biochemical pulldown assays, crystal structure determination, structure-based mutagenesis in transgenic flies, chromatin immunoprecipitation","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure solved, direct binding confirmed by pulldown, mutagenesis validated in vivo in transgenic flies, multiple orthogonal methods in one rigorous study","pmids":["24788516"],"is_preprint":false},{"year":2010,"finding":"KANSL2 (NSL2) is a subunit of the NSL complex (NSL1, NSL2, NSL3, MCRS2, MBD-R2, WDS) that associates with the histone acetyltransferase MOF in both Drosophila and mammals. NSL complex subunits bind target gene promoters and regulate gene expression genome-wide; NSL complex stability is interdependent and relies mainly on NSL1 and MCRS2.","method":"Biochemical purification/co-immunoprecipitation, ChIP-Seq, RNAi depletion with transcriptome readout","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP for complex composition, ChIP-Seq for chromatin targeting, RNAi with genome-wide expression readout, replicated across Drosophila and mammalian systems","pmids":["20620954"],"is_preprint":false},{"year":2016,"finding":"A subset of NSL complex partners including KANSL2 resides in mitochondria alongside MOF, which regulates oxidative phosphorylation and mitochondrial DNA transcription. MOF binding to mtDNA is dependent on KANSL3.","method":"Subcellular fractionation, mitochondrial Co-IP, mtDNA ChIP, conditional knockout mouse model with cardiac phenotype readout","journal":"Cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — fractionation and Co-IP establish mitochondrial localization of complex members including KANSL2; the mtDNA binding dependency is shown for KANSL3, not directly for KANSL2; single lab","pmids":["27768893"],"is_preprint":false},{"year":2019,"finding":"The Drosophila NSL2 ortholog (Dgt1/Nsl2, corresponding to KANSL2) localizes to centrosomes and the telophase midbody during mitosis. RNAi depletion of NSL2 leads to defects in chromosome segregation, reduced CENP-A and Ndc80 kinetochore levels, and impaired centriole duplication, primarily through reduced transcription of centromere/kinetochore and centriole duplication genes.","method":"RNAi depletion in Drosophila S2 cells, live imaging of GFP-tagged NSL2, RT-qPCR, immunofluorescence for kinetochore markers","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization by live imaging, RNAi with defined mitotic phenotypes and transcriptional mechanism, single lab with multiple orthogonal methods","pmids":["31527906"],"is_preprint":false},{"year":2020,"finding":"Neural-specific depletion of KANSL2 (along with MOF or KANSL3) disrupts the epigenetic landscape, causing accumulation of free long-chain fatty acids (LCFAs) in neural cells. LCFAs activate a TLR4-NFκB-dependent pro-inflammatory signalling cascade in neighbouring vascular pericytes, causing vascular breakdown and brain haemorrhaging.","method":"Conditional neural-specific knockout mouse model, metabolomics (LCFA measurement), TLR4 inhibitor rescue, pericyte functional assays","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with defined metabolic and vascular phenotype, pharmacological rescue with TLR4 inhibitor, multiple orthogonal methods establishing pathway position","pmids":["32541879"],"is_preprint":false},{"year":2016,"finding":"KANSL2 regulates cancer stem cell self-renewal in glioblastoma, correlating with POU5F1 (OCT4) expression. RNAi silencing of POU5F1 reduced KANSL2 levels, and KANSL2 silencing impaired tumorigenic capacity in xenograft models, placing KANSL2 and POU5F1 in a mutual regulatory relationship for stemness control.","method":"RNAi-mediated silencing, mouse xenograft assay, gene expression correlation in clinical specimens","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNAi with in vivo xenograft phenotype and bidirectional regulatory relationship shown, but pathway placement based largely on expression correlations; single lab","pmids":["27406830"],"is_preprint":false},{"year":2023,"finding":"KANSL2 deletion in postmitotic kidney podocytes causes catastrophic kidney dysfunction associated with loss of intraciliary transport gene expression, altered microtubule dynamics, and obliterated podocyte functions. Overexpression of wild-type KANSL2, but not a double zinc finger (ZF-ZF) domain mutant, rescues transcriptional defects, revealing a critical function of the ZF-ZF domain in NSL complex assembly and transcriptional function.","method":"Conditional knockout in podocytes, domain mutagenesis (ZF-ZF mutant), RNA-seq, cilia assays, comparison with ciliated fibroblasts","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — conditional KO with defined kidney phenotype, domain mutagenesis rescue experiment establishing ZF-ZF domain function, multiple cell type comparisons and orthogonal molecular readouts","pmids":["37624894"],"is_preprint":false},{"year":2023,"finding":"The KANSL2-containing NSL complex and the BCL7C-containing BAF complex form a 'supercomplex' that increases inhibitory histone acetylation at the HIV LTR and promotes occupancy by the short variant of Brd4, thereby silencing HIV transcription. KANSL2 overexpression reduces HIV reactivation in Jurkat T cells and CD4 T cells from people living with HIV.","method":"CRISPRi synergy screening (REACTS), overexpression in primary CD4 T cells, co-immunoprecipitation demonstrating BAF-NSL supercomplex, histone acetylation assays, ChIP for Brd4","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP establishing supercomplex, functional overexpression in primary cells, histone acetylation and ChIP readouts, single lab with multiple orthogonal methods","pmids":["37682714"],"is_preprint":false},{"year":2023,"finding":"In Drosophila, NSL2 (KANSL2 ortholog) is required for piRNA production from telomeric piRNA clusters. Germline-specific NSL2 depletion reduces piRNA production from telomeric clusters, decreases H3K9me3, HP1a, and Rhino at those clusters, and leads to reduction of nuclear Piwi in nurse cells. NSL2 ChIP-seq shows direct binding to promoters of telomeric transposons HeT-A, TAHRE, and TART.","method":"Germline-specific RNAi, ChIP-seq for NSL2 and histone marks, piRNA sequencing, immunofluorescence for Piwi","journal":"Life science alliance","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct ChIP-seq binding at telomeric transposon promoters, RNAi with piRNA-seq and chromatin mark readouts, single lab with multiple orthogonal methods","pmids":["37399316"],"is_preprint":false},{"year":2025,"finding":"KANSL2 acetylates lamin A/C (as part of the NSL complex containing MOF), which is required for maintaining nuclear architecture and genome stability in muscle stem cells. TAF4A, as part of a TAF4A-NF-Y complex, directly controls cell-type-specific transcription of Kansl2. Loss of Kansl2 reduces lamin A/C post-translational modification, decreases nuclear stiffness, causes heterochromatin loss and genomic instability, activates but impairs proliferation of muscle stem cells, and abolishes skeletal muscle regeneration.","method":"Conditional Taf4a knockout mouse, expression analysis of Kansl2, lamin A/C modification assays (nuclear stiffness/AFM), heterochromatin immunofluorescence, muscle regeneration assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with defined molecular (lamin modification, heterochromatin) and physiological (muscle regeneration) phenotypes, TAF4A-NF-Y upstream regulatory mechanism established, multiple orthogonal methods","pmids":["41028714"],"is_preprint":false},{"year":2026,"finding":"KANSL2 localizes dynamically to nucleoli during G1/early S and G2 phases of the cell cycle in glioblastoma cells. KANSL2 overexpression increases 45S pre-rRNA and 28S rRNA levels; silencing reduces rRNA expression and histone H4 acetylation at lysines 5 and 8 (H4K5ac and H4K8ac) within rDNA promoters, and globally downregulates ribosome biogenesis genes.","method":"Immunofluorescence and cell cycle analysis for nucleolar localization, overexpression and RNAi with RT-qPCR for rRNA, ChIP for H4K5ac/H4K8ac at rDNA, RNA-seq in patient-derived GBM spheroids","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization by immunofluorescence with cell cycle staging, ChIP for specific histone marks at rDNA promoters, RNA-seq in patient-derived cells; single lab with multiple orthogonal methods","pmids":["41787092"],"is_preprint":false},{"year":2020,"finding":"KANSL2 is a strong regulator of invasion in pancreatic ductal adenocarcinoma (PDAC) cells. CRISPR screening identified KANSL2 as required for PANC-1 cell invasion; validation with doxycycline-inducible shRNA confirmed this effect. KANSL2 knockdown does not affect cell proliferation.","method":"Genome-wide CRISPR screen for invasion, doxycycline-inducible shRNA validation, in vitro invasion assay, proliferation assay (negative result for proliferation)","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR screen with orthogonal shRNA validation, specific invasion phenotype with negative proliferation result establishing specificity; no molecular mechanism identified; single lab","pmids":["32001790"],"is_preprint":false},{"year":2026,"finding":"KANSL2 mediates resistance to genotoxic stress in multiple myeloma cells, and high KANSL2 expression increases sensitivity to HDAC inhibitor panobinostat and BET inhibitor OTX-015. Transcriptomics, proteomics, and quantitative acetylome profiling revealed a KANSL2-dependent molecular program involving histone acetylation that can be targeted by these inhibitors.","method":"Genetic gain- and loss-of-function models, transcriptomics, proteomics, quantitative acetylome profiling, ex vivo drug response profiling in patient samples","journal":"Molecular cancer therapeutics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multi-omics profiling with genetic KO/OE, in vivo screen, patient sample validation; acetylome identifies downstream modification program; single lab","pmids":["41294048"],"is_preprint":false},{"year":2014,"finding":"SUMV-1 (C. elegans homolog of KANSL2/NSL2) physically interacts with SUMV-2 (NSL3 homolog) in yeast two-hybrid assays, and both interact genetically with MYS-2 (MOF homolog), suggesting conservation of the NSL complex in C. elegans. Loss of sumv-1 function suppresses ectopic lin-3 expression and the synMuv phenotype, placing SUMV-1 as an antagonist of synMuv gene activity in vulval development.","method":"Yeast two-hybrid for protein-protein interaction, genetic epistasis (forward screen and RNAi), reporter gene assays in C. elegans","journal":"Developmental biology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — yeast two-hybrid interaction plus genetic epistasis with defined developmental phenotype; in a model organism ortholog; single lab","pmids":["24882710"],"is_preprint":false}],"current_model":"KANSL2 is an integral structural subunit of the NSL (non-specific lethal) chromatin-modifying complex, where it directly binds WDR5 via a conserved linear motif (ZF-ZF domain essential for complex assembly) and together with KANSL1 and other subunits recruits the histone acetyltransferase MOF to gene promoters to regulate transcription genome-wide; the complex controls nuclear and mitochondrial gene expression, acetylates lamin A/C to maintain nuclear architecture and genome stability, promotes rRNA transcription in nucleoli, regulates piRNA production from telomeric clusters, governs intraciliary transport gene expression in differentiated cells, and participates in a BAF-NSL supercomplex that silences HIV transcription through inhibitory histone acetylation at the LTR."},"narrative":{"mechanistic_narrative":"KANSL2 is an integral structural subunit of the NSL (non-specific lethal) chromatin-modifying complex, which associates with the histone acetyltransferase MOF and binds target gene promoters to regulate transcription genome-wide in both Drosophila and mammals [PMID:20620954]. KANSL2 directly binds WDR5 through a conserved linear motif, and WDR5 in turn bridges KANSL1, forming a KANSL1/WDR5/KANSL2 subcomplex required for efficient NSL complex assembly and its recruitment to promoters; this WDR5 interaction is mutually exclusive with MLL/COMPASS [PMID:24788516]. The integrity of KANSL2's double zinc-finger (ZF-ZF) domain is essential for complex assembly and transcriptional output, as wild-type but not ZF-ZF-mutant KANSL2 rescues transcriptional and ciliary gene defects in postmitotic podocytes [PMID:37624894]. Through this complex KANSL2 governs cell-type-specific transcriptional programs: it controls intraciliary transport and microtubule-related gene expression in differentiated cells [PMID:37624894], drives mitotic fidelity in Drosophila by sustaining transcription of centromere/kinetochore and centriole-duplication genes [PMID:31527906], and acetylates lamin A/C to maintain nuclear stiffness, heterochromatin organization, and genome stability [PMID:41028714]. Beyond the nucleus, KANSL2 promotes nucleolar rRNA transcription, increasing 45S pre-rRNA and depositing H4K5ac/H4K8ac at rDNA promoters [PMID:41787092], and a subset of the complex localizes to mitochondria alongside MOF where it participates in oxidative phosphorylation and mtDNA transcription [PMID:27768893]. KANSL2 also functions in genome defense and gene silencing, being required for piRNA production from telomeric clusters in the Drosophila germline [PMID:37399316] and forming a BAF-NSL supercomplex that imposes inhibitory histone acetylation at the HIV LTR to silence proviral transcription [PMID:37682714]. Disruption of KANSL2 produces tissue-specific catastrophic phenotypes, including kidney failure [PMID:37624894], failure of skeletal muscle regeneration [PMID:41028714], and a neural epigenetic defect that drives long-chain fatty acid accumulation and TLR4-NFκB-dependent vascular breakdown and brain haemorrhage [PMID:32541879]. In cancer, KANSL2 supports glioblastoma stem-cell self-renewal in a mutual regulatory relationship with POU5F1/OCT4 [PMID:27406830], drives pancreatic adenocarcinoma cell invasion independently of proliferation [PMID:32001790], and mediates genotoxic-stress resistance and acetylation-dependent drug sensitivity in multiple myeloma [PMID:41294048].","teleology":[{"year":2010,"claim":"Establishing that KANSL2 is a stable subunit of the MOF-associated NSL complex defined its core molecular context as a chromatin-modifying, promoter-binding transcriptional regulator.","evidence":"Biochemical purification/co-IP, ChIP-Seq, and RNAi transcriptome profiling in Drosophila and mammalian cells","pmids":["20620954"],"confidence":"High","gaps":["Did not resolve how individual subunits contribute to complex assembly","No direct enzymatic role assigned to KANSL2 itself"]},{"year":2014,"claim":"Determining that KANSL2 directly binds WDR5 via a linear motif, with WDR5 bridging KANSL1, explained how the NSL complex is assembled and targeted to promoters and distinguished it from MLL/COMPASS.","evidence":"Pulldown assays, crystal structure, structure-based mutagenesis in transgenic flies, ChIP","pmids":["24788516"],"confidence":"High","gaps":["Did not define the full architecture including MOF positioning","Mechanism of promoter selectivity not resolved"]},{"year":2014,"claim":"Conservation of the NSL complex and a developmental antagonist role was extended to C. elegans, where the KANSL2 ortholog physically and genetically links to NSL3 and MOF orthologs and restrains synMuv gene activity.","evidence":"Yeast two-hybrid, genetic epistasis, and reporter assays in C. elegans","pmids":["24882710"],"confidence":"Medium","gaps":["Y2H interaction not biochemically validated in the native complex","Direct transcriptional targets in worm not mapped"]},{"year":2016,"claim":"Localization of NSL subunits including KANSL2 to mitochondria broadened the complex's role beyond the nucleus to oxidative phosphorylation and mtDNA transcription.","evidence":"Subcellular fractionation, mitochondrial Co-IP, mtDNA ChIP, conditional knockout mouse","pmids":["27768893"],"confidence":"Medium","gaps":["mtDNA binding dependency shown for KANSL3, not directly for KANSL2","Functional necessity of KANSL2 specifically in mitochondria not established"]},{"year":2016,"claim":"Linking KANSL2 to glioblastoma stem-cell self-renewal via a mutual regulatory loop with POU5F1 connected the complex to cancer stemness control.","evidence":"RNAi silencing, xenograft tumorigenesis assays, expression correlation in clinical specimens","pmids":["27406830"],"confidence":"Medium","gaps":["Pathway placement relies largely on expression correlation","Direct transcriptional mechanism connecting KANSL2 and OCT4 not defined"]},{"year":2019,"claim":"Demonstrating that the Drosophila ortholog localizes to centrosomes/midbody and sustains transcription of kinetochore and centriole genes established a transcriptional basis for KANSL2's role in mitotic fidelity.","evidence":"RNAi in S2 cells, live imaging of GFP-tagged NSL2, RT-qPCR, immunofluorescence","pmids":["31527906"],"confidence":"Medium","gaps":["Whether centrosome localization is functionally required versus a transcriptional effect unclear","Mammalian conservation of mitotic role not tested"]},{"year":2020,"claim":"Neural KANSL2 loss was placed upstream of a metabolic-inflammatory axis, showing that an epigenetic defect causes LCFA accumulation that triggers TLR4-NFκB signalling and vascular breakdown.","evidence":"Conditional neural knockout mouse, metabolomics, TLR4 inhibitor rescue, pericyte assays","pmids":["32541879"],"confidence":"High","gaps":["Direct KANSL2 target genes driving LCFA accumulation not pinpointed","Whether effect is cell-autonomous to the lipid program unresolved"]},{"year":2020,"claim":"An unbiased CRISPR screen identified KANSL2 as a specific driver of pancreatic cancer cell invasion uncoupled from proliferation.","evidence":"Genome-wide CRISPR invasion screen, doxycycline-inducible shRNA validation, invasion and proliferation assays","pmids":["32001790"],"confidence":"Medium","gaps":["No molecular mechanism for invasion identified","Downstream effector genes not defined"]},{"year":2023,"claim":"Domain mutagenesis in podocytes established that KANSL2's ZF-ZF domain is essential for NSL complex assembly and transcriptional control of intraciliary transport genes, linking the complex to ciliary biology in differentiated cells.","evidence":"Conditional podocyte knockout, ZF-ZF domain mutant rescue, RNA-seq, cilia assays","pmids":["37624894"],"confidence":"High","gaps":["Structural basis of how ZF-ZF mediates assembly not solved","Direct ciliary gene targets versus indirect effects not fully separated"]},{"year":2023,"claim":"KANSL2 was shown to drive piRNA production from telomeric clusters, binding telomeric transposon promoters and sustaining heterochromatin marks, extending the complex's role to genome defense.","evidence":"Germline RNAi, NSL2 and histone-mark ChIP-seq, piRNA sequencing, Piwi immunofluorescence in Drosophila","pmids":["37399316"],"confidence":"Medium","gaps":["Mechanistic link between promoter binding and heterochromatin establishment unresolved","Mammalian conservation not tested"]},{"year":2023,"claim":"Identifying a BAF-NSL supercomplex that deposits inhibitory acetylation at the HIV LTR revealed a gene-silencing function for KANSL2 and a potential latency-control target.","evidence":"CRISPRi synergy screen, primary CD4 T cell overexpression, Co-IP, histone acetylation assays, Brd4 ChIP","pmids":["37682714"],"confidence":"Medium","gaps":["Stoichiometry and direct KANSL2-BAF contacts not mapped","Generality of inhibitory acetylation beyond the LTR unknown"]},{"year":2025,"claim":"Defining lamin A/C acetylation by the KANSL2/MOF complex, with TAF4A-NF-Y as an upstream transcriptional regulator of Kansl2, mechanistically linked the complex to nuclear mechanics, heterochromatin maintenance, and muscle stem-cell regeneration.","evidence":"Conditional Taf4a knockout mouse, lamin modification and nuclear stiffness (AFM) assays, heterochromatin immunofluorescence, muscle regeneration assays","pmids":["41028714"],"confidence":"High","gaps":["Specific lamin residues acetylated not enumerated","Whether KANSL2 directly contacts lamin or acts via MOF recruitment unresolved"]},{"year":2026,"claim":"Cell-cycle-dependent nucleolar localization and rDNA H4K5ac/H4K8ac deposition established KANSL2 as a positive regulator of rRNA transcription and ribosome biogenesis.","evidence":"Immunofluorescence with cell-cycle staging, overexpression/RNAi with rRNA RT-qPCR, H4K5ac/H4K8ac ChIP at rDNA, RNA-seq in patient-derived GBM spheroids","pmids":["41787092"],"confidence":"Medium","gaps":["What recruits KANSL2 to nucleoli during specific cell-cycle phases unknown","Direct versus MOF-mediated acetylation at rDNA not separated"]},{"year":2026,"claim":"KANSL2 was shown to mediate genotoxic-stress resistance in multiple myeloma and to set sensitivity to HDAC and BET inhibitors through an acetylation-dependent program, connecting the complex to therapeutic vulnerability.","evidence":"Genetic gain/loss models, transcriptomics, proteomics, quantitative acetylome profiling, ex vivo patient drug response","pmids":["41294048"],"confidence":"Medium","gaps":["Causal acetylation targets driving stress resistance not pinpointed","Mechanism of synergy with panobinostat/OTX-015 not fully resolved"]},{"year":null,"claim":"It remains unresolved whether KANSL2 itself possesses or directly confers catalytic activity versus serving purely as a structural/assembly subunit, and how its tissue-specific transcriptional programs are selected across the diverse contexts (nucleolar, mitochondrial, telomeric, lamin) in which the complex acts.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No catalytic activity directly assigned to KANSL2","Determinants of context-specific target selection by the NSL complex unknown","No high-resolution structure of the assembled mammalian NSL complex"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,1,6,9]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,6]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1,9]},{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[10]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[2]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[3]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,1,6]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[9,8,10]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[3]}],"complexes":["NSL complex","BAF-NSL supercomplex"],"partners":["WDR5","KANSL1","MOF","KANSL3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9H9L4","full_name":"KAT8 regulatory NSL complex subunit 2","aliases":["NSL complex protein NSL2","Non-specific lethal 2 homolog"],"length_aa":492,"mass_kda":55.0,"function":"Non-catalytic component of the NSL histone acetyltransferase complex, a multiprotein complex that mediates histone H4 acetylation at 'Lys-5'- and 'Lys-8' (H4K5ac and H4K8ac) at transcription start sites and promotes transcription initiation (PubMed:20018852, PubMed:33657400). Required for NSL complex stability and for transcription of intraciliary transport genes in both ciliated and non-ciliated cells by regulating histone H4 acetylation at 'Lys-5'- and 'Lys-12' (H4K5ac and H4K12ac) (By similarity). This is necessary for cilium assembly in ciliated cells and for organization of the microtubule cytoskeleton in non-ciliated cells (By similarity). Required within the NSL complex to maintain nuclear architecture stability by promoting KAT8-mediated acetylation of lamin LMNA (By similarity)","subcellular_location":"Nucleus; Mitochondrion","url":"https://www.uniprot.org/uniprotkb/Q9H9L4/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/KANSL2","classification":"Common Essential","n_dependent_lines":1155,"n_total_lines":1208,"dependency_fraction":0.9561258278145696},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/KANSL2","total_profiled":1310},"omim":[{"mim_id":"615488","title":"KAT8 REGULATORY NSL COMPLEX, SUBUNIT 2; KANSL2","url":"https://www.omim.org/entry/615488"},{"mim_id":"615487","title":"SMALL NUCLEOLAR RNA, H/ACA BOX, 2C; SNORA2C","url":"https://www.omim.org/entry/615487"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Plasma membrane","reliability":"Supported"},{"location":"Cytosol","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/KANSL2"},"hgnc":{"alias_symbol":["FLJ20436","NSL2"],"prev_symbol":["C12orf41"]},"alphafold":{"accession":"Q9H9L4","domains":[{"cath_id":"-","chopping":"26-111","consensus_level":"medium","plddt":82.7417,"start":26,"end":111},{"cath_id":"1.20.5","chopping":"186-264","consensus_level":"high","plddt":84.4653,"start":186,"end":264}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H9L4","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H9L4-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H9L4-F1-predicted_aligned_error_v6.png","plddt_mean":65.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=KANSL2","jax_strain_url":"https://www.jax.org/strain/search?query=KANSL2"},"sequence":{"accession":"Q9H9L4","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9H9L4.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9H9L4/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H9L4"}},"corpus_meta":[{"pmid":"27768893","id":"PMC_27768893","title":"MOF Acetyl Transferase Regulates Transcription and Respiration in Mitochondria.","date":"2016","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/27768893","citation_count":150,"is_preprint":false},{"pmid":"20620954","id":"PMC_20620954","title":"The nonspecific lethal complex is a transcriptional regulator in Drosophila.","date":"2010","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/20620954","citation_count":121,"is_preprint":false},{"pmid":"24788516","id":"PMC_24788516","title":"Structural analysis of the KANSL1/WDR5/KANSL2 complex reveals that WDR5 is required for efficient assembly and chromatin targeting of the NSL complex.","date":"2014","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/24788516","citation_count":99,"is_preprint":false},{"pmid":"32108986","id":"PMC_32108986","title":"Genome-wide association study of word reading: Overlap with risk genes for neurodevelopmental disorders.","date":"2020","source":"Genes, brain, and behavior","url":"https://pubmed.ncbi.nlm.nih.gov/32108986","citation_count":41,"is_preprint":false},{"pmid":"32541879","id":"PMC_32541879","title":"Neural metabolic imbalance induced by MOF dysfunction triggers pericyte activation and breakdown of vasculature.","date":"2020","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/32541879","citation_count":30,"is_preprint":false},{"pmid":"21496223","id":"PMC_21496223","title":"A 5'-proximal stem-loop structure of 5' untranslated region of porcine reproductive and respiratory syndrome virus genome is key for virus replication.","date":"2011","source":"Virology journal","url":"https://pubmed.ncbi.nlm.nih.gov/21496223","citation_count":25,"is_preprint":false},{"pmid":"27406830","id":"PMC_27406830","title":"The NSL Chromatin-Modifying Complex Subunit KANSL2 Regulates Cancer Stem-like Properties in Glioblastoma That Contribute to Tumorigenesis.","date":"2016","source":"Cancer 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NSL complex subunit 2 axis.","date":"2022","source":"Bioengineered","url":"https://pubmed.ncbi.nlm.nih.gov/35191804","citation_count":4,"is_preprint":false},{"pmid":"40826382","id":"PMC_40826382","title":"Unveiling migraine subtype heterogeneity and risk loci: integrated genome-wide association study and single-cell transcriptomics discovery.","date":"2025","source":"The journal of headache and pain","url":"https://pubmed.ncbi.nlm.nih.gov/40826382","citation_count":4,"is_preprint":false},{"pmid":"37399316","id":"PMC_37399316","title":"The NSL complex is required for piRNA production from telomeric clusters.","date":"2023","source":"Life science alliance","url":"https://pubmed.ncbi.nlm.nih.gov/37399316","citation_count":2,"is_preprint":false},{"pmid":"41787092","id":"PMC_41787092","title":"Nucleoli-localized KANSL2 as an epigenetic regulator of ribosome biogenesis in glioblastoma cells.","date":"2026","source":"Communications 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Observed ubiquitous expression in goat and transgenic mice allowed to restrict the location of an hypothesised insulator element.","date":"2003","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/14637001","citation_count":0,"is_preprint":false},{"pmid":"41294048","id":"PMC_41294048","title":"The Histone Modifier KANSL2 Is an Actionable Biomarker in Multiple Myeloma.","date":"2026","source":"Molecular cancer therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/41294048","citation_count":0,"is_preprint":false},{"pmid":"41028714","id":"PMC_41028714","title":"Regulation of NSL by TAF4A is critical for genome stability and quiescence of muscle stem cells.","date":"2025","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/41028714","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":13064,"output_tokens":3967,"usd":0.049348,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11831,"output_tokens":4951,"usd":0.091465,"stage2_stop_reason":"end_turn"},"total_usd":0.140813,"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\": 2014,\n      \"finding\": \"KANSL2 directly binds WDR5 via a conserved linear motif, and WDR5 in turn binds KANSL1, forming a KANSL1/WDR5/KANSL2 subcomplex within the NSL complex. Crystal structure analysis revealed that WDR5 is required for efficient assembly of the NSL complex and its recruitment to target promoters. The interactions of WDR5 with the NSL complex and MLL/COMPASS are mutually exclusive.\",\n      \"method\": \"Biochemical pulldown assays, crystal structure determination, structure-based mutagenesis in transgenic flies, chromatin immunoprecipitation\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure solved, direct binding confirmed by pulldown, mutagenesis validated in vivo in transgenic flies, multiple orthogonal methods in one rigorous study\",\n      \"pmids\": [\"24788516\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"KANSL2 (NSL2) is a subunit of the NSL complex (NSL1, NSL2, NSL3, MCRS2, MBD-R2, WDS) that associates with the histone acetyltransferase MOF in both Drosophila and mammals. NSL complex subunits bind target gene promoters and regulate gene expression genome-wide; NSL complex stability is interdependent and relies mainly on NSL1 and MCRS2.\",\n      \"method\": \"Biochemical purification/co-immunoprecipitation, ChIP-Seq, RNAi depletion with transcriptome readout\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP for complex composition, ChIP-Seq for chromatin targeting, RNAi with genome-wide expression readout, replicated across Drosophila and mammalian systems\",\n      \"pmids\": [\"20620954\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"A subset of NSL complex partners including KANSL2 resides in mitochondria alongside MOF, which regulates oxidative phosphorylation and mitochondrial DNA transcription. MOF binding to mtDNA is dependent on KANSL3.\",\n      \"method\": \"Subcellular fractionation, mitochondrial Co-IP, mtDNA ChIP, conditional knockout mouse model with cardiac phenotype readout\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — fractionation and Co-IP establish mitochondrial localization of complex members including KANSL2; the mtDNA binding dependency is shown for KANSL3, not directly for KANSL2; single lab\",\n      \"pmids\": [\"27768893\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"The Drosophila NSL2 ortholog (Dgt1/Nsl2, corresponding to KANSL2) localizes to centrosomes and the telophase midbody during mitosis. RNAi depletion of NSL2 leads to defects in chromosome segregation, reduced CENP-A and Ndc80 kinetochore levels, and impaired centriole duplication, primarily through reduced transcription of centromere/kinetochore and centriole duplication genes.\",\n      \"method\": \"RNAi depletion in Drosophila S2 cells, live imaging of GFP-tagged NSL2, RT-qPCR, immunofluorescence for kinetochore markers\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization by live imaging, RNAi with defined mitotic phenotypes and transcriptional mechanism, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"31527906\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Neural-specific depletion of KANSL2 (along with MOF or KANSL3) disrupts the epigenetic landscape, causing accumulation of free long-chain fatty acids (LCFAs) in neural cells. LCFAs activate a TLR4-NFκB-dependent pro-inflammatory signalling cascade in neighbouring vascular pericytes, causing vascular breakdown and brain haemorrhaging.\",\n      \"method\": \"Conditional neural-specific knockout mouse model, metabolomics (LCFA measurement), TLR4 inhibitor rescue, pericyte functional assays\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with defined metabolic and vascular phenotype, pharmacological rescue with TLR4 inhibitor, multiple orthogonal methods establishing pathway position\",\n      \"pmids\": [\"32541879\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"KANSL2 regulates cancer stem cell self-renewal in glioblastoma, correlating with POU5F1 (OCT4) expression. RNAi silencing of POU5F1 reduced KANSL2 levels, and KANSL2 silencing impaired tumorigenic capacity in xenograft models, placing KANSL2 and POU5F1 in a mutual regulatory relationship for stemness control.\",\n      \"method\": \"RNAi-mediated silencing, mouse xenograft assay, gene expression correlation in clinical specimens\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNAi with in vivo xenograft phenotype and bidirectional regulatory relationship shown, but pathway placement based largely on expression correlations; single lab\",\n      \"pmids\": [\"27406830\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"KANSL2 deletion in postmitotic kidney podocytes causes catastrophic kidney dysfunction associated with loss of intraciliary transport gene expression, altered microtubule dynamics, and obliterated podocyte functions. Overexpression of wild-type KANSL2, but not a double zinc finger (ZF-ZF) domain mutant, rescues transcriptional defects, revealing a critical function of the ZF-ZF domain in NSL complex assembly and transcriptional function.\",\n      \"method\": \"Conditional knockout in podocytes, domain mutagenesis (ZF-ZF mutant), RNA-seq, cilia assays, comparison with ciliated fibroblasts\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — conditional KO with defined kidney phenotype, domain mutagenesis rescue experiment establishing ZF-ZF domain function, multiple cell type comparisons and orthogonal molecular readouts\",\n      \"pmids\": [\"37624894\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"The KANSL2-containing NSL complex and the BCL7C-containing BAF complex form a 'supercomplex' that increases inhibitory histone acetylation at the HIV LTR and promotes occupancy by the short variant of Brd4, thereby silencing HIV transcription. KANSL2 overexpression reduces HIV reactivation in Jurkat T cells and CD4 T cells from people living with HIV.\",\n      \"method\": \"CRISPRi synergy screening (REACTS), overexpression in primary CD4 T cells, co-immunoprecipitation demonstrating BAF-NSL supercomplex, histone acetylation assays, ChIP for Brd4\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP establishing supercomplex, functional overexpression in primary cells, histone acetylation and ChIP readouts, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"37682714\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In Drosophila, NSL2 (KANSL2 ortholog) is required for piRNA production from telomeric piRNA clusters. Germline-specific NSL2 depletion reduces piRNA production from telomeric clusters, decreases H3K9me3, HP1a, and Rhino at those clusters, and leads to reduction of nuclear Piwi in nurse cells. NSL2 ChIP-seq shows direct binding to promoters of telomeric transposons HeT-A, TAHRE, and TART.\",\n      \"method\": \"Germline-specific RNAi, ChIP-seq for NSL2 and histone marks, piRNA sequencing, immunofluorescence for Piwi\",\n      \"journal\": \"Life science alliance\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct ChIP-seq binding at telomeric transposon promoters, RNAi with piRNA-seq and chromatin mark readouts, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"37399316\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"KANSL2 acetylates lamin A/C (as part of the NSL complex containing MOF), which is required for maintaining nuclear architecture and genome stability in muscle stem cells. TAF4A, as part of a TAF4A-NF-Y complex, directly controls cell-type-specific transcription of Kansl2. Loss of Kansl2 reduces lamin A/C post-translational modification, decreases nuclear stiffness, causes heterochromatin loss and genomic instability, activates but impairs proliferation of muscle stem cells, and abolishes skeletal muscle regeneration.\",\n      \"method\": \"Conditional Taf4a knockout mouse, expression analysis of Kansl2, lamin A/C modification assays (nuclear stiffness/AFM), heterochromatin immunofluorescence, muscle regeneration assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with defined molecular (lamin modification, heterochromatin) and physiological (muscle regeneration) phenotypes, TAF4A-NF-Y upstream regulatory mechanism established, multiple orthogonal methods\",\n      \"pmids\": [\"41028714\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"KANSL2 localizes dynamically to nucleoli during G1/early S and G2 phases of the cell cycle in glioblastoma cells. KANSL2 overexpression increases 45S pre-rRNA and 28S rRNA levels; silencing reduces rRNA expression and histone H4 acetylation at lysines 5 and 8 (H4K5ac and H4K8ac) within rDNA promoters, and globally downregulates ribosome biogenesis genes.\",\n      \"method\": \"Immunofluorescence and cell cycle analysis for nucleolar localization, overexpression and RNAi with RT-qPCR for rRNA, ChIP for H4K5ac/H4K8ac at rDNA, RNA-seq in patient-derived GBM spheroids\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization by immunofluorescence with cell cycle staging, ChIP for specific histone marks at rDNA promoters, RNA-seq in patient-derived cells; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"41787092\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"KANSL2 is a strong regulator of invasion in pancreatic ductal adenocarcinoma (PDAC) cells. CRISPR screening identified KANSL2 as required for PANC-1 cell invasion; validation with doxycycline-inducible shRNA confirmed this effect. KANSL2 knockdown does not affect cell proliferation.\",\n      \"method\": \"Genome-wide CRISPR screen for invasion, doxycycline-inducible shRNA validation, in vitro invasion assay, proliferation assay (negative result for proliferation)\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR screen with orthogonal shRNA validation, specific invasion phenotype with negative proliferation result establishing specificity; no molecular mechanism identified; single lab\",\n      \"pmids\": [\"32001790\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"KANSL2 mediates resistance to genotoxic stress in multiple myeloma cells, and high KANSL2 expression increases sensitivity to HDAC inhibitor panobinostat and BET inhibitor OTX-015. Transcriptomics, proteomics, and quantitative acetylome profiling revealed a KANSL2-dependent molecular program involving histone acetylation that can be targeted by these inhibitors.\",\n      \"method\": \"Genetic gain- and loss-of-function models, transcriptomics, proteomics, quantitative acetylome profiling, ex vivo drug response profiling in patient samples\",\n      \"journal\": \"Molecular cancer therapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multi-omics profiling with genetic KO/OE, in vivo screen, patient sample validation; acetylome identifies downstream modification program; single lab\",\n      \"pmids\": [\"41294048\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"SUMV-1 (C. elegans homolog of KANSL2/NSL2) physically interacts with SUMV-2 (NSL3 homolog) in yeast two-hybrid assays, and both interact genetically with MYS-2 (MOF homolog), suggesting conservation of the NSL complex in C. elegans. Loss of sumv-1 function suppresses ectopic lin-3 expression and the synMuv phenotype, placing SUMV-1 as an antagonist of synMuv gene activity in vulval development.\",\n      \"method\": \"Yeast two-hybrid for protein-protein interaction, genetic epistasis (forward screen and RNAi), reporter gene assays in C. elegans\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — yeast two-hybrid interaction plus genetic epistasis with defined developmental phenotype; in a model organism ortholog; single lab\",\n      \"pmids\": [\"24882710\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"KANSL2 is an integral structural subunit of the NSL (non-specific lethal) chromatin-modifying complex, where it directly binds WDR5 via a conserved linear motif (ZF-ZF domain essential for complex assembly) and together with KANSL1 and other subunits recruits the histone acetyltransferase MOF to gene promoters to regulate transcription genome-wide; the complex controls nuclear and mitochondrial gene expression, acetylates lamin A/C to maintain nuclear architecture and genome stability, promotes rRNA transcription in nucleoli, regulates piRNA production from telomeric clusters, governs intraciliary transport gene expression in differentiated cells, and participates in a BAF-NSL supercomplex that silences HIV transcription through inhibitory histone acetylation at the LTR.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"KANSL2 is an integral structural subunit of the NSL (non-specific lethal) chromatin-modifying complex, which associates with the histone acetyltransferase MOF and binds target gene promoters to regulate transcription genome-wide in both Drosophila and mammals [#1]. KANSL2 directly binds WDR5 through a conserved linear motif, and WDR5 in turn bridges KANSL1, forming a KANSL1/WDR5/KANSL2 subcomplex required for efficient NSL complex assembly and its recruitment to promoters; this WDR5 interaction is mutually exclusive with MLL/COMPASS [#0]. The integrity of KANSL2's double zinc-finger (ZF-ZF) domain is essential for complex assembly and transcriptional output, as wild-type but not ZF-ZF-mutant KANSL2 rescues transcriptional and ciliary gene defects in postmitotic podocytes [#6]. Through this complex KANSL2 governs cell-type-specific transcriptional programs: it controls intraciliary transport and microtubule-related gene expression in differentiated cells [#6], drives mitotic fidelity in Drosophila by sustaining transcription of centromere/kinetochore and centriole-duplication genes [#3], and acetylates lamin A/C to maintain nuclear stiffness, heterochromatin organization, and genome stability [#9]. Beyond the nucleus, KANSL2 promotes nucleolar rRNA transcription, increasing 45S pre-rRNA and depositing H4K5ac/H4K8ac at rDNA promoters [#10], and a subset of the complex localizes to mitochondria alongside MOF where it participates in oxidative phosphorylation and mtDNA transcription [#2]. KANSL2 also functions in genome defense and gene silencing, being required for piRNA production from telomeric clusters in the Drosophila germline [#8] and forming a BAF-NSL supercomplex that imposes inhibitory histone acetylation at the HIV LTR to silence proviral transcription [#7]. Disruption of KANSL2 produces tissue-specific catastrophic phenotypes, including kidney failure [#6], failure of skeletal muscle regeneration [#9], and a neural epigenetic defect that drives long-chain fatty acid accumulation and TLR4-NF\\u03baB-dependent vascular breakdown and brain haemorrhage [#4]. In cancer, KANSL2 supports glioblastoma stem-cell self-renewal in a mutual regulatory relationship with POU5F1/OCT4 [#5], drives pancreatic adenocarcinoma cell invasion independently of proliferation [#11], and mediates genotoxic-stress resistance and acetylation-dependent drug sensitivity in multiple myeloma [#12].\",\n  \"teleology\": [\n    {\n      \"year\": 2010,\n      \"claim\": \"Establishing that KANSL2 is a stable subunit of the MOF-associated NSL complex defined its core molecular context as a chromatin-modifying, promoter-binding transcriptional regulator.\",\n      \"evidence\": \"Biochemical purification/co-IP, ChIP-Seq, and RNAi transcriptome profiling in Drosophila and mammalian cells\",\n      \"pmids\": [\"20620954\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve how individual subunits contribute to complex assembly\", \"No direct enzymatic role assigned to KANSL2 itself\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Determining that KANSL2 directly binds WDR5 via a linear motif, with WDR5 bridging KANSL1, explained how the NSL complex is assembled and targeted to promoters and distinguished it from MLL/COMPASS.\",\n      \"evidence\": \"Pulldown assays, crystal structure, structure-based mutagenesis in transgenic flies, ChIP\",\n      \"pmids\": [\"24788516\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the full architecture including MOF positioning\", \"Mechanism of promoter selectivity not resolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Conservation of the NSL complex and a developmental antagonist role was extended to C. elegans, where the KANSL2 ortholog physically and genetically links to NSL3 and MOF orthologs and restrains synMuv gene activity.\",\n      \"evidence\": \"Yeast two-hybrid, genetic epistasis, and reporter assays in C. elegans\",\n      \"pmids\": [\"24882710\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Y2H interaction not biochemically validated in the native complex\", \"Direct transcriptional targets in worm not mapped\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Localization of NSL subunits including KANSL2 to mitochondria broadened the complex's role beyond the nucleus to oxidative phosphorylation and mtDNA transcription.\",\n      \"evidence\": \"Subcellular fractionation, mitochondrial Co-IP, mtDNA ChIP, conditional knockout mouse\",\n      \"pmids\": [\"27768893\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"mtDNA binding dependency shown for KANSL3, not directly for KANSL2\", \"Functional necessity of KANSL2 specifically in mitochondria not established\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Linking KANSL2 to glioblastoma stem-cell self-renewal via a mutual regulatory loop with POU5F1 connected the complex to cancer stemness control.\",\n      \"evidence\": \"RNAi silencing, xenograft tumorigenesis assays, expression correlation in clinical specimens\",\n      \"pmids\": [\"27406830\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Pathway placement relies largely on expression correlation\", \"Direct transcriptional mechanism connecting KANSL2 and OCT4 not defined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrating that the Drosophila ortholog localizes to centrosomes/midbody and sustains transcription of kinetochore and centriole genes established a transcriptional basis for KANSL2's role in mitotic fidelity.\",\n      \"evidence\": \"RNAi in S2 cells, live imaging of GFP-tagged NSL2, RT-qPCR, immunofluorescence\",\n      \"pmids\": [\"31527906\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether centrosome localization is functionally required versus a transcriptional effect unclear\", \"Mammalian conservation of mitotic role not tested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Neural KANSL2 loss was placed upstream of a metabolic-inflammatory axis, showing that an epigenetic defect causes LCFA accumulation that triggers TLR4-NF\\u03baB signalling and vascular breakdown.\",\n      \"evidence\": \"Conditional neural knockout mouse, metabolomics, TLR4 inhibitor rescue, pericyte assays\",\n      \"pmids\": [\"32541879\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct KANSL2 target genes driving LCFA accumulation not pinpointed\", \"Whether effect is cell-autonomous to the lipid program unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"An unbiased CRISPR screen identified KANSL2 as a specific driver of pancreatic cancer cell invasion uncoupled from proliferation.\",\n      \"evidence\": \"Genome-wide CRISPR invasion screen, doxycycline-inducible shRNA validation, invasion and proliferation assays\",\n      \"pmids\": [\"32001790\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No molecular mechanism for invasion identified\", \"Downstream effector genes not defined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Domain mutagenesis in podocytes established that KANSL2's ZF-ZF domain is essential for NSL complex assembly and transcriptional control of intraciliary transport genes, linking the complex to ciliary biology in differentiated cells.\",\n      \"evidence\": \"Conditional podocyte knockout, ZF-ZF domain mutant rescue, RNA-seq, cilia assays\",\n      \"pmids\": [\"37624894\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of how ZF-ZF mediates assembly not solved\", \"Direct ciliary gene targets versus indirect effects not fully separated\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"KANSL2 was shown to drive piRNA production from telomeric clusters, binding telomeric transposon promoters and sustaining heterochromatin marks, extending the complex's role to genome defense.\",\n      \"evidence\": \"Germline RNAi, NSL2 and histone-mark ChIP-seq, piRNA sequencing, Piwi immunofluorescence in Drosophila\",\n      \"pmids\": [\"37399316\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic link between promoter binding and heterochromatin establishment unresolved\", \"Mammalian conservation not tested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identifying a BAF-NSL supercomplex that deposits inhibitory acetylation at the HIV LTR revealed a gene-silencing function for KANSL2 and a potential latency-control target.\",\n      \"evidence\": \"CRISPRi synergy screen, primary CD4 T cell overexpression, Co-IP, histone acetylation assays, Brd4 ChIP\",\n      \"pmids\": [\"37682714\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Stoichiometry and direct KANSL2-BAF contacts not mapped\", \"Generality of inhibitory acetylation beyond the LTR unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defining lamin A/C acetylation by the KANSL2/MOF complex, with TAF4A-NF-Y as an upstream transcriptional regulator of Kansl2, mechanistically linked the complex to nuclear mechanics, heterochromatin maintenance, and muscle stem-cell regeneration.\",\n      \"evidence\": \"Conditional Taf4a knockout mouse, lamin modification and nuclear stiffness (AFM) assays, heterochromatin immunofluorescence, muscle regeneration assays\",\n      \"pmids\": [\"41028714\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific lamin residues acetylated not enumerated\", \"Whether KANSL2 directly contacts lamin or acts via MOF recruitment unresolved\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Cell-cycle-dependent nucleolar localization and rDNA H4K5ac/H4K8ac deposition established KANSL2 as a positive regulator of rRNA transcription and ribosome biogenesis.\",\n      \"evidence\": \"Immunofluorescence with cell-cycle staging, overexpression/RNAi with rRNA RT-qPCR, H4K5ac/H4K8ac ChIP at rDNA, RNA-seq in patient-derived GBM spheroids\",\n      \"pmids\": [\"41787092\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"What recruits KANSL2 to nucleoli during specific cell-cycle phases unknown\", \"Direct versus MOF-mediated acetylation at rDNA not separated\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"KANSL2 was shown to mediate genotoxic-stress resistance in multiple myeloma and to set sensitivity to HDAC and BET inhibitors through an acetylation-dependent program, connecting the complex to therapeutic vulnerability.\",\n      \"evidence\": \"Genetic gain/loss models, transcriptomics, proteomics, quantitative acetylome profiling, ex vivo patient drug response\",\n      \"pmids\": [\"41294048\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal acetylation targets driving stress resistance not pinpointed\", \"Mechanism of synergy with panobinostat/OTX-015 not fully resolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved whether KANSL2 itself possesses or directly confers catalytic activity versus serving purely as a structural/assembly subunit, and how its tissue-specific transcriptional programs are selected across the diverse contexts (nucleolar, mitochondrial, telomeric, lamin) in which the complex acts.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No catalytic activity directly assigned to KANSL2\", \"Determinants of context-specific target selection by the NSL complex unknown\", \"No high-resolution structure of the assembled mammalian NSL complex\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 1, 6, 9]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 9]},\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [10]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 1, 6]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [9, 8, 10]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"complexes\": [\n      \"NSL complex\",\n      \"BAF-NSL supercomplex\"\n    ],\n    \"partners\": [\n      \"WDR5\",\n      \"KANSL1\",\n      \"MOF\",\n      \"KANSL3\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}