{"gene":"ACTL6A","run_date":"2026-06-09T22:02:40","timeline":{"discoveries":[{"year":2013,"finding":"ACTL6A (BAF53a) prevents SWI/SNF complex binding to promoters of KLF4 and other differentiation genes in epidermal progenitors, thereby suppressing differentiation; conditional loss leads to terminal differentiation and SWI/SNF-dependent induction of KLF4 targets","method":"Conditional knockout, ChIP, ectopic expression, gene expression analysis","journal":"Cell Stem Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal genetic and chromatin occupancy data, conditional KO with defined phenotype, replicated by multiple orthogonal methods in one rigorous study","pmids":["23395444"],"is_preprint":false},{"year":2012,"finding":"BAF53a/ACTL6A is an essential subunit of BAF chromatin remodeling complexes required for hematopoietic stem cell (HSC) function; conditional deletion causes multilineage bone marrow failure and HSC proliferative impairment in a cell-autonomous manner","method":"Conditional knockout mouse, hematopoietic chimeras, flow cytometry, bone marrow transplantation","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with well-defined cellular phenotype, cell-autonomy confirmed by chimera experiments","pmids":["23018638"],"is_preprint":false},{"year":2023,"finding":"ACTL6A acts as a co-transcription factor with NRF2 to upregulate GCLC expression, increasing glutathione synthesis and reducing lipid ROS, thereby protecting gastric cancer cells against ferroptosis; the hydrophobic region of ACTL6A is required for this activity","method":"Co-immunoprecipitation, ChIP, luciferase reporter assay, ROS/GSH measurements, knockdown/overexpression","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP, ChIP, reporter assay, and functional rescue in single lab with multiple orthogonal methods","pmids":["37443154"],"is_preprint":false},{"year":2021,"finding":"ACTL6A overexpression enhances repair of cisplatin-DNA adducts, conferring platinum resistance; this regulation is mediated through the SWI/SNF chromatin remodeling complex, and HDAC inhibitors can reverse the effect of ACTL6A overexpression on DNA damage repair","method":"Overexpression/knockdown, cisplatin-DNA adduct repair assays, xenograft mouse model, HDAC inhibitor treatment","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple functional assays (DNA repair, drug sensitivity, in vivo xenograft), pathway placement via SWI/SNF dependence, single lab","pmids":["33408251"],"is_preprint":false},{"year":2021,"finding":"In squamous cell carcinomas (SCCs), increased ACTL6A levels lead to its stoichiometric assembly into BAF complexes; elevated ACTL6A occupancy enhances polycomb opposition genome-wide and facilitates co-dependent loading of BAF and TEAD-YAP complexes on chromatin to activate SCC genes","method":"ATAC-seq, ChIP-seq, ectopic expression, CUT&RUN, quantitative proteomics of BAF complex composition","journal":"Molecular Cell","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — genome-wide chromatin occupancy, quantitative complex assembly measurements, multiple orthogonal methods in single rigorous study","pmids":["34687603"],"is_preprint":false},{"year":2015,"finding":"Actl6a interacts with Nanog and Sox2 in mouse ESCs, promotes Nanog binding to pluripotency gene promoters (Oct4, Sox2), and targets promoters of PrE regulators (Sall4, Fgf4) to repress their expression; mutant Actl6a with impaired Tip60/p400 binding fails to block primitive endoderm differentiation, indicating dependence on the Tip60-p400 complex","method":"Co-immunoprecipitation, ChIP, RNAi knockdown, ectopic expression, domain-mutant rescue experiments","journal":"Stem Cells","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP, ChIP, mutant rescue experiments with multiple orthogonal methods in single lab","pmids":["25802002"],"is_preprint":false},{"year":2013,"finding":"BAF53a/ACTL6A is a direct target of miR-206 in rhabdomyosarcoma; sustained BAF53a expression blocks myogenic differentiation, while its silencing promotes differentiation marker expression, reduces proliferation, and impairs anchorage-independent growth and tumor formation","method":"miR-206 re-expression, BAF53a silencing (siRNA/shRNA), differentiation assays, in vivo tumor growth","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct miRNA targeting validated, functional KD with defined phenotype, single lab","pmids":["23728344"],"is_preprint":false},{"year":2017,"finding":"Baf53a interacts with Oct3/4 in mouse ES cells; Baf53a-deficient ES cells show increased p53, p21, and cleaved Caspase 3 and undergo cell death; a Baf53a M3 mutant (E388A/R389A/R390A) fails to rescue cell death, and Baf53b can compensate for Baf53a loss in ES cell survival","method":"Co-immunoprecipitation, tetracycline-inducible conditional knockout, domain mutagenesis (M3 mutant), rescue by overexpression of Baf53a or Baf53b","journal":"Scientific Reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, conditional KO, mutagenesis rescue, single lab","pmids":["29070872"],"is_preprint":false},{"year":2018,"finding":"ACTL6A interacts with and co-localizes with Sox2 and p53 in acute promyelocytic leukemia cells; knockdown of ACTL6A promotes differentiation and decreases Sox2 and Notch1 levels; p53 activator CBL0137 decreases ACTL6A expression and promotes differentiation","method":"Co-immunoprecipitation, co-localization assays, siRNA knockdown, pharmacological p53 activation","journal":"Cellular Signalling","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP and co-localization with functional KD, single lab, moderate methods","pmids":["30448346"],"is_preprint":false},{"year":2018,"finding":"Mitochondrially produced ATP promotes Actl6a expression and histone acetylation; Actl6a knockdown reduces histone acetylation and pluripotency of ESCs, and this reduction cannot be rescued by exogenous ATP, placing Actl6a downstream of ATP in regulating pluripotency-associated histone acetylation","method":"Actl6a knockdown in ESCs, ATP supplementation, rotenone treatment, histone acetylation measurement","journal":"FASEB Journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis via ATP supplementation/inhibition rescue experiments with histone acetylation readout, single lab","pmids":["29222327"],"is_preprint":false},{"year":2020,"finding":"HIF-1α knockdown inhibits Actl6a expression and H3K9 acetylation in hiPSCs; Actl6a knockdown in turn reduces H3K9ac and pluripotency, placing Actl6a downstream of HIF-1α in regulating histone acetylation and pluripotency maintenance","method":"shRNA knockdown of HIF-1α and Actl6a, histone acetylation measurement, EB and teratoma formation assays","journal":"FASEB Journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis via sequential knockdown, defined molecular readout (H3K9ac), single lab","pmids":["32112486"],"is_preprint":false},{"year":2020,"finding":"Long non-coding RNA uc.291 physically interacts with ACTL6A and modulates chromatin remodeling; upon uc.291 depletion, ACTL6A binds to promoters of differentiation genes and inhibits BAF complex targeting; presence of uc.291 releases the ACTL6A inhibitory effect to allow expression of terminal differentiation genes","method":"RNA immunoprecipitation, ChIP, knockdown of uc.291 in primary keratinocytes and 3D skin equivalents","journal":"EMBO Reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA-protein interaction (RIP), ChIP showing differential promoter occupancy, defined differentiation phenotype, single lab","pmids":["32017402"],"is_preprint":false},{"year":2020,"finding":"ACTL6A interacts with p53 DNA response elements and Sp1 binding sites in the p21Cip1 gene promoter to suppress p21Cip1 promoter activity, mRNA, and protein levels in epidermal SCC cells; increased p21Cip1 in ACTL6A knockdown cells is required for suppression of the SCC phenotype, and this regulation is p53-independent","method":"ChIP, luciferase reporter assay, siRNA knockdown, rescue experiments","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP showing promoter occupancy, reporter assay, p53-independence established, single lab","pmids":["32616890"],"is_preprint":false},{"year":2021,"finding":"ACTL6A suppresses p21Cip1 expression by interacting with Sp1 and p53 binding elements in the p21Cip1 promoter in mesothelioma cells; ACTL6A knockout reduces tumor formation with elevated p21Cip1 in vivo","method":"ChIP, luciferase reporter assay, ACTL6A knockout, in vivo tumor formation","journal":"Oncogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP, reporter assay, in vivo KO, single lab, corroborates findings in SCC","pmids":["34689163"],"is_preprint":false},{"year":2022,"finding":"ACTL6A knockdown impairs DNA replication initiation in glioblastoma cells by downregulating genes of the CDC45-MCM-GINS (CMG) complex; specifically, ACTL6A transcriptionally regulates MCM5 expression; ACTL6A knockdown also diminishes ATR-Chk1 pathway activity, leading to apoptosis","method":"siRNA knockdown, DNA replication assays, gene expression analysis, Western blot for ATR-Chk1 pathway components","journal":"Biochemical and Biophysical Research Communications","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — defined molecular target (MCM5), pathway placement (ATR-Chk1), single lab, single method per claim","pmids":["35182941"],"is_preprint":false},{"year":2022,"finding":"ACTL6A (BAF53A) interacts with p63 in colorectal cancer cells; this interaction decreases DUSP5 expression, leading to increased ERK1/2 phosphorylation and enhanced cancer cell proliferation","method":"Co-immunoprecipitation, gene expression analysis, siRNA knockdown, Western blot for ERK1/2 phosphorylation","journal":"Cell Death & Disease","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP showing interaction, functional epistasis placing ACTL6A upstream of DUSP5-ERK, single lab","pmids":["36526622"],"is_preprint":false},{"year":2023,"finding":"ACTL6A interacts with MYC and VPS72; the ACTL6A/VPS72/MYC complex enhances MYC affinity for target gene promoters to promote transcription; ACTL6A also protects VPS72 from TRIM21-mediated ubiquitination and degradation","method":"Co-immunoprecipitation, protein co-localization, in vivo ubiquitination assay, ChIP","journal":"Hepatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, ChIP for MYC target occupancy, single lab","pmids":["36631007"],"is_preprint":false},{"year":2022,"finding":"FBXW7 binds ACTL6A and promotes its ubiquitin-dependent degradation; FBXW7 overexpression reduces cancer stem cell-like properties and tumorigenicity of HCC cells, and ACTL6A overexpression reverses these effects, placing ACTL6A as a downstream oncogenic target of FBXW7","method":"Co-immunoprecipitation, protein co-localization, in vivo ubiquitination assay, rescue experiments with ACTL6A overexpression","journal":"Stem Cells International","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, epistasis rescue, single lab","pmids":["36159747"],"is_preprint":false},{"year":2022,"finding":"In Schwann cells, nuclear levels of ACTL6A are increased by contact with large-caliber axons or nanofibers; ACTL6A is required to evict repressive histone marks and facilitate myelination transcriptional programs; loss of Actl6a in conditional knockout mice causes defective radial sorting, hypo-myelination of large axons, and redundant myelin around small axons","method":"Conditional knockout mouse, live imaging, histone mark analysis, nanofiber contact assay","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with defined cellular and motor phenotype, mechanistic histone mark analysis, single lab","pmids":["35434551"],"is_preprint":false},{"year":2025,"finding":"ACTL6A depletion in colorectal cancer enhances KLF4 binding at newly accessible chromatin regions, where KLF4 cooperates with SWI/SNF and INO80 complexes to activate p53 pathway-related genes and induce apoptosis; multi-omics analysis shows ACTL6A deficiency alters chromatin accessibility genome-wide","method":"ATAC-seq, ChIP-seq, RNA-seq (multi-omics), ACTL6A knockdown","journal":"Cell Death & Disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multi-omics (ATAC-seq, ChIP-seq, RNA-seq), defined mechanism, single lab","pmids":["40877226"],"is_preprint":false},{"year":2025,"finding":"BAF53A (ACTL6A) collaborates with BACH1 to transcriptionally activate GCLM (glutamate-cysteine ligase modifier subunit) in esophageal squamous cell carcinoma; this BAF53A-BACH1-GCLM axis maintains glutathione metabolism and ferroptosis resistance; GCLM overexpression rescues redox balance in BAF53A- or BACH1-silenced cells","method":"Co-immunoprecipitation, ChIP-seq, shRNA knockdown, rescue by GCLM overexpression, GSH/GSSG and ROS measurement","journal":"PeerJ","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ChIP-seq, functional rescue, single lab","pmids":["41059410"],"is_preprint":false},{"year":2025,"finding":"BAP18 recruits ACTL6A and PAF1 to Wnt target gene promoters, enhancing β-catenin-mediated transcription in NSCLC; co-immunoprecipitation confirmed the BAP18-ACTL6A-PAF1 interaction","method":"Co-immunoprecipitation, luciferase reporter assay, RNA-seq, knockdown experiments","journal":"Journal of Biological Chemistry","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP for complex formation, reporter assay for transcriptional activity, single lab","pmids":["40818609"],"is_preprint":false},{"year":2025,"finding":"Loss of Actl6a in zebrafish leads to cilia disassembly and cystic kidney by downregulating master ciliogenesis regulators foxj1a and rfx2 at the transcriptional, chromatin accessibility, and SWI/SNF binding levels; overexpression of foxj1a or rfx2 mRNA partially rescues the cystic kidney and cilia disassembly phenotypes in actl6a mutants","method":"Zebrafish genetic knockout, ATAC-seq, ChIP-seq, mRNA rescue experiments, omics analyses","journal":"bioRxiv (preprint)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis via mRNA rescue, chromatin accessibility and SWI/SNF occupancy data, defined phenotype in zebrafish, preprint not peer-reviewed","pmids":["bio_10.1101_2025.06.10.658863"],"is_preprint":true},{"year":2019,"finding":"ACTL6A positively regulates PGK1 expression in ovarian cancer; enforced ACTL6A expression increases PGK1 while knockdown decreases it; ACTL6A regulates FSH-enhanced glycolysis via PI3K/AKT pathway signaling upstream of ACTL6A","method":"Overexpression/knockdown, in vivo xenograft, qRT-PCR/Western blot, correlation in patient tissues","journal":"Cell Death & Disease","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, no direct ChIP/binding assay for PGK1 regulation, mechanism inferred from expression changes","pmids":["31649264"],"is_preprint":false},{"year":2025,"finding":"ACTL6A knockdown in HNSCC reduces aerobic glycolysis (Warburg effect) and blunts HIF1α/HIF2α protein induction under hypoxia; ACTL6A mediates chromatin accessibility at AP-1 transcription factor sites and regulates upstream MAPK signaling through induction of Ras and Galectin-1","method":"ATAC-seq, Seahorse metabolic assay, shRNA knockdown, in vivo IACS-010759 treatment, Western blot","journal":"bioRxiv (preprint)","confidence":"Low","confidence_rationale":"Tier 2 / Weak — ATAC-seq and metabolic assays, preprint not peer-reviewed, single lab","pmids":["40950224"],"is_preprint":true},{"year":2025,"finding":"Actl6a interacts with Sox2 in spinal cord neurons and collaboratively upregulates Atg5 and Atg7 expression to promote autophagy; Fto demethylase modulates Actl6a mRNA stability via m6A demethylation, placing Fto upstream of Actl6a in this pathway","method":"Co-immunoprecipitation, RNA immunoprecipitation (RIP), m6A dot blot, overexpression/knockdown, rat SCI model with AAV delivery","journal":"Journal of Advanced Research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — Co-IP and RIP for interactions, in vivo AAV rescue, single lab, mechanism only partially validated","pmids":["39875055"],"is_preprint":false}],"current_model":"ACTL6A (BAF53a) is an actin-related protein subunit shared by multiple chromatin remodeling complexes (SWI/SNF/BAF, INO80, and Tip60-p400/NuA4) that controls gene expression by modulating complex occupancy at target promoters: in progenitor and stem cells it prevents SWI/SNF binding to differentiation gene promoters (e.g., KLF4) to maintain the progenitor state, while in cancer contexts its stoichiometric overassembly into BAF complexes drives oncogenic gene programs by opposing Polycomb repression and co-engaging TEAD-YAP; it also acts as a co-transcription factor with NRF2 or BACH1 to activate glutathione biosynthesis genes (GCLC, GCLM) and thereby suppress ferroptosis, interacts with MYC and VPS72 to enhance MYC transcriptional activity, suppresses p21Cip1 by occupying its promoter, promotes cisplatin-DNA adduct repair through SWI/SNF, and is itself subject to ubiquitin-dependent degradation by FBXW7."},"narrative":{"mechanistic_narrative":"ACTL6A (BAF53a) is an actin-related subunit of ATP-dependent chromatin remodeling complexes (SWI/SNF/BAF, INO80, and Tip60-p400) that controls cell fate by modulating which genes these complexes can access, acting both to maintain progenitor/stem states and, when overexpressed, to drive oncogenic transcription [PMID:23395444, PMID:34687603]. In progenitor and stem cells it restrains differentiation: it blocks SWI/SNF binding to differentiation-gene promoters such as KLF4 in epidermal progenitors [PMID:23395444], is an essential, cell-autonomous requirement for hematopoietic stem cell function [PMID:23018638], and cooperates with pluripotency factors Nanog, Sox2, and Oct3/4 through a Tip60-p400-dependent activity to sustain the undifferentiated state and cell survival [PMID:25802002, PMID:29070872]. In cancer, increased ACTL6A is stoichiometrically incorporated into BAF complexes, where it enhances genome-wide opposition to Polycomb repression and enables co-dependent loading of BAF and TEAD-YAP complexes to activate squamous-cell-carcinoma gene programs [PMID:34687603]; it also suppresses the cell-cycle inhibitor p21Cip1 in a p53-independent manner by occupying Sp1 and p53 response elements in its promoter [PMID:32616890, PMID:34689163]. ACTL6A additionally functions as a co-activator of redox and growth programs—partnering with NRF2 and BACH1 to drive glutathione-biosynthesis genes (GCLC, GCLM) and thereby suppress ferroptosis [PMID:37443154, PMID:41059410], interacting with MYC and VPS72 to enhance MYC target promoter binding [PMID:36631007], and promoting cisplatin-DNA adduct repair via SWI/SNF [PMID:33408251]—and is itself targeted for ubiquitin-dependent degradation by FBXW7 [PMID:36159747]. Loss-of-function studies across glioblastoma, Schwann cells, and zebrafish further implicate ACTL6A in DNA replication initiation, myelination transcriptional programs, and ciliogenesis, in each case through chromatin-level control of lineage regulators [PMID:35182941, PMID:35434551, PMID:bio_10.1101_2025.06.10.658863].","teleology":[{"year":2012,"claim":"Established that ACTL6A is not merely a passive structural subunit but is functionally essential for an adult stem cell compartment in vivo, answering whether its BAF-complex role has organism-level consequences.","evidence":"Conditional knockout mouse with hematopoietic chimeras and bone marrow transplantation","pmids":["23018638"],"confidence":"High","gaps":["Did not resolve which specific target genes mediate HSC failure","Did not separate BAF-specific from INO80/Tip60 contributions"]},{"year":2013,"claim":"Defined a mechanistic model in which ACTL6A actively gates SWI/SNF access to differentiation promoters, explaining how it maintains progenitor identity rather than simply enabling remodeling.","evidence":"Conditional knockout, ChIP, and ectopic expression in epidermal progenitors","pmids":["23395444"],"confidence":"High","gaps":["Did not establish how ACTL6A is itself regulated to release this block during normal differentiation","Targets beyond KLF4 only partially mapped"]},{"year":2015,"claim":"Connected ACTL6A to the pluripotency transcription factor network and assigned the activity to a specific complex, showing it works through Tip60-p400 rather than BAF alone in ESCs.","evidence":"Co-IP, ChIP, RNAi, and Tip60/p400-binding domain-mutant rescue in mouse ESCs","pmids":["25802002"],"confidence":"High","gaps":["Did not quantify partitioning of ACTL6A among BAF, INO80, and Tip60-p400 in ESCs","Direct versus indirect promoter effects not fully separated"]},{"year":2018,"claim":"Placed ACTL6A downstream of cellular energy and oxygen sensing, linking metabolic state to chromatin acetylation and pluripotency.","evidence":"Knockdown with ATP supplementation/rotenone (PMID 29222327) and sequential HIF-1α/Actl6a knockdown with H3K9ac readout (PMID 32112486) in ESCs/hiPSCs","pmids":["29222327","32112486"],"confidence":"Medium","gaps":["Mechanism linking ATP/HIF-1α to ACTL6A expression not defined","Whether ACTL6A directly enables acetyltransferase activity not shown"]},{"year":2021,"claim":"Provided the quantitative basis for ACTL6A oncogenicity by showing dose-dependent stoichiometric assembly into BAF complexes drives Polycomb opposition and co-recruits TEAD-YAP, distinguishing tumor from normal function.","evidence":"ATAC-seq, ChIP-seq, CUT&RUN, and quantitative proteomics of BAF composition in SCCs","pmids":["34687603"],"confidence":"High","gaps":["Mechanism of co-dependent BAF/TEAD-YAP loading not structurally resolved","Did not address whether the same applies outside squamous lineages"]},{"year":2020,"claim":"Identified p21Cip1 suppression as a concrete, p53-independent route by which ACTL6A enforces a proliferative cancer phenotype, naming the promoter elements engaged.","evidence":"ChIP, luciferase reporter, knockdown/rescue in SCC (PMID 32616890) and knockout with in vivo tumor assay in mesothelioma (PMID 34689163)","pmids":["32616890","34689163"],"confidence":"Medium","gaps":["How ACTL6A is recruited to Sp1/p53 elements not defined","Whether repression is BAF-dependent not directly tested"]},{"year":2021,"claim":"Extended ACTL6A function from transcription into the DNA damage response, showing it promotes platinum-adduct repair through SWI/SNF and underlies chemoresistance.","evidence":"Overexpression/knockdown, cisplatin-DNA adduct repair assays, xenografts, and HDAC inhibitor reversal","pmids":["33408251"],"confidence":"High","gaps":["Direct repair-factor recruitment by ACTL6A not demonstrated","Link between HDAC inhibition reversal and chromatin state mechanistic only"]},{"year":2023,"claim":"Revealed a non-canonical co-transcription-factor role in redox metabolism, with ACTL6A partnering NRF2 to drive glutathione synthesis and suppress ferroptosis.","evidence":"Co-IP, ChIP, luciferase reporter, and ROS/GSH measurements in gastric cancer; hydrophobic-region requirement mapped","pmids":["37443154"],"confidence":"High","gaps":["Whether this depends on a remodeling complex or is complex-independent unclear","Direct GCLC promoter binding by ACTL6A versus via NRF2 not separated"]},{"year":2023,"claim":"Defined ACTL6A as a co-activator that boosts MYC transcriptional output and stabilizes its partner VPS72 against degradation, broadening its oncogenic interactome beyond chromatin remodeling subunits.","evidence":"Co-IP, co-localization, ChIP for MYC occupancy, and in vivo ubiquitination assay in HCC","pmids":["36631007"],"confidence":"Medium","gaps":["Stoichiometry and structure of the ACTL6A/VPS72/MYC complex unknown","Single-lab evidence without reciprocal validation"]},{"year":2022,"claim":"Positioned ACTL6A within a degradative regulatory loop, identifying FBXW7 as the E3 ligase that limits ACTL6A levels and thereby its cancer-stem-cell-promoting activity.","evidence":"Co-IP, in vivo ubiquitination assay, and ACTL6A-overexpression rescue in HCC cells","pmids":["36159747"],"confidence":"Medium","gaps":["Degron site on ACTL6A not mapped","Whether FBXW7 regulation is signal-responsive not addressed"]},{"year":2022,"claim":"Demonstrated tissue-specific requirements for ACTL6A in differentiated cell programs, showing it evicts repressive histone marks to license myelination and that loss of ACTL6A independently impairs DNA replication initiation.","evidence":"Conditional KO with histone mark analysis in Schwann cells (PMID 35434551) and knockdown with replication and ATR-Chk1 assays in glioblastoma (PMID 35182941)","pmids":["35434551","35182941"],"confidence":"Medium","gaps":["Which complex mediates myelination versus replication roles not resolved","Direct versus indirect regulation of MCM5/CMG genes not fully established"]},{"year":2025,"claim":"Resolved the chromatin logic of ACTL6A loss in cancer, showing depletion opens new accessible regions where KLF4 recruits SWI/SNF and INO80 to activate p53-pathway apoptotic genes, mirroring the progenitor-state model in a tumor context.","evidence":"Multi-omics (ATAC-seq, ChIP-seq, RNA-seq) with knockdown in colorectal cancer","pmids":["40877226"],"confidence":"Medium","gaps":["Mechanism by which ACTL6A normally occludes these regions not defined","Generalizability across tumor types untested"]},{"year":2025,"claim":"Expanded the co-activator repertoire to additional transcription factors and pathways, linking ACTL6A to BACH1-driven glutathione metabolism, BAP18/PAF1-Wnt/β-catenin signaling, and ciliogenesis master regulators.","evidence":"Co-IP/ChIP-seq with GCLM rescue in ESCC (PMID 41059410), Co-IP/reporter in NSCLC (PMID 40818609), and zebrafish KO with mRNA rescue (PMID bio_10.1101_2025.06.10.658863, preprint)","pmids":["41059410","40818609","bio_10.1101_2025.06.10.658863"],"confidence":"Medium","gaps":["Whether these reflect distinct complexes or a shared mechanism unclear","Direct binding versus recruitment by partners not always separated"]},{"year":null,"claim":"It remains unresolved how ACTL6A is partitioned among its distinct complexes (BAF, INO80, Tip60-p400) and how this partitioning is set by cell state to switch between maintaining progenitor identity and driving the diverse oncogenic and metabolic programs attributed to it.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of ACTL6A within each complex in the corpus","No unified determinant of complex choice identified","Direct DNA/histone-binding contribution of ACTL6A itself not defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[2,12,16,20]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0,4,5]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[12,13]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,5,18]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[4,11]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[0,4,11,19]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[2,12,16,20]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[1,5,18]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[3]},{"term_id":"R-HSA-69306","term_label":"DNA Replication","supporting_discovery_ids":[14]}],"complexes":["SWI/SNF (BAF)","INO80","Tip60-p400 (NuA4)"],"partners":["NANOG","SOX2","POU5F1","MYC","VPS72","FBXW7","NFE2L2","BACH1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O96019","full_name":"Actin-like protein 6A","aliases":["53 kDa BRG1-associated factor A","Actin-related protein Baf53a","ArpNbeta","BRG1-associated factor 53A","BAF53A","INO80 complex subunit K"],"length_aa":429,"mass_kda":47.5,"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. Required for maximal ATPase activity of SMARCA4/BRG1/BAF190A and for association of the SMARCA4/BRG1/BAF190A containing remodeling complex BAF with chromatin/nuclear matrix. Belongs to the neural progenitors-specific chromatin remodeling complex (npBAF complex) and is required for the proliferation of neural progenitors. During neural development a switch from a stem/progenitor to a postmitotic chromatin remodeling mechanism occurs as neurons exit the cell cycle and become committed to their adult state. The transition from proliferating neural stem/progenitor cells to postmitotic neurons requires a switch in subunit composition of the npBAF and nBAF complexes. As neural progenitors exit mitosis and differentiate into neurons, npBAF complexes which contain ACTL6A/BAF53A and PHF10/BAF45A, are exchanged for homologous alternative ACTL6B/BAF53B and DPF1/BAF45B or DPF3/BAF45C subunits in neuron-specific complexes (nBAF). The npBAF complex is essential for the self-renewal/proliferative capacity of the multipotent neural stem cells. The nBAF complex along with CREST plays a role regulating the activity of genes essential for dendrite growth (By similarity). Component of the NuA4 histone acetyltransferase (HAT) complex which is involved in transcriptional activation of select genes principally by acetylation of nucleosomal histones H4 and H2A. This modification may both alter nucleosome - DNA interactions and promote interaction of the modified histones with other proteins which positively regulate transcription. This complex may be required for the activation of transcriptional programs associated with oncogene and proto-oncogene mediated growth induction, tumor suppressor mediated growth arrest and replicative senescence, apoptosis, and DNA repair. NuA4 may also play a direct role in DNA repair when recruited to sites of DNA damage. Putative core component of the chromatin remodeling INO80 complex which is involved in transcriptional regulation, DNA replication and probably DNA repair","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/O96019/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/ACTL6A","classification":"Common Essential","n_dependent_lines":1202,"n_total_lines":1208,"dependency_fraction":0.9950331125827815},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"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":"SMARCD1","stoichiometry":10.0},{"gene":"SMARCD2","stoichiometry":10.0},{"gene":"SMARCE1","stoichiometry":10.0},{"gene":"PHF10","stoichiometry":4.0},{"gene":"TOP1","stoichiometry":4.0}],"url":"https://opencell.sf.czbiohub.org/search/ACTL6A","total_profiled":1310},"omim":[{"mim_id":"618502","title":"BRD4-INTERACTING CHROMATIN REMODELING COMPLEX-ASSOCIATED PROTEIN-LIKE; BICRAL","url":"https://www.omim.org/entry/618502"},{"mim_id":"612458","title":"ACTIN-LIKE 6B; ACTL6B","url":"https://www.omim.org/entry/612458"},{"mim_id":"605690","title":"BRD4-INTERACTING CHROMATIN REMODELING 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publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico","url":"https://pubmed.ncbi.nlm.nih.gov/34181232","citation_count":6,"is_preprint":false},{"pmid":"38221767","id":"PMC_38221767","title":"Sulforaphane suppresses cell proliferation and induces apoptosis in glioma via the ACTL6A/PGK1 axis.","date":"2024","source":"Toxicology mechanisms and methods","url":"https://pubmed.ncbi.nlm.nih.gov/38221767","citation_count":5,"is_preprint":false},{"pmid":"31994175","id":"PMC_31994175","title":"The p.Arg377Trp variant in ACTL6A underlines a recognizable BAF-opathy phenotype.","date":"2020","source":"Clinical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/31994175","citation_count":5,"is_preprint":false},{"pmid":"34689163","id":"PMC_34689163","title":"ACTL6A suppresses p21Cip1 tumor suppressor expression to maintain an aggressive mesothelioma cancer cell 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complexes","date":"2025-06-14","source":"bioRxiv","url":"https://doi.org/10.1101/2025.06.10.658863","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":22178,"output_tokens":6048,"usd":0.078627,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":14766,"output_tokens":4698,"usd":0.09564,"stage2_stop_reason":"end_turn"},"total_usd":0.174267,"stage1_batch_id":"msgbatch_0179Z2pxRYBsXi2xADneafRw","stage2_batch_id":"msgbatch_01LaY9ZaVdgjWArcZo9eqQE5","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2013,\n      \"finding\": \"ACTL6A (BAF53a) prevents SWI/SNF complex binding to promoters of KLF4 and other differentiation genes in epidermal progenitors, thereby suppressing differentiation; conditional loss leads to terminal differentiation and SWI/SNF-dependent induction of KLF4 targets\",\n      \"method\": \"Conditional knockout, ChIP, ectopic expression, gene expression analysis\",\n      \"journal\": \"Cell Stem Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal genetic and chromatin occupancy data, conditional KO with defined phenotype, replicated by multiple orthogonal methods in one rigorous study\",\n      \"pmids\": [\"23395444\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"BAF53a/ACTL6A is an essential subunit of BAF chromatin remodeling complexes required for hematopoietic stem cell (HSC) function; conditional deletion causes multilineage bone marrow failure and HSC proliferative impairment in a cell-autonomous manner\",\n      \"method\": \"Conditional knockout mouse, hematopoietic chimeras, flow cytometry, bone marrow transplantation\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with well-defined cellular phenotype, cell-autonomy confirmed by chimera experiments\",\n      \"pmids\": [\"23018638\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ACTL6A acts as a co-transcription factor with NRF2 to upregulate GCLC expression, increasing glutathione synthesis and reducing lipid ROS, thereby protecting gastric cancer cells against ferroptosis; the hydrophobic region of ACTL6A is required for this activity\",\n      \"method\": \"Co-immunoprecipitation, ChIP, luciferase reporter assay, ROS/GSH measurements, knockdown/overexpression\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ChIP, reporter assay, and functional rescue in single lab with multiple orthogonal methods\",\n      \"pmids\": [\"37443154\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ACTL6A overexpression enhances repair of cisplatin-DNA adducts, conferring platinum resistance; this regulation is mediated through the SWI/SNF chromatin remodeling complex, and HDAC inhibitors can reverse the effect of ACTL6A overexpression on DNA damage repair\",\n      \"method\": \"Overexpression/knockdown, cisplatin-DNA adduct repair assays, xenograft mouse model, HDAC inhibitor treatment\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple functional assays (DNA repair, drug sensitivity, in vivo xenograft), pathway placement via SWI/SNF dependence, single lab\",\n      \"pmids\": [\"33408251\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In squamous cell carcinomas (SCCs), increased ACTL6A levels lead to its stoichiometric assembly into BAF complexes; elevated ACTL6A occupancy enhances polycomb opposition genome-wide and facilitates co-dependent loading of BAF and TEAD-YAP complexes on chromatin to activate SCC genes\",\n      \"method\": \"ATAC-seq, ChIP-seq, ectopic expression, CUT&RUN, quantitative proteomics of BAF complex composition\",\n      \"journal\": \"Molecular Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — genome-wide chromatin occupancy, quantitative complex assembly measurements, multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"34687603\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Actl6a interacts with Nanog and Sox2 in mouse ESCs, promotes Nanog binding to pluripotency gene promoters (Oct4, Sox2), and targets promoters of PrE regulators (Sall4, Fgf4) to repress their expression; mutant Actl6a with impaired Tip60/p400 binding fails to block primitive endoderm differentiation, indicating dependence on the Tip60-p400 complex\",\n      \"method\": \"Co-immunoprecipitation, ChIP, RNAi knockdown, ectopic expression, domain-mutant rescue experiments\",\n      \"journal\": \"Stem Cells\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ChIP, mutant rescue experiments with multiple orthogonal methods in single lab\",\n      \"pmids\": [\"25802002\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"BAF53a/ACTL6A is a direct target of miR-206 in rhabdomyosarcoma; sustained BAF53a expression blocks myogenic differentiation, while its silencing promotes differentiation marker expression, reduces proliferation, and impairs anchorage-independent growth and tumor formation\",\n      \"method\": \"miR-206 re-expression, BAF53a silencing (siRNA/shRNA), differentiation assays, in vivo tumor growth\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct miRNA targeting validated, functional KD with defined phenotype, single lab\",\n      \"pmids\": [\"23728344\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Baf53a interacts with Oct3/4 in mouse ES cells; Baf53a-deficient ES cells show increased p53, p21, and cleaved Caspase 3 and undergo cell death; a Baf53a M3 mutant (E388A/R389A/R390A) fails to rescue cell death, and Baf53b can compensate for Baf53a loss in ES cell survival\",\n      \"method\": \"Co-immunoprecipitation, tetracycline-inducible conditional knockout, domain mutagenesis (M3 mutant), rescue by overexpression of Baf53a or Baf53b\",\n      \"journal\": \"Scientific Reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, conditional KO, mutagenesis rescue, single lab\",\n      \"pmids\": [\"29070872\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ACTL6A interacts with and co-localizes with Sox2 and p53 in acute promyelocytic leukemia cells; knockdown of ACTL6A promotes differentiation and decreases Sox2 and Notch1 levels; p53 activator CBL0137 decreases ACTL6A expression and promotes differentiation\",\n      \"method\": \"Co-immunoprecipitation, co-localization assays, siRNA knockdown, pharmacological p53 activation\",\n      \"journal\": \"Cellular Signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP and co-localization with functional KD, single lab, moderate methods\",\n      \"pmids\": [\"30448346\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Mitochondrially produced ATP promotes Actl6a expression and histone acetylation; Actl6a knockdown reduces histone acetylation and pluripotency of ESCs, and this reduction cannot be rescued by exogenous ATP, placing Actl6a downstream of ATP in regulating pluripotency-associated histone acetylation\",\n      \"method\": \"Actl6a knockdown in ESCs, ATP supplementation, rotenone treatment, histone acetylation measurement\",\n      \"journal\": \"FASEB Journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis via ATP supplementation/inhibition rescue experiments with histone acetylation readout, single lab\",\n      \"pmids\": [\"29222327\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"HIF-1α knockdown inhibits Actl6a expression and H3K9 acetylation in hiPSCs; Actl6a knockdown in turn reduces H3K9ac and pluripotency, placing Actl6a downstream of HIF-1α in regulating histone acetylation and pluripotency maintenance\",\n      \"method\": \"shRNA knockdown of HIF-1α and Actl6a, histone acetylation measurement, EB and teratoma formation assays\",\n      \"journal\": \"FASEB Journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis via sequential knockdown, defined molecular readout (H3K9ac), single lab\",\n      \"pmids\": [\"32112486\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Long non-coding RNA uc.291 physically interacts with ACTL6A and modulates chromatin remodeling; upon uc.291 depletion, ACTL6A binds to promoters of differentiation genes and inhibits BAF complex targeting; presence of uc.291 releases the ACTL6A inhibitory effect to allow expression of terminal differentiation genes\",\n      \"method\": \"RNA immunoprecipitation, ChIP, knockdown of uc.291 in primary keratinocytes and 3D skin equivalents\",\n      \"journal\": \"EMBO Reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA-protein interaction (RIP), ChIP showing differential promoter occupancy, defined differentiation phenotype, single lab\",\n      \"pmids\": [\"32017402\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ACTL6A interacts with p53 DNA response elements and Sp1 binding sites in the p21Cip1 gene promoter to suppress p21Cip1 promoter activity, mRNA, and protein levels in epidermal SCC cells; increased p21Cip1 in ACTL6A knockdown cells is required for suppression of the SCC phenotype, and this regulation is p53-independent\",\n      \"method\": \"ChIP, luciferase reporter assay, siRNA knockdown, rescue experiments\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP showing promoter occupancy, reporter assay, p53-independence established, single lab\",\n      \"pmids\": [\"32616890\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ACTL6A suppresses p21Cip1 expression by interacting with Sp1 and p53 binding elements in the p21Cip1 promoter in mesothelioma cells; ACTL6A knockout reduces tumor formation with elevated p21Cip1 in vivo\",\n      \"method\": \"ChIP, luciferase reporter assay, ACTL6A knockout, in vivo tumor formation\",\n      \"journal\": \"Oncogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP, reporter assay, in vivo KO, single lab, corroborates findings in SCC\",\n      \"pmids\": [\"34689163\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ACTL6A knockdown impairs DNA replication initiation in glioblastoma cells by downregulating genes of the CDC45-MCM-GINS (CMG) complex; specifically, ACTL6A transcriptionally regulates MCM5 expression; ACTL6A knockdown also diminishes ATR-Chk1 pathway activity, leading to apoptosis\",\n      \"method\": \"siRNA knockdown, DNA replication assays, gene expression analysis, Western blot for ATR-Chk1 pathway components\",\n      \"journal\": \"Biochemical and Biophysical Research Communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — defined molecular target (MCM5), pathway placement (ATR-Chk1), single lab, single method per claim\",\n      \"pmids\": [\"35182941\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ACTL6A (BAF53A) interacts with p63 in colorectal cancer cells; this interaction decreases DUSP5 expression, leading to increased ERK1/2 phosphorylation and enhanced cancer cell proliferation\",\n      \"method\": \"Co-immunoprecipitation, gene expression analysis, siRNA knockdown, Western blot for ERK1/2 phosphorylation\",\n      \"journal\": \"Cell Death & Disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP showing interaction, functional epistasis placing ACTL6A upstream of DUSP5-ERK, single lab\",\n      \"pmids\": [\"36526622\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ACTL6A interacts with MYC and VPS72; the ACTL6A/VPS72/MYC complex enhances MYC affinity for target gene promoters to promote transcription; ACTL6A also protects VPS72 from TRIM21-mediated ubiquitination and degradation\",\n      \"method\": \"Co-immunoprecipitation, protein co-localization, in vivo ubiquitination assay, ChIP\",\n      \"journal\": \"Hepatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, ChIP for MYC target occupancy, single lab\",\n      \"pmids\": [\"36631007\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"FBXW7 binds ACTL6A and promotes its ubiquitin-dependent degradation; FBXW7 overexpression reduces cancer stem cell-like properties and tumorigenicity of HCC cells, and ACTL6A overexpression reverses these effects, placing ACTL6A as a downstream oncogenic target of FBXW7\",\n      \"method\": \"Co-immunoprecipitation, protein co-localization, in vivo ubiquitination assay, rescue experiments with ACTL6A overexpression\",\n      \"journal\": \"Stem Cells International\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, epistasis rescue, single lab\",\n      \"pmids\": [\"36159747\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In Schwann cells, nuclear levels of ACTL6A are increased by contact with large-caliber axons or nanofibers; ACTL6A is required to evict repressive histone marks and facilitate myelination transcriptional programs; loss of Actl6a in conditional knockout mice causes defective radial sorting, hypo-myelination of large axons, and redundant myelin around small axons\",\n      \"method\": \"Conditional knockout mouse, live imaging, histone mark analysis, nanofiber contact assay\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with defined cellular and motor phenotype, mechanistic histone mark analysis, single lab\",\n      \"pmids\": [\"35434551\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ACTL6A depletion in colorectal cancer enhances KLF4 binding at newly accessible chromatin regions, where KLF4 cooperates with SWI/SNF and INO80 complexes to activate p53 pathway-related genes and induce apoptosis; multi-omics analysis shows ACTL6A deficiency alters chromatin accessibility genome-wide\",\n      \"method\": \"ATAC-seq, ChIP-seq, RNA-seq (multi-omics), ACTL6A knockdown\",\n      \"journal\": \"Cell Death & Disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multi-omics (ATAC-seq, ChIP-seq, RNA-seq), defined mechanism, single lab\",\n      \"pmids\": [\"40877226\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"BAF53A (ACTL6A) collaborates with BACH1 to transcriptionally activate GCLM (glutamate-cysteine ligase modifier subunit) in esophageal squamous cell carcinoma; this BAF53A-BACH1-GCLM axis maintains glutathione metabolism and ferroptosis resistance; GCLM overexpression rescues redox balance in BAF53A- or BACH1-silenced cells\",\n      \"method\": \"Co-immunoprecipitation, ChIP-seq, shRNA knockdown, rescue by GCLM overexpression, GSH/GSSG and ROS measurement\",\n      \"journal\": \"PeerJ\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ChIP-seq, functional rescue, single lab\",\n      \"pmids\": [\"41059410\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"BAP18 recruits ACTL6A and PAF1 to Wnt target gene promoters, enhancing β-catenin-mediated transcription in NSCLC; co-immunoprecipitation confirmed the BAP18-ACTL6A-PAF1 interaction\",\n      \"method\": \"Co-immunoprecipitation, luciferase reporter assay, RNA-seq, knockdown experiments\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP for complex formation, reporter assay for transcriptional activity, single lab\",\n      \"pmids\": [\"40818609\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Loss of Actl6a in zebrafish leads to cilia disassembly and cystic kidney by downregulating master ciliogenesis regulators foxj1a and rfx2 at the transcriptional, chromatin accessibility, and SWI/SNF binding levels; overexpression of foxj1a or rfx2 mRNA partially rescues the cystic kidney and cilia disassembly phenotypes in actl6a mutants\",\n      \"method\": \"Zebrafish genetic knockout, ATAC-seq, ChIP-seq, mRNA rescue experiments, omics analyses\",\n      \"journal\": \"bioRxiv (preprint)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis via mRNA rescue, chromatin accessibility and SWI/SNF occupancy data, defined phenotype in zebrafish, preprint not peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.06.10.658863\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ACTL6A positively regulates PGK1 expression in ovarian cancer; enforced ACTL6A expression increases PGK1 while knockdown decreases it; ACTL6A regulates FSH-enhanced glycolysis via PI3K/AKT pathway signaling upstream of ACTL6A\",\n      \"method\": \"Overexpression/knockdown, in vivo xenograft, qRT-PCR/Western blot, correlation in patient tissues\",\n      \"journal\": \"Cell Death & Disease\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, no direct ChIP/binding assay for PGK1 regulation, mechanism inferred from expression changes\",\n      \"pmids\": [\"31649264\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ACTL6A knockdown in HNSCC reduces aerobic glycolysis (Warburg effect) and blunts HIF1α/HIF2α protein induction under hypoxia; ACTL6A mediates chromatin accessibility at AP-1 transcription factor sites and regulates upstream MAPK signaling through induction of Ras and Galectin-1\",\n      \"method\": \"ATAC-seq, Seahorse metabolic assay, shRNA knockdown, in vivo IACS-010759 treatment, Western blot\",\n      \"journal\": \"bioRxiv (preprint)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 2 / Weak — ATAC-seq and metabolic assays, preprint not peer-reviewed, single lab\",\n      \"pmids\": [\"40950224\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Actl6a interacts with Sox2 in spinal cord neurons and collaboratively upregulates Atg5 and Atg7 expression to promote autophagy; Fto demethylase modulates Actl6a mRNA stability via m6A demethylation, placing Fto upstream of Actl6a in this pathway\",\n      \"method\": \"Co-immunoprecipitation, RNA immunoprecipitation (RIP), m6A dot blot, overexpression/knockdown, rat SCI model with AAV delivery\",\n      \"journal\": \"Journal of Advanced Research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-IP and RIP for interactions, in vivo AAV rescue, single lab, mechanism only partially validated\",\n      \"pmids\": [\"39875055\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ACTL6A (BAF53a) is an actin-related protein subunit shared by multiple chromatin remodeling complexes (SWI/SNF/BAF, INO80, and Tip60-p400/NuA4) that controls gene expression by modulating complex occupancy at target promoters: in progenitor and stem cells it prevents SWI/SNF binding to differentiation gene promoters (e.g., KLF4) to maintain the progenitor state, while in cancer contexts its stoichiometric overassembly into BAF complexes drives oncogenic gene programs by opposing Polycomb repression and co-engaging TEAD-YAP; it also acts as a co-transcription factor with NRF2 or BACH1 to activate glutathione biosynthesis genes (GCLC, GCLM) and thereby suppress ferroptosis, interacts with MYC and VPS72 to enhance MYC transcriptional activity, suppresses p21Cip1 by occupying its promoter, promotes cisplatin-DNA adduct repair through SWI/SNF, and is itself subject to ubiquitin-dependent degradation by FBXW7.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ACTL6A (BAF53a) is an actin-related subunit of ATP-dependent chromatin remodeling complexes (SWI/SNF/BAF, INO80, and Tip60-p400) that controls cell fate by modulating which genes these complexes can access, acting both to maintain progenitor/stem states and, when overexpressed, to drive oncogenic transcription [#0, #4]. In progenitor and stem cells it restrains differentiation: it blocks SWI/SNF binding to differentiation-gene promoters such as KLF4 in epidermal progenitors [#0], is an essential, cell-autonomous requirement for hematopoietic stem cell function [#1], and cooperates with pluripotency factors Nanog, Sox2, and Oct3/4 through a Tip60-p400-dependent activity to sustain the undifferentiated state and cell survival [#5, #7]. In cancer, increased ACTL6A is stoichiometrically incorporated into BAF complexes, where it enhances genome-wide opposition to Polycomb repression and enables co-dependent loading of BAF and TEAD-YAP complexes to activate squamous-cell-carcinoma gene programs [#4]; it also suppresses the cell-cycle inhibitor p21Cip1 in a p53-independent manner by occupying Sp1 and p53 response elements in its promoter [#12, #13]. ACTL6A additionally functions as a co-activator of redox and growth programs—partnering with NRF2 and BACH1 to drive glutathione-biosynthesis genes (GCLC, GCLM) and thereby suppress ferroptosis [#2, #20], interacting with MYC and VPS72 to enhance MYC target promoter binding [#16], and promoting cisplatin-DNA adduct repair via SWI/SNF [#3]—and is itself targeted for ubiquitin-dependent degradation by FBXW7 [#17]. Loss-of-function studies across glioblastoma, Schwann cells, and zebrafish further implicate ACTL6A in DNA replication initiation, myelination transcriptional programs, and ciliogenesis, in each case through chromatin-level control of lineage regulators [#14, #18, #22].\",\n  \"teleology\": [\n    {\n      \"year\": 2012,\n      \"claim\": \"Established that ACTL6A is not merely a passive structural subunit but is functionally essential for an adult stem cell compartment in vivo, answering whether its BAF-complex role has organism-level consequences.\",\n      \"evidence\": \"Conditional knockout mouse with hematopoietic chimeras and bone marrow transplantation\",\n      \"pmids\": [\"23018638\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve which specific target genes mediate HSC failure\", \"Did not separate BAF-specific from INO80/Tip60 contributions\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined a mechanistic model in which ACTL6A actively gates SWI/SNF access to differentiation promoters, explaining how it maintains progenitor identity rather than simply enabling remodeling.\",\n      \"evidence\": \"Conditional knockout, ChIP, and ectopic expression in epidermal progenitors\",\n      \"pmids\": [\"23395444\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish how ACTL6A is itself regulated to release this block during normal differentiation\", \"Targets beyond KLF4 only partially mapped\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Connected ACTL6A to the pluripotency transcription factor network and assigned the activity to a specific complex, showing it works through Tip60-p400 rather than BAF alone in ESCs.\",\n      \"evidence\": \"Co-IP, ChIP, RNAi, and Tip60/p400-binding domain-mutant rescue in mouse ESCs\",\n      \"pmids\": [\"25802002\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not quantify partitioning of ACTL6A among BAF, INO80, and Tip60-p400 in ESCs\", \"Direct versus indirect promoter effects not fully separated\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Placed ACTL6A downstream of cellular energy and oxygen sensing, linking metabolic state to chromatin acetylation and pluripotency.\",\n      \"evidence\": \"Knockdown with ATP supplementation/rotenone (PMID 29222327) and sequential HIF-1α/Actl6a knockdown with H3K9ac readout (PMID 32112486) in ESCs/hiPSCs\",\n      \"pmids\": [\"29222327\", \"32112486\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking ATP/HIF-1α to ACTL6A expression not defined\", \"Whether ACTL6A directly enables acetyltransferase activity not shown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Provided the quantitative basis for ACTL6A oncogenicity by showing dose-dependent stoichiometric assembly into BAF complexes drives Polycomb opposition and co-recruits TEAD-YAP, distinguishing tumor from normal function.\",\n      \"evidence\": \"ATAC-seq, ChIP-seq, CUT&RUN, and quantitative proteomics of BAF composition in SCCs\",\n      \"pmids\": [\"34687603\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of co-dependent BAF/TEAD-YAP loading not structurally resolved\", \"Did not address whether the same applies outside squamous lineages\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified p21Cip1 suppression as a concrete, p53-independent route by which ACTL6A enforces a proliferative cancer phenotype, naming the promoter elements engaged.\",\n      \"evidence\": \"ChIP, luciferase reporter, knockdown/rescue in SCC (PMID 32616890) and knockout with in vivo tumor assay in mesothelioma (PMID 34689163)\",\n      \"pmids\": [\"32616890\", \"34689163\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How ACTL6A is recruited to Sp1/p53 elements not defined\", \"Whether repression is BAF-dependent not directly tested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Extended ACTL6A function from transcription into the DNA damage response, showing it promotes platinum-adduct repair through SWI/SNF and underlies chemoresistance.\",\n      \"evidence\": \"Overexpression/knockdown, cisplatin-DNA adduct repair assays, xenografts, and HDAC inhibitor reversal\",\n      \"pmids\": [\"33408251\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct repair-factor recruitment by ACTL6A not demonstrated\", \"Link between HDAC inhibition reversal and chromatin state mechanistic only\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Revealed a non-canonical co-transcription-factor role in redox metabolism, with ACTL6A partnering NRF2 to drive glutathione synthesis and suppress ferroptosis.\",\n      \"evidence\": \"Co-IP, ChIP, luciferase reporter, and ROS/GSH measurements in gastric cancer; hydrophobic-region requirement mapped\",\n      \"pmids\": [\"37443154\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether this depends on a remodeling complex or is complex-independent unclear\", \"Direct GCLC promoter binding by ACTL6A versus via NRF2 not separated\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined ACTL6A as a co-activator that boosts MYC transcriptional output and stabilizes its partner VPS72 against degradation, broadening its oncogenic interactome beyond chromatin remodeling subunits.\",\n      \"evidence\": \"Co-IP, co-localization, ChIP for MYC occupancy, and in vivo ubiquitination assay in HCC\",\n      \"pmids\": [\"36631007\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Stoichiometry and structure of the ACTL6A/VPS72/MYC complex unknown\", \"Single-lab evidence without reciprocal validation\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Positioned ACTL6A within a degradative regulatory loop, identifying FBXW7 as the E3 ligase that limits ACTL6A levels and thereby its cancer-stem-cell-promoting activity.\",\n      \"evidence\": \"Co-IP, in vivo ubiquitination assay, and ACTL6A-overexpression rescue in HCC cells\",\n      \"pmids\": [\"36159747\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Degron site on ACTL6A not mapped\", \"Whether FBXW7 regulation is signal-responsive not addressed\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrated tissue-specific requirements for ACTL6A in differentiated cell programs, showing it evicts repressive histone marks to license myelination and that loss of ACTL6A independently impairs DNA replication initiation.\",\n      \"evidence\": \"Conditional KO with histone mark analysis in Schwann cells (PMID 35434551) and knockdown with replication and ATR-Chk1 assays in glioblastoma (PMID 35182941)\",\n      \"pmids\": [\"35434551\", \"35182941\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Which complex mediates myelination versus replication roles not resolved\", \"Direct versus indirect regulation of MCM5/CMG genes not fully established\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Resolved the chromatin logic of ACTL6A loss in cancer, showing depletion opens new accessible regions where KLF4 recruits SWI/SNF and INO80 to activate p53-pathway apoptotic genes, mirroring the progenitor-state model in a tumor context.\",\n      \"evidence\": \"Multi-omics (ATAC-seq, ChIP-seq, RNA-seq) with knockdown in colorectal cancer\",\n      \"pmids\": [\"40877226\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which ACTL6A normally occludes these regions not defined\", \"Generalizability across tumor types untested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Expanded the co-activator repertoire to additional transcription factors and pathways, linking ACTL6A to BACH1-driven glutathione metabolism, BAP18/PAF1-Wnt/β-catenin signaling, and ciliogenesis master regulators.\",\n      \"evidence\": \"Co-IP/ChIP-seq with GCLM rescue in ESCC (PMID 41059410), Co-IP/reporter in NSCLC (PMID 40818609), and zebrafish KO with mRNA rescue (PMID bio_10.1101_2025.06.10.658863, preprint)\",\n      \"pmids\": [\"41059410\", \"40818609\", \"bio_10.1101_2025.06.10.658863\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether these reflect distinct complexes or a shared mechanism unclear\", \"Direct binding versus recruitment by partners not always separated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how ACTL6A is partitioned among its distinct complexes (BAF, INO80, Tip60-p400) and how this partitioning is set by cell state to switch between maintaining progenitor identity and driving the diverse oncogenic and metabolic programs attributed to it.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of ACTL6A within each complex in the corpus\", \"No unified determinant of complex choice identified\", \"Direct DNA/histone-binding contribution of ACTL6A itself not defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [2, 12, 16, 20]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 4, 5]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [12, 13]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 5, 18]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [4, 11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [0, 4, 11, 19]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [2, 12, 16, 20]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [1, 5, 18]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"R-HSA-69306\", \"supporting_discovery_ids\": [14]}\n    ],\n    \"complexes\": [\"SWI/SNF (BAF)\", \"INO80\", \"Tip60-p400 (NuA4)\"],\n    \"partners\": [\"NANOG\", \"SOX2\", \"POU5F1\", \"MYC\", \"VPS72\", \"FBXW7\", \"NFE2L2\", \"BACH1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}