Affinage

KANSL2

KAT8 regulatory NSL complex subunit 2 · UniProt Q9H9L4

Length
492 aa
Mass
55.0 kDa
Annotated
2026-06-10
23 papers in source corpus 14 papers cited in narrative 14 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 2010 High

    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

    PMID:20620954

    Open questions at the time
    • Did not resolve how individual subunits contribute to complex assembly
    • No direct enzymatic role assigned to KANSL2 itself
  2. 2014 High

    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

    PMID:24788516

    Open questions at the time
    • Did not define the full architecture including MOF positioning
    • Mechanism of promoter selectivity not resolved
  3. 2014 Medium

    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

    PMID:24882710

    Open questions at the time
    • Y2H interaction not biochemically validated in the native complex
    • Direct transcriptional targets in worm not mapped
  4. 2016 Medium

    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

    PMID:27768893

    Open questions at the time
    • mtDNA binding dependency shown for KANSL3, not directly for KANSL2
    • Functional necessity of KANSL2 specifically in mitochondria not established
  5. 2016 Medium

    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

    PMID:27406830

    Open questions at the time
    • Pathway placement relies largely on expression correlation
    • Direct transcriptional mechanism connecting KANSL2 and OCT4 not defined
  6. 2019 Medium

    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

    PMID:31527906

    Open questions at the time
    • Whether centrosome localization is functionally required versus a transcriptional effect unclear
    • Mammalian conservation of mitotic role not tested
  7. 2020 High

    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

    PMID:32541879

    Open questions at the time
    • Direct KANSL2 target genes driving LCFA accumulation not pinpointed
    • Whether effect is cell-autonomous to the lipid program unresolved
  8. 2020 Medium

    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

    PMID:32001790

    Open questions at the time
    • No molecular mechanism for invasion identified
    • Downstream effector genes not defined
  9. 2023 High

    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

    PMID:37624894

    Open questions at the time
    • Structural basis of how ZF-ZF mediates assembly not solved
    • Direct ciliary gene targets versus indirect effects not fully separated
  10. 2023 Medium

    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

    PMID:37399316

    Open questions at the time
    • Mechanistic link between promoter binding and heterochromatin establishment unresolved
    • Mammalian conservation not tested
  11. 2023 Medium

    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

    PMID:37682714

    Open questions at the time
    • Stoichiometry and direct KANSL2-BAF contacts not mapped
    • Generality of inhibitory acetylation beyond the LTR unknown
  12. 2025 High

    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

    PMID:41028714

    Open questions at the time
    • Specific lamin residues acetylated not enumerated
    • Whether KANSL2 directly contacts lamin or acts via MOF recruitment unresolved
  13. 2026 Medium

    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

    PMID:41787092

    Open questions at the time
    • What recruits KANSL2 to nucleoli during specific cell-cycle phases unknown
    • Direct versus MOF-mediated acetylation at rDNA not separated
  14. 2026 Medium

    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

    PMID:41294048

    Open questions at the time
    • Causal acetylation targets driving stress resistance not pinpointed
    • Mechanism of synergy with panobinostat/OTX-015 not fully resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 4 GO:0060090 molecular adaptor activity 2
Localization
GO:0005634 nucleus 2 GO:0005730 nucleolus 1 GO:0005739 mitochondrion 1 GO:0005815 microtubule organizing center 1
Pathway
R-HSA-4839726 Chromatin organization 3 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-1640170 Cell Cycle 1
Partners
KANSL1KANSL3MOFWDR5
Complex memberships
BAF-NSL supercomplexNSL complex

Evidence

Reading pass · 14 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2014 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. Biochemical pulldown assays, crystal structure determination, structure-based mutagenesis in transgenic flies, chromatin immunoprecipitation Genes & development High 24788516
2010 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. Biochemical purification/co-immunoprecipitation, ChIP-Seq, RNAi depletion with transcriptome readout Molecular cell High 20620954
2016 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. Subcellular fractionation, mitochondrial Co-IP, mtDNA ChIP, conditional knockout mouse model with cardiac phenotype readout Cell Medium 27768893
2019 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. RNAi depletion in Drosophila S2 cells, live imaging of GFP-tagged NSL2, RT-qPCR, immunofluorescence for kinetochore markers PLoS genetics Medium 31527906
2020 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. Conditional neural-specific knockout mouse model, metabolomics (LCFA measurement), TLR4 inhibitor rescue, pericyte functional assays Nature cell biology High 32541879
2016 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. RNAi-mediated silencing, mouse xenograft assay, gene expression correlation in clinical specimens Cancer research Medium 27406830
2023 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. Conditional knockout in podocytes, domain mutagenesis (ZF-ZF mutant), RNA-seq, cilia assays, comparison with ciliated fibroblasts Science advances High 37624894
2023 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. CRISPRi synergy screening (REACTS), overexpression in primary CD4 T cells, co-immunoprecipitation demonstrating BAF-NSL supercomplex, histone acetylation assays, ChIP for Brd4 Cell reports Medium 37682714
2023 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. Germline-specific RNAi, ChIP-seq for NSL2 and histone marks, piRNA sequencing, immunofluorescence for Piwi Life science alliance Medium 37399316
2025 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. Conditional Taf4a knockout mouse, expression analysis of Kansl2, lamin A/C modification assays (nuclear stiffness/AFM), heterochromatin immunofluorescence, muscle regeneration assays Nature communications High 41028714
2026 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. 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 Communications biology Medium 41787092
2020 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. Genome-wide CRISPR screen for invasion, doxycycline-inducible shRNA validation, in vitro invasion assay, proliferation assay (negative result for proliferation) Scientific reports Medium 32001790
2026 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. Genetic gain- and loss-of-function models, transcriptomics, proteomics, quantitative acetylome profiling, ex vivo drug response profiling in patient samples Molecular cancer therapeutics Medium 41294048
2014 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. Yeast two-hybrid for protein-protein interaction, genetic epistasis (forward screen and RNAi), reporter gene assays in C. elegans Developmental biology Medium 24882710

Source papers

Stage 0 corpus · 23 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2016 MOF Acetyl Transferase Regulates Transcription and Respiration in Mitochondria. Cell 150 27768893
2010 The nonspecific lethal complex is a transcriptional regulator in Drosophila. Molecular cell 121 20620954
2014 Structural analysis of the KANSL1/WDR5/KANSL2 complex reveals that WDR5 is required for efficient assembly and chromatin targeting of the NSL complex. Genes & development 99 24788516
2020 Genome-wide association study of word reading: Overlap with risk genes for neurodevelopmental disorders. Genes, brain, and behavior 41 32108986
2020 Neural metabolic imbalance induced by MOF dysfunction triggers pericyte activation and breakdown of vasculature. Nature cell biology 30 32541879
2011 A 5'-proximal stem-loop structure of 5' untranslated region of porcine reproductive and respiratory syndrome virus genome is key for virus replication. Virology journal 25 21496223
2016 The NSL Chromatin-Modifying Complex Subunit KANSL2 Regulates Cancer Stem-like Properties in Glioblastoma That Contribute to Tumorigenesis. Cancer research 16 27406830
2022 EPIKOL, a chromatin-focused CRISPR/Cas9-based screening platform, to identify cancer-specific epigenetic vulnerabilities. Cell death & disease 14 35973998
2019 RNAi-mediated depletion of the NSL complex subunits leads to abnormal chromosome segregation and defective centrosome duplication in Drosophila mitosis. PLoS genetics 12 31527906
2020 KANSL2 and MBNL3 are regulators of pancreatic ductal adenocarcinoma invasion. Scientific reports 10 32001790
2014 Evidence of a MOF histone acetyltransferase-containing NSL complex in C. elegans. Worm 8 26430553
2023 Narrow and Stripe Leaf 2 Regulates Leaf Width by Modulating Cell Cycle Progression in Rice. Rice (New York, N.Y.) 7 37071312
2006 Parsing the genetic heterogeneity of chromosome 12q susceptibility genes for Alzheimer disease by family-based association analysis. Neurogenetics 7 16770605
2014 SUMV-1 antagonizes the activity of synthetic multivulva genes in Caenorhabditis elegans. Developmental biology 6 24882710
2023 Transcriptional regulation by the NSL complex enables diversification of IFT functions in ciliated versus nonciliated cells. Science advances 5 37624894
2023 Comprehensive synergy mapping links a BAF- and NSL-containing "supercomplex" to the transcriptional silencing of HIV-1. Cell reports 5 37682714
2025 Unveiling migraine subtype heterogeneity and risk loci: integrated genome-wide association study and single-cell transcriptomics discovery. The journal of headache and pain 4 40826382
2022 Ropivacaine represses the proliferation, invasion, and migration of glioblastoma via modulating the microRNA-21-5p/KAT8 regulatory NSL complex subunit 2 axis. Bioengineered 4 35191804
2023 The NSL complex is required for piRNA production from telomeric clusters. Life science alliance 2 37399316
2026 The Histone Modifier KANSL2 Is an Actionable Biomarker in Multiple Myeloma. Molecular cancer therapeutics 0 41294048
2026 Nucleoli-localized KANSL2 as an epigenetic regulator of ribosome biogenesis in glioblastoma cells. Communications biology 0 41787092
2025 Regulation of NSL by TAF4A is critical for genome stability and quiescence of muscle stem cells. Nature communications 0 41028714
2003 Putative FLJ20436 gene characterisation in goat. Observed ubiquitous expression in goat and transgenic mice allowed to restrict the location of an hypothesised insulator element. Gene 0 14637001

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