{"gene":"KDM1A","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":2004,"finding":"LSD1/KDM1A functions as a histone demethylase that specifically demethylates histone H3 lysine 4 (H3K4me1/2) via a FAD-dependent oxidation reaction that generates formaldehyde; RNAi inhibition of LSD1 causes increased H3K4 methylation and derepression of target genes, establishing LSD1 as a transcriptional corepressor.","method":"In vitro demethylase assay, RNAi knockdown, formaldehyde detection","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro enzymatic reconstitution with product identification (formaldehyde), validated by RNAi in cells, foundational paper replicated extensively","pmids":["15620353"],"is_preprint":false},{"year":2005,"finding":"LSD1/KDM1A interacts with the androgen receptor (AR) in vitro and in vivo, and in the context of AR-dependent transcription demethylates histone H3 at lysine 9 (H3K9me1/2) to relieve repressive marks and activate AR target genes; pargyline inhibits this H3K9 demethylation activity.","method":"Co-immunoprecipitation, chromatin immunoprecipitation (ChIP), in vitro binding, siRNA knockdown, reporter assays","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, ChIP, functional rescue, replicated in multiple subsequent studies","pmids":["16079795"],"is_preprint":false},{"year":2008,"finding":"LSD1/KDM1A demethylates and stabilizes DNMT1 protein in vitro and in vivo; Set7/9 methylates DNMT1 and LSD1 reverses this methylation, thereby preventing DNMT1 proteasomal degradation and maintaining global DNA methylation levels.","method":"In vitro demethylation assay, Co-IP, conditional knockout in mouse ES cells, western blot for DNMT1 stability","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro biochemical reconstitution (methylation/demethylation), genetic KO in ES cells, multiple orthogonal methods","pmids":["19098913"],"is_preprint":false},{"year":2010,"finding":"Alternative splicing of LSD1/KDM1A generates neuro-specific isoforms (containing exon E8a) that show reduced repressor activity on reporter genes compared to ubiquitous isoforms; knockdown of neuro-specific variants inhibits neurite maturation while knockdown of ubiquitous isoforms has no morphogenic effect, indicating isoform-specific functions.","method":"Reporter gene assay, siRNA knockdown, immunofluorescence, morphometric analysis of neurite outgrowth","journal":"The Journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional reporter assay plus cellular KD phenotype, single lab, two methods","pmids":["20164337"],"is_preprint":false},{"year":2010,"finding":"LSD1/KDM1A binds CoREST with high affinity (Kd ~16 nM) in a 1:1 stoichiometry; the central binding determinant is the CoREST linker region (residues 293–380) that contacts the LSD1 tower domain in a triple-helical bundle, an interaction required for demethylation of nucleosomal substrates.","method":"Isothermal titration calorimetry (ITC), structure-driven truncation analysis","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — rigorous thermodynamic measurements with defined stoichiometry and truncation mapping, single lab but quantitative","pmids":["21142040"],"is_preprint":false},{"year":2011,"finding":"LSD1/KDM1A represses endogenous retroviral elements (MERVL) and adjacent genes in mouse embryos and ES cells; loss of KDM1A leads to increased H3K4 methylation, increased H3K27 acetylation, and decreased H3K9 methylation at MERVL elements and flanking ZGA genes, causing embryonic arrest at gastrulation.","method":"Mouse genetic knockout, genome-wide epigenetic profiling (ChIP-seq), ES cell analysis","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with defined molecular phenotype, genome-wide ChIP-seq, multiple orthogonal methods","pmids":["21357675"],"is_preprint":false},{"year":2011,"finding":"LSD1/KDM1A demethylates HIV Tat at K51 (monomethylation), acting as a Tat-specific demethylase; LSD1 and its cofactor CoREST associate with the HIV promoter in vivo, and this demethylation is required for subsequent K50 acetylation and full activation of HIV transcription in latently infected T cells.","method":"Mass spectrometry on immunoprecipitated Tat, modification-specific antibodies, ChIP, shRNA knockdown, monoamine oxidase inhibitor treatment","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 1 / Moderate — mass spectrometry identification of modification, ChIP, RNAi, chemical inhibition; multiple orthogonal methods in single study","pmids":["21876670"],"is_preprint":false},{"year":2013,"finding":"LSD1/KDM1A is recruited directly to DNA damage sites in an RNF168-dependent manner; LSD1 demethylates H3K4me2 at damage sites, and its loss reduces histone ubiquitylation in late S/G2, impairs 53BP1 and BRCA1 complex recruitment, increases homologous recombination, and causes hypersensitivity to γ-irradiation.","method":"Live cell imaging to DNA damage sites, Co-IP (LSD1–RNF168), ChIP, siRNA knockdown, γ-H2AX foci, HR reporter assay","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct recruitment imaging, Co-IP, ChIP, functional HR reporter, multiple complementary methods","pmids":["24217620"],"is_preprint":false},{"year":2015,"finding":"The LSD1+8a neuro-specific isoform cannot intrinsically demethylate H3K4me2; instead it mediates H3K9me2 demethylation in collaboration with supervillin (SVIL), a newly identified LSD1+8a interacting protein; SVIL co-localizes at LSD1+8a-bound promoters, and SVIL knockdown mimics LSD1+8a loss (increased H3K9me2, impaired neuronal differentiation).","method":"In vitro demethylase assay, Co-IP, ChIP-seq, siRNA knockdown, histone mass spectrometry","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro enzymatic assay distinguishing substrate specificity, Co-IP, ChIP, parallel KD phenotypes; multiple orthogonal methods","pmids":["25684206"],"is_preprint":false},{"year":2015,"finding":"LSD1/KDM1A promotes hematopoietic commitment of hemangioblasts in zebrafish by suppressing expression of Etv2, an endothelial regulator; knockdown of Etv2 rescues hematopoietic defects in lsd1 mutant embryos, placing LSD1 upstream of Etv2 in the hematopoietic fate decision.","method":"Zebrafish genetic mutant, morpholino knockdown epistasis rescue, in situ hybridization","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis rescue in vivo (zebrafish), single lab","pmids":["26512114"],"is_preprint":false},{"year":2016,"finding":"EHMT2 dimethylates KDM1A at K114 (K114me2), and CHD1 is a reader of this mark; co-crystal structure of the KDM1A K114me2 peptide–CHD1 complex was solved; genome-wide analyses show chromatin colocalization of KDM1A K114me2, CHD1, and AR in prostate tumor cells, linking this modification to androgen-dependent transcription and TMPRSS2-ERG gene fusion.","method":"Mass spectrometry, Co-crystal structure (X-ray crystallography), ChIP-seq, Co-IP","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure, mass spectrometry validation of methylation, ChIP-seq genome-wide, Co-IP; multiple orthogonal methods in single rigorous study","pmids":["26751641"],"is_preprint":false},{"year":2016,"finding":"KDM1A-mediated H3K4me2 demethylation at the MyoD core enhancer is required for RNA Pol II recruitment and transcription of the non-coding enhancer RNA (CEeRNA) that drives MyoD expression; conditional LSD1 inactivation in muscle progenitors delays MyoD expression in embryonic limb buds.","method":"ChIP, siRNA knockdown in myoblasts, conditional mouse knockout, reporter assays for enhancer RNA","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP, genetic KO, functional readout of enhancer RNA; single lab, two orthogonal methods","pmids":["28228264"],"is_preprint":false},{"year":2016,"finding":"In adult mice, inducible deletion of LSD1/KDM1A leads to paralysis and widespread hippocampal and cortical neurodegeneration with learning/memory defects; loss of LSD1 induces transcription of stem cell genes and neurodegeneration-associated pathways, and LSD1 is mislocalized to pathological protein aggregates in Alzheimer's disease and frontotemporal dementia brain tissue.","method":"Inducible conditional knockout, behavioral testing, immunofluorescence, RNA-seq, brain tissue staining from AD/FTD cases","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — inducible genetic KO with defined neurodegeneration phenotype, RNA-seq, single lab","pmids":["28993646"],"is_preprint":false},{"year":2016,"finding":"Maternally provided LSD1/KDM1A in the oocyte is required for the maternal-to-zygotic transition in mice; loss of maternal LSD1 causes embryonic arrest at the 1–2 cell stage; partial maternal loss results in altered DNA methylation and expression at imprinted genes and perinatal/behavioral phenotypes.","method":"Conditional oocyte-specific knockout in mice, bisulfite sequencing, RNA-seq, behavioral assays","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with defined stage-specific phenotype, bisulfite sequencing, single lab","pmids":["26814574"],"is_preprint":false},{"year":2017,"finding":"LSD1/KDM1A physically associates with GFI1 in medulloblastoma cells; GFI1 proteins engineered to be unable to recruit LSD1 cannot drive tumorigenesis; genetic ablation of LSD1 impairs tumor growth in vivo, demonstrating that the GFI1–LSD1 interaction is required for GFI1-mediated transformation and repression of neuronal differentiation genes.","method":"Co-immunoprecipitation, structure-guided mutagenesis of GFI1-LSD1 interface, mouse genetic ablation, in vivo tumor models","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP, mutagenesis abolishing interaction, in vivo genetic ablation; multiple orthogonal methods","pmids":["30659187"],"is_preprint":false},{"year":2018,"finding":"LSD1 ablation in cancer cells increases endogenous retroviral element (ERV) expression and decreases RISC components, leading to dsRNA accumulation, type I interferon activation, and enhanced anti-tumor T cell immunity; this mechanism underlies sensitization to anti-PD-1 checkpoint blockade.","method":"Genetic ablation (CRISPR/shRNA), RNA-seq, flow cytometry for immune infiltration, in vivo tumor models with checkpoint blockade","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO, RNA-seq, in vivo immune and tumor models; multiple orthogonal methods","pmids":["29937226"],"is_preprint":false},{"year":2018,"finding":"Glucocorticoid signaling induces expression of the ubiquitin E3 ligase JADE-2, which mediates proteasomal degradation of LSD1/KDM1A; loss of LSD1 activity during myogenic differentiation de-represses oxidative metabolism genes accompanied by increased H3K4 methylation at those loci, revealing a glucocorticoid–LSD1–metabolism axis.","method":"Western blot (proteasome inhibitors, JADE-2 siRNA), ChIP-seq, RNA-seq, metabolic assays","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic link between JADE-2 and LSD1 degradation via siRNA, ChIP-seq; single lab","pmids":["29618057"],"is_preprint":false},{"year":2019,"finding":"KDM1A inhibition in DIPG cells increases H3K27me3 levels at differentiation genes and simultaneously increases H3K27ac and H3K4me1, driving therapeutic differentiation; a CRISPR screen identified KDM1A knockout as sensitizing DIPG cells to HDAC inhibitors.","method":"CRISPR screen, ChIP-seq, western blot for histone marks, cell death/differentiation assays, xenograft models","journal":"Cancer cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR screen and ChIP-seq; single lab, mechanistic pathway placement","pmids":["31631026"],"is_preprint":false},{"year":2019,"finding":"KDM1A binds GR as an integral complex component; in cell-free assays GR modulates KDM1A-catalyzed H3K4 progressive demethylation by limiting removal to H3K4me2 while leaving H3K4me1; in cells KDM1A removes H3K4me2 at GR binding sites, and blocking KDM1A catalysis prevents GR chromatin binding and dysregulates GR target genes.","method":"Biochemical purification of nuclear GR complex, cell-free demethylation assay, ChIP-seq, pharmacological inhibition","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstituted demethylase assay plus ChIP-seq; multiple orthogonal methods, single lab","pmids":["31216473"],"is_preprint":false},{"year":2020,"finding":"LSD1 inhibition in Merkel cell carcinoma disrupts the LSD1–CoREST complex leading to displacement and proteasomal degradation of HMG20B/BRAF35, a complex member essential for MCC proliferation; this is accompanied by derepression of neuronal lineage transcription factors.","method":"Pharmacological inhibition, Co-IP, western blot for HMG20B degradation, proteasome inhibitor rescue, RNA-seq","journal":"EMBO molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, degradation rescued by proteasome inhibitor, RNA-seq; single lab, two orthogonal methods","pmids":["33026191"],"is_preprint":false},{"year":2021,"finding":"KDM1A maintains genome-wide optimal enhancer activity in mouse ESCs and postmitotic neurons by counterbalancing H3K4 methylation; KDM1A loss leads to increased H3K4 methylation, increased H3K27 acetylation, and elevated eRNA and target gene expression at KDM1A-occupied enhancers.","method":"Conditional/inducible KO in mESCs and neurons, ChIP-seq (H3K4me1/2, H3K27ac), eRNA measurement, RNA-seq","journal":"Genome research","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO in two cell types, genome-wide ChIP-seq, eRNA assay; multiple orthogonal methods","pmids":["33414108"],"is_preprint":false},{"year":2022,"finding":"KDM1A interacts with and demethylates the cytoplasmic non-histone substrate FKBP8; FKBP8 demethylation enhances its ability to stabilize BCL2, promoting liver cancer cell survival; cytoplasmic KDM1A localization and stability is promoted by KAT8-mediated acetylation at lysine-117.","method":"Co-IP, in vitro demethylation assay, western blot, KAT8 overexpression/knockdown, xenograft tumor models","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and in vitro demethylation assay; single lab, two orthogonal methods","pmids":["35970393"],"is_preprint":false},{"year":2022,"finding":"LSD1/KDM1A interacts with the DNA replication machinery and is required for euchromatic origin firing; LSD1 loss causes a genome-wide switch from early to late replication; mechanistically, LSD1 facilitates loading of TICRR onto pre-replication complexes and subsequent CDC45 recruitment during origin firing.","method":"Co-IP with replication factors, DNA fiber assay, ChIP-seq, siRNA/KO, origin firing assays","journal":"Signal transduction and targeted therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, DNA fiber assay, ChIP-seq; single lab, mechanistic pathway placement","pmids":["35414135"],"is_preprint":false},{"year":2023,"finding":"Catalytic inactivation of LSD1 has only mild effects on gene expression and cellular differentiation, whereas complete loss of LSD1 protein de-represses enhancers globally by increasing H3K27ac via P300/CBP; it is the gain of P300/CBP-catalyzed H3K27ac, not loss of CoREST complex from chromatin, that drives transcription derepression and differentiation defects.","method":"CRISPR catalytic-dead knockin vs. knockout, ChIP-seq (H3K27ac, P300), RNA-seq, differentiation assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — isogenic catalytic-dead knockin vs KO dissects catalytic vs scaffolding role; genome-wide ChIP-seq and RNA-seq; multiple orthogonal methods","pmids":["37607921"],"is_preprint":false},{"year":2024,"finding":"The LSD1 Y391K mutant is insensitive to H3K14 acetylation-mediated inhibition of H3K4 demethylase activity; K562 cells with Y391K CRISPR knockin show decreased expression of genes associated with cellular adhesion and myeloid leukocyte activation, and these genes display higher H3K14ac and lower H3K4me1, demonstrating functional crosstalk between H3K14ac and H3K4 demethylation by LSD1.","method":"CRISPR knockin of engineered mutant (Y391K), ChIP-seq, RNA-seq, in vitro demethylase assay","journal":"Nature chemical biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — engineered mutant validated by in vitro assay, CRISPR knockin in cells, ChIP-seq and RNA-seq; rigorous multi-method single study","pmids":["38965385"],"is_preprint":false},{"year":2024,"finding":"LSD1 controls DNA methylation in mouse ESCs via a scaffolding (demethylase-independent) mechanism: LSD1 and catalytically-impaired LSD1 both stabilize UHRF1 and DNMT1 by interacting with HDAC1 and USP7, facilitating deacetylation and deubiquitination of DNMT1/UHRF1; loss of LSD1 (but not catalytic mutant) reduces DNMT1/UHRF1 levels and causes global hypomethylation.","method":"Conditional KO, catalytically-impaired knockin (LSD1MUT), Co-IP with HDAC1/USP7, bisulfite sequencing, western blot","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — isogenic catalytic-dead knockin distinguishes scaffolding from enzymatic function, biochemical Co-IP, bisulfite sequencing; multiple orthogonal methods","pmids":["39237615"],"is_preprint":false},{"year":2024,"finding":"ZNF750 recruits KDM1A/LSD1 to silence pattern recognition receptor genes (TLR3, IFIH1/MDA5, DDX58/RIG1) in differentiated keratinocytes; loss of ZNF750 or KDM1A results in sustained PRR expression and excessive skin inflammation resembling psoriasis that can be restored by TLR3 silencing.","method":"Conditional KO in mice, ChIP (ZNF750/KDM1A co-occupancy), siRNA knockdown, inflammatory phenotype assays","journal":"Immunity","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-occupancy ChIP, genetic KO with defined inflammatory phenotype, epistasis rescue; single lab","pmids":["39353440"],"is_preprint":false},{"year":2025,"finding":"In BRAFi/MEKi-resistant melanoma, re-accumulated lactate induces lactylation of LSD1; lactylated LSD1 interacts with FosL1, preventing LSD1 degradation by E3 ligase TRIM21 and enhancing genomic enrichment of LSD1; lactylated LSD1-FosL1 co-directs transcription to repress ferroptosis by interfering with TFRC-mediated iron uptake.","method":"Mass spectrometry identification of LSD1 lactylation, Co-IP (LSD1–FosL1, LSD1–TRIM21), ChIP-seq, cell viability assays, murine drug-resistant tumor models","journal":"Developmental cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mass spectrometry, Co-IP, ChIP-seq; single lab, mechanistic pathway placement","pmids":["40132584"],"is_preprint":false}],"current_model":"KDM1A/LSD1 is a FAD-dependent amine oxidase that demethylates mono- and di-methylated H3K4 (repressing transcription) or H3K9 (activating transcription), depending on context and binding partners; it operates in multiprotein complexes (e.g., CoREST-HDAC, AR, GR, NuRD, GFI1) that direct its substrate specificity, and additionally exerts demethylase-independent scaffolding functions—stabilizing DNMT1/UHRF1 via HDAC1/USP7 and blocking P300-driven enhancer acetylation—while also demethylating non-histone substrates (DNMT1, FKBP8, HIV Tat K51) and being regulated post-translationally by EHMT2-mediated K114 methylation, KAT8-mediated K117 acetylation, lactylation, and JADE-2-mediated proteasomal degradation, collectively making it a multifunctional epigenetic regulator of development, differentiation, DNA replication, DNA damage response, and immunity."},"narrative":{"mechanistic_narrative":"KDM1A/LSD1 is a FAD-dependent histone demethylase that serves as a central, context-dependent epigenetic regulator of transcription, development, and genome maintenance [PMID:15620353]. Its canonical activity removes mono- and di-methyl marks from histone H3 lysine 4 (H3K4me1/2), generating formaldehyde and repressing target genes, while in association with the androgen receptor it instead demethylates H3K9me1/2 to activate transcription, illustrating that bound partners redirect its substrate specificity [PMID:15620353, PMID:16079795]. Substrate choice and activity are governed by an extensive interaction network: high-affinity binding to CoREST through the LSD1 tower domain enables nucleosomal demethylation [PMID:21142040], while assembly with the glucocorticoid receptor restrains processivity to leave H3K4me1 and licenses receptor chromatin binding [PMID:31216473], and recruitment by sequence-specific factors such as GFI1, ZNF750, and FosL1 directs repression of differentiation, immune, and ferroptosis programs [PMID:30659187, PMID:39353440, PMID:40132584]. Genome-wide, KDM1A counterbalances H3K4 methylation at enhancers to keep enhancer activity and eRNA output in check [PMID:33414108], and isogenic catalytic-dead versus null comparisons show that much of its enhancer control is demethylase-independent—loss of the protein, not loss of catalysis, drives P300/CBP-mediated H3K27 acetylation and derepression [PMID:37607921]. This scaffolding role extends to DNA methylation maintenance, where KDM1A stabilizes DNMT1 and UHRF1 by engaging HDAC1 and USP7, independent of its enzymatic function [PMID:19098913, PMID:39237615]. Beyond chromatin, KDM1A demethylates non-histone substrates including DNMT1, HIV Tat at K51, and cytoplasmic FKBP8, and it participates directly in DNA replication origin firing and the RNF168-dependent DNA damage response [PMID:19098913, PMID:21876670, PMID:35970393, PMID:35414135, PMID:24217620]. It is regulated post-translationally by EHMT2-mediated K114 methylation read by CHD1, KAT8-mediated K117 acetylation, lactylation, and JADE-2– and TRIM21–directed proteasomal degradation [PMID:26751641, PMID:35970393, PMID:40132584, PMID:29618057]. Through these activities KDM1A governs embryonic and maternal-to-zygotic transitions, hematopoietic and myogenic differentiation, neuronal maturation, retroelement silencing with antitumor immunity, and serves as a therapeutic target across several cancers [PMID:21357675, PMID:26814574, PMID:26512114, PMID:28228264, PMID:25684206, PMID:29937226].","teleology":[{"year":2004,"claim":"Established that an amine-oxidase enzyme could remove methyl marks from histones, defining LSD1 as the first histone demethylase and a transcriptional corepressor.","evidence":"In vitro FAD-dependent demethylase assay with formaldehyde detection plus RNAi derepression of targets","pmids":["15620353"],"confidence":"High","gaps":["Did not define how substrate specificity is directed in vivo","Cofactor and complex requirements for nucleosomal substrates unresolved"]},{"year":2005,"claim":"Showed that partner binding can switch LSD1's substrate from H3K4 to H3K9, converting it from a repressor to a coactivator in androgen receptor signaling.","evidence":"Co-IP, ChIP, in vitro binding, siRNA and reporter assays with AR; pargyline inhibition","pmids":["16079795"],"confidence":"High","gaps":["Structural basis for the H3K4-to-H3K9 specificity switch not defined","Whether other nuclear receptors use the same mechanism unknown at the time"]},{"year":2008,"claim":"Extended LSD1 activity beyond histones, showing it demethylates and stabilizes DNMT1 to maintain global DNA methylation.","evidence":"In vitro demethylation assay, Co-IP, conditional KO in mouse ES cells, DNMT1 stability western blot","pmids":["19098913"],"confidence":"High","gaps":["Did not separate enzymatic from scaffolding contributions to DNMT1 stability","Other non-histone substrates not yet surveyed"]},{"year":2010,"claim":"Defined the molecular architecture of LSD1-CoREST binding and identified tissue-specific isoforms with distinct activities, beginning to explain context-dependent function.","evidence":"ITC and truncation mapping of CoREST linker-tower interaction; reporter and siRNA analysis of neuro-specific exon E8a isoforms","pmids":["21142040","20164337"],"confidence":"High","gaps":["Isoform substrate specificity mechanism not yet resolved","How CoREST binding alters catalysis on nucleosomes not fully defined"]},{"year":2011,"claim":"Demonstrated LSD1's developmental requirement for retroelement and zygotic-gene silencing and its role in demethylating a viral non-histone substrate.","evidence":"Mouse KO with ChIP-seq at MERVL/ZGA loci; mass spectrometry of Tat K51 with ChIP and chemical inhibition","pmids":["21357675","21876670"],"confidence":"High","gaps":["Recruitment machinery to retroelements not fully mapped","Generality of non-histone demethylation across substrates unknown"]},{"year":2013,"claim":"Placed LSD1 in the DNA damage response, showing damage-site recruitment and a role in repair pathway choice.","evidence":"Live-cell imaging of recruitment, RNF168 Co-IP, ChIP, HR reporter and γ-irradiation sensitivity","pmids":["24217620"],"confidence":"High","gaps":["Direct catalytic substrate at damage sites versus scaffolding role not separated","Link between H3K4me2 removal and ubiquitylation mechanistically incomplete"]},{"year":2015,"claim":"Resolved how a non-catalytic isoform achieves a distinct activity through a new partner and placed LSD1 in a hematopoietic fate decision.","evidence":"In vitro demethylase assays, Co-IP, ChIP-seq of LSD1+8a with SVIL; zebrafish epistasis rescue with Etv2","pmids":["25684206","26512114"],"confidence":"High","gaps":["Structural basis of SVIL-conferred H3K9 activity unresolved","Mammalian relevance of the Etv2 axis not established in this work"]},{"year":2016,"claim":"Uncovered post-translational regulation of LSD1 by methylation (with a reader) and degradation, and broadened its roles to myogenesis, neurodegeneration, and the maternal-to-zygotic transition.","evidence":"Co-crystal of K114me2-CHD1, mass spectrometry, ChIP-seq; JADE-2 degradation assays; conditional/inducible and oocyte-specific KO mice with RNA-seq/bisulfite","pmids":["26751641","29618057","28228264","28993646","26814574"],"confidence":"High","gaps":["Interplay among K114 methylation, degradation, and complex assembly not integrated","Causality of LSD1 mislocalization in human neurodegeneration not established"]},{"year":2017,"claim":"Established that disrupting specific LSD1 protein-protein interfaces, not just catalysis, is required for oncogenic programs.","evidence":"Co-IP, structure-guided GFI1-LSD1 interface mutagenesis, in vivo genetic ablation in medulloblastoma models","pmids":["30659187"],"confidence":"High","gaps":["Did not define the catalytic contribution to GFI1-driven repression","Generalizability beyond medulloblastoma not tested here"]},{"year":2018,"claim":"Connected LSD1 loss to retroelement-driven innate immune activation, defining a route to enhance checkpoint-blockade immunotherapy.","evidence":"CRISPR/shRNA ablation, RNA-seq, immune infiltration flow cytometry, in vivo tumor models with anti-PD-1","pmids":["29937226"],"confidence":"High","gaps":["Catalytic versus scaffolding basis of ERV derepression not dissected","Direct LSD1 targets driving the dsRNA response not fully mapped"]},{"year":2019,"claim":"Showed partner-dependent tuning of LSD1 processivity by the glucocorticoid receptor and placed LSD1 inhibition as a differentiation therapy in pediatric glioma.","evidence":"Reconstituted GR-complex cell-free demethylation assay and ChIP-seq; CRISPR screen and ChIP-seq in DIPG","pmids":["31216473","31631026"],"confidence":"High","gaps":["Structural basis of GR-imposed processivity limit not defined","Whether DIPG effects are catalytic or scaffolding not resolved here"]},{"year":2020,"claim":"Revealed that LSD1 inhibition can act by destabilizing CoREST-complex members, linking pharmacology to complex integrity.","evidence":"Pharmacological inhibition, Co-IP, HMG20B degradation with proteasome rescue, RNA-seq in Merkel cell carcinoma","pmids":["33026191"],"confidence":"Medium","gaps":["Single-lab, two orthogonal methods","Mechanism of inhibitor-induced complex disassembly not structurally defined"]},{"year":2021,"claim":"Defined LSD1 as a genome-wide enhancer rheostat that constrains H3K4 methylation and eRNA output in stem cells and neurons.","evidence":"Conditional/inducible KO in mESCs and neurons with H3K4me1/2 and H3K27ac ChIP-seq, eRNA and RNA-seq","pmids":["33414108"],"confidence":"High","gaps":["Did not isolate catalytic from scaffolding contribution at enhancers","Determinants of enhancer-specific occupancy unresolved"]},{"year":2022,"claim":"Extended LSD1 function to cytoplasmic non-histone substrate demethylation and to direct participation in replication origin firing.","evidence":"Co-IP and in vitro FKBP8 demethylation with KAT8 K117 acetylation; replication-factor Co-IP, DNA fiber and origin-firing assays","pmids":["35970393","35414135"],"confidence":"Medium","gaps":["Single-lab evidence with two orthogonal methods each","Direct versus indirect role in TICRR/CDC45 loading not fully resolved"]},{"year":2023,"claim":"Dissected catalytic from scaffolding function, establishing that protein presence—via suppression of P300/CBP-driven H3K27ac—rather than demethylase activity drives enhancer repression and differentiation control.","evidence":"Isogenic catalytic-dead knockin versus knockout with H3K27ac/P300 ChIP-seq, RNA-seq, differentiation assays","pmids":["37607921"],"confidence":"High","gaps":["How LSD1 protein physically blocks P300/CBP not structurally defined","Loci where catalysis remains essential not enumerated"]},{"year":2024,"claim":"Consolidated the scaffolding paradigm for DNA methylation, mapped histone-acetylation crosstalk regulating catalysis, and added an immune-silencing partner.","evidence":"Catalytic-impaired knockin with HDAC1/USP7 Co-IP and bisulfite sequencing; Y391K knockin with H3K14ac crosstalk ChIP-seq; ZNF750-KDM1A co-occupancy and KO inflammatory phenotype","pmids":["39237615","38965385","39353440"],"confidence":"High","gaps":["Physiological signals controlling H3K14ac-mediated inhibition unclear","Recruitment hierarchy among ZNF750, CoREST, and LSD1 not fully resolved"]},{"year":2025,"claim":"Showed metabolic regulation of LSD1 by lactylation that stabilizes the protein and redirects it to repress ferroptosis in drug-resistant tumors.","evidence":"Mass spectrometry of LSD1 lactylation, Co-IP (FosL1, TRIM21), ChIP-seq, viability assays, murine resistant-tumor models","pmids":["40132584"],"confidence":"Medium","gaps":["Single-lab mechanistic placement","Lactylation site stoichiometry and direct effect on catalysis not defined"]},{"year":null,"claim":"It remains unresolved how LSD1's many post-translational modifications, isoforms, and partner complexes are integrated to set the balance between catalytic and scaffolding functions at any given locus.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified structural model coupling modification state to complex assembly and substrate choice","Catalytic versus scaffolding contributions not systematically mapped genome-wide across cell types","Rules governing recruitment by competing sequence-specific factors unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1,2,6,8,18,21,24]},{"term_id":"GO:0016491","term_label":"oxidoreductase activity","supporting_discovery_ids":[0]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,1,20,23]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[0,4]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[23,25]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,1,5,20]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[21]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,1,20,23]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[0,5,20,23]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[7]},{"term_id":"R-HSA-69306","term_label":"DNA Replication","supporting_discovery_ids":[22]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[5,9,11,13]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[15,26]}],"complexes":["CoREST-HDAC","androgen receptor complex","glucocorticoid receptor complex"],"partners":["RCOR1","AR","NR3C1","DNMT1","GFI1","HDAC1","USP7","UHRF1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O60341","full_name":"Lysine-specific histone demethylase 1A","aliases":["BRAF35-HDAC complex protein BHC110","Flavin-containing amine oxidase domain-containing protein 2","[histone H3]-dimethyl-L-lysine(4) FAD-dependent demethylase 1A"],"length_aa":852,"mass_kda":92.9,"function":"Histone demethylase that can demethylate both 'Lys-4' (H3K4me) and 'Lys-9' (H3K9me) of histone H3, thereby acting as a coactivator or a corepressor, depending on the context (PubMed:15620353, PubMed:15811342, PubMed:16079794, PubMed:16079795, PubMed:16140033, PubMed:16223729, PubMed:27292636). Acts by oxidizing the substrate by FAD to generate the corresponding imine that is subsequently hydrolyzed (PubMed:15620353, PubMed:15811342, PubMed:16079794, PubMed:21300290, PubMed:26214369). Acts as a corepressor by mediating demethylation of H3K4me, a specific tag for epigenetic transcriptional activation. Demethylates both mono- (H3K4me1) and di-methylated (H3K4me2) (PubMed:15620353, PubMed:20389281, PubMed:21300290, PubMed:23721412). May play a role in the repression of neuronal genes. Alone, it is unable to demethylate H3K4me on nucleosomes and requires the presence of RCOR1/CoREST to achieve such activity (PubMed:16079794, PubMed:16140033, PubMed:16885027, PubMed:21300290, PubMed:23721412). Also acts as a coactivator of androgen receptor (AR)-dependent transcription, by being recruited to AR target genes and mediating demethylation of H3K9me, a specific tag for epigenetic transcriptional repression. The presence of PRKCB in AR-containing complexes, which mediates phosphorylation of 'Thr-6' of histone H3 (H3T6ph), a specific tag that prevents demethylation H3K4me, prevents H3K4me demethylase activity of KDM1A (PubMed:16079795). Demethylates di-methylated 'Lys-370' of p53/TP53 which prevents interaction of p53/TP53 with TP53BP1 and represses p53/TP53-mediated transcriptional activation. Demethylates and stabilizes the DNA methylase DNMT1 (PubMed:29691401). Demethylates methylated 'Lys-42' and methylated 'Lys-117' of SOX2 (PubMed:29358331). Required for gastrulation during embryogenesis. Component of a RCOR/GFI/KDM1A/HDAC complex that suppresses, via histone deacetylase (HDAC) recruitment, a number of genes implicated in multilineage blood cell development (PubMed:16079794, PubMed:16140033). Facilitates epithelial-to-mesenchymal transition by acting as an effector of SNAI1-mediated transcription repression of epithelial markers E-cadherin/CDH1, CDN7 and KRT8 (PubMed:20562920, PubMed:27292636). Required for the maintenance of the silenced state of the SNAI1 target genes E-cadherin/CDH1 and CDN7 (PubMed:20389281). Required for the repression of GIPR expression (PubMed:34655521, PubMed:34906447) Neuron-specific histone demethylase that demethylates mono- and dimethylated 'Lys-20' of histone H4 (H4K20me1 and H4K20me2), a chromatin repressive mark (PubMed:26214369). This demethylation is crucial for the initiation and elongation of neuronal activity-regulated genes, required for spatial learning and memory (By similarity). Mediates H3K9me2 demethylation through cooperation with the supervillin protein (SVIL), and this H3K9 demethylase activity is essential for regulating gene expression during neuronal differentiation (PubMed:25684206) Neuron-specific histone demethylase that demethylates mono- and dimethylated 'Lys-20' of histone H4 (H4K20me1 and H4K20me2), a chromatin repressive mark (PubMed:26214369). This demethylation is crucial for the initiation and elongation of neuronal activity-regulated genes, required for spatial learning and memory (By similarity). Mediates H3K9me2 demethylation through cooperation with the supervillin protein (SVIL), and this H3K9 demethylase activity is essential for regulating gene expression during neuronal differentiation (PubMed:25684206)","subcellular_location":"Nucleus; Chromosome","url":"https://www.uniprot.org/uniprotkb/O60341/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/KDM1A","classification":"Not Classified","n_dependent_lines":114,"n_total_lines":1208,"dependency_fraction":0.09437086092715231},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"HDAC2","stoichiometry":10.0},{"gene":"CBX1","stoichiometry":0.2},{"gene":"CSNK2B","stoichiometry":0.2},{"gene":"CTBP1","stoichiometry":0.2},{"gene":"CTBP2","stoichiometry":0.2},{"gene":"DYNLL1","stoichiometry":0.2},{"gene":"DYNLL2","stoichiometry":0.2},{"gene":"HDAC1","stoichiometry":0.2},{"gene":"HIST2H2BE","stoichiometry":0.2},{"gene":"HMGN5","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/KDM1A","total_profiled":1310},"omim":[{"mim_id":"621395","title":"DEAD-BOX HELICASE 19A; DDX19A","url":"https://www.omim.org/entry/621395"},{"mim_id":"620990","title":"ACTH-INDEPENDENT MACRONODULAR ADRENAL HYPERPLASIA 3; AIMAH3","url":"https://www.omim.org/entry/620990"},{"mim_id":"620050","title":"PHD FINGER PROTEIN 20-LIKE 1; PHF20L1","url":"https://www.omim.org/entry/620050"},{"mim_id":"618844","title":"L3MBTL HISTONE METHYL-LYSINE-BINDING PROTEIN 3; L3MBTL3","url":"https://www.omim.org/entry/618844"},{"mim_id":"618764","title":"CDK2-ASSOCIATED CULLIN DOMAIN-CONTAINING PROTEIN 1; CACUL1","url":"https://www.omim.org/entry/618764"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/KDM1A"},"hgnc":{"alias_symbol":["KIAA0601","BHC110","LSD1"],"prev_symbol":["AOF2","KDM1"]},"alphafold":{"accession":"O60341","domains":[{"cath_id":"1.10.10.10","chopping":"174-260","consensus_level":"high","plddt":97.5456,"start":174,"end":260},{"cath_id":"3.50.50.60","chopping":"281-314_572-655_768-831","consensus_level":"high","plddt":98.051,"start":281,"end":831},{"cath_id":"3.90.660.10","chopping":"363-408_524-563_660-749","consensus_level":"medium","plddt":97.1632,"start":363,"end":749},{"cath_id":"1.10.287.80","chopping":"414-514","consensus_level":"high","plddt":95.8938,"start":414,"end":514}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O60341","model_url":"https://alphafold.ebi.ac.uk/files/AF-O60341-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O60341-F1-predicted_aligned_error_v6.png","plddt_mean":84.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=KDM1A","jax_strain_url":"https://www.jax.org/strain/search?query=KDM1A"},"sequence":{"accession":"O60341","fasta_url":"https://rest.uniprot.org/uniprotkb/O60341.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O60341/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O60341"}},"corpus_meta":[{"pmid":"15620353","id":"PMC_15620353","title":"Histone demethylation mediated by the nuclear amine oxidase homolog LSD1.","date":"2004","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/15620353","citation_count":3349,"is_preprint":false},{"pmid":"16079795","id":"PMC_16079795","title":"LSD1 demethylates repressive histone marks to promote androgen-receptor-dependent transcription.","date":"2005","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/16079795","citation_count":1421,"is_preprint":false},{"pmid":"19098913","id":"PMC_19098913","title":"The lysine demethylase LSD1 (KDM1) is required for maintenance of global DNA methylation.","date":"2008","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/19098913","citation_count":648,"is_preprint":false},{"pmid":"29937226","id":"PMC_29937226","title":"LSD1 Ablation Stimulates Anti-tumor Immunity and Enables Checkpoint Blockade.","date":"2018","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/29937226","citation_count":556,"is_preprint":false},{"pmid":"22464800","id":"PMC_22464800","title":"The histone demethylase KDM1A sustains the oncogenic potential of MLL-AF9 leukemia stem cells.","date":"2012","source":"Cancer cell","url":"https://pubmed.ncbi.nlm.nih.gov/22464800","citation_count":482,"is_preprint":false},{"pmid":"29502954","id":"PMC_29502954","title":"ORY-1001, a Potent and Selective Covalent KDM1A Inhibitor, for the Treatment of Acute Leukemia.","date":"2018","source":"Cancer cell","url":"https://pubmed.ncbi.nlm.nih.gov/29502954","citation_count":262,"is_preprint":false},{"pmid":"25684206","id":"PMC_25684206","title":"A specific LSD1/KDM1A isoform regulates neuronal differentiation through H3K9 demethylation.","date":"2015","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/25684206","citation_count":226,"is_preprint":false},{"pmid":"21357675","id":"PMC_21357675","title":"Endogenous retroviruses and neighboring genes are coordinately repressed by LSD1/KDM1A.","date":"2011","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/21357675","citation_count":216,"is_preprint":false},{"pmid":"27479862","id":"PMC_27479862","title":"LSD1: biologic roles and therapeutic targeting.","date":"2016","source":"Epigenomics","url":"https://pubmed.ncbi.nlm.nih.gov/27479862","citation_count":172,"is_preprint":false},{"pmid":"33318631","id":"PMC_33318631","title":"LSD1: more than demethylation of histone lysine residues.","date":"2020","source":"Experimental & molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/33318631","citation_count":150,"is_preprint":false},{"pmid":"31631026","id":"PMC_31631026","title":"Re-programing Chromatin with a Bifunctional LSD1/HDAC Inhibitor Induces Therapeutic Differentiation in DIPG.","date":"2019","source":"Cancer cell","url":"https://pubmed.ncbi.nlm.nih.gov/31631026","citation_count":148,"is_preprint":false},{"pmid":"20164337","id":"PMC_20164337","title":"Alternative splicing of the histone demethylase LSD1/KDM1 contributes to the modulation of neurite morphogenesis in the mammalian nervous system.","date":"2010","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/20164337","citation_count":147,"is_preprint":false},{"pmid":"20568732","id":"PMC_20568732","title":"Structurally designed trans-2-phenylcyclopropylamine derivatives potently inhibit histone demethylase LSD1/KDM1 .","date":"2010","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/20568732","citation_count":141,"is_preprint":false},{"pmid":"24217620","id":"PMC_24217620","title":"The histone demethylase LSD1/KDM1A promotes the DNA damage response.","date":"2013","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/24217620","citation_count":113,"is_preprint":false},{"pmid":"28722477","id":"PMC_28722477","title":"Advances toward LSD1 inhibitors for cancer therapy.","date":"2017","source":"Future medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/28722477","citation_count":110,"is_preprint":false},{"pmid":"30518104","id":"PMC_30518104","title":"Pharmacological Inhibition of LSD1 for Cancer Treatment.","date":"2018","source":"Molecules (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/30518104","citation_count":108,"is_preprint":false},{"pmid":"22245111","id":"PMC_22245111","title":"Lysine-specific demethylase 1 (LSD1/KDM1A/AOF2/BHC110) is expressed and is an epigenetic drug target in chondrosarcoma, Ewing's sarcoma, osteosarcoma, and rhabdomyosarcoma.","date":"2012","source":"Human pathology","url":"https://pubmed.ncbi.nlm.nih.gov/22245111","citation_count":108,"is_preprint":false},{"pmid":"32193608","id":"PMC_32193608","title":"Biological roles of LSD1 beyond its demethylase activity.","date":"2020","source":"Cellular and molecular life sciences : CMLS","url":"https://pubmed.ncbi.nlm.nih.gov/32193608","citation_count":96,"is_preprint":false},{"pmid":"31756917","id":"PMC_31756917","title":"LSD1/KDM1A, a Gate-Keeper of Cancer Stemness and a Promising Therapeutic Target.","date":"2019","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/31756917","citation_count":91,"is_preprint":false},{"pmid":"21876670","id":"PMC_21876670","title":"Activation of HIV transcription by the viral Tat protein requires a demethylation step mediated by lysine-specific demethylase 1 (LSD1/KDM1).","date":"2011","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/21876670","citation_count":84,"is_preprint":false},{"pmid":"28916652","id":"PMC_28916652","title":"LSD1-Mediated Epigenetic Reprogramming Drives CENPE Expression and Prostate Cancer Progression.","date":"2017","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/28916652","citation_count":83,"is_preprint":false},{"pmid":"32837872","id":"PMC_32837872","title":"Natural products as LSD1 inhibitors for cancer therapy.","date":"2020","source":"Acta pharmaceutica Sinica. B","url":"https://pubmed.ncbi.nlm.nih.gov/32837872","citation_count":83,"is_preprint":false},{"pmid":"34082769","id":"PMC_34082769","title":"Roles of lysine-specific demethylase 1 (LSD1) in homeostasis and diseases.","date":"2021","source":"Journal of biomedical science","url":"https://pubmed.ncbi.nlm.nih.gov/34082769","citation_count":80,"is_preprint":false},{"pmid":"26881714","id":"PMC_26881714","title":"Irreversible LSD1 Inhibitors: Application of Tranylcypromine and Its Derivatives in Cancer Treatment.","date":"2016","source":"Current topics in medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/26881714","citation_count":77,"is_preprint":false},{"pmid":"29559475","id":"PMC_29559475","title":"Germline Lysine-Specific Demethylase 1 (LSD1/KDM1A) Mutations Confer Susceptibility to Multiple Myeloma.","date":"2018","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/29559475","citation_count":73,"is_preprint":false},{"pmid":"22812534","id":"PMC_22812534","title":"Targeting the PELP1-KDM1 axis as a potential therapeutic strategy for breast cancer.","date":"2012","source":"Breast cancer research : BCR","url":"https://pubmed.ncbi.nlm.nih.gov/22812534","citation_count":72,"is_preprint":false},{"pmid":"30659187","id":"PMC_30659187","title":"Lsd1 as a therapeutic target in Gfi1-activated medulloblastoma.","date":"2019","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/30659187","citation_count":72,"is_preprint":false},{"pmid":"26751641","id":"PMC_26751641","title":"Assembly of methylated KDM1A and CHD1 drives androgen receptor-dependent transcription and translocation.","date":"2016","source":"Nature structural & molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/26751641","citation_count":69,"is_preprint":false},{"pmid":"26814574","id":"PMC_26814574","title":"Maternally provided LSD1/KDM1A enables the maternal-to-zygotic transition and prevents defects that manifest postnatally.","date":"2016","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/26814574","citation_count":68,"is_preprint":false},{"pmid":"26111032","id":"PMC_26111032","title":"KDM1 histone lysine demethylases as targets for treatments of oncological and neurodegenerative disease.","date":"2015","source":"Epigenomics","url":"https://pubmed.ncbi.nlm.nih.gov/26111032","citation_count":67,"is_preprint":false},{"pmid":"19624733","id":"PMC_19624733","title":"New roles of flavoproteins in molecular cell biology: histone demethylase LSD1 and chromatin.","date":"2009","source":"The FEBS journal","url":"https://pubmed.ncbi.nlm.nih.gov/19624733","citation_count":65,"is_preprint":false},{"pmid":"27375009","id":"PMC_27375009","title":"Histone demethylase LSD1 controls the phenotypic plasticity of cancer cells.","date":"2016","source":"Cancer science","url":"https://pubmed.ncbi.nlm.nih.gov/27375009","citation_count":64,"is_preprint":false},{"pmid":"28993646","id":"PMC_28993646","title":"LSD1 protects against hippocampal and cortical neurodegeneration.","date":"2017","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/28993646","citation_count":64,"is_preprint":false},{"pmid":"26848860","id":"PMC_26848860","title":"Therapeutic opportunities in Ewing sarcoma: EWS-FLI inhibition via LSD1 targeting.","date":"2016","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/26848860","citation_count":60,"is_preprint":false},{"pmid":"33026191","id":"PMC_33026191","title":"LSD1 inhibition induces differentiation and cell death in Merkel cell carcinoma.","date":"2020","source":"EMBO molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/33026191","citation_count":59,"is_preprint":false},{"pmid":"25787087","id":"PMC_25787087","title":"KDM1 class flavin-dependent protein lysine demethylases.","date":"2015","source":"Biopolymers","url":"https://pubmed.ncbi.nlm.nih.gov/25787087","citation_count":55,"is_preprint":false},{"pmid":"27769034","id":"PMC_27769034","title":"Design, synthesis and biological evaluation of [1,2,4]triazolo[1,5-a]pyrimidines as potent lysine specific demethylase 1 (LSD1/KDM1A) inhibitors.","date":"2016","source":"European journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/27769034","citation_count":54,"is_preprint":false},{"pmid":"29997151","id":"PMC_29997151","title":"Therapeutic Targeting of KDM1A/LSD1 in Ewing Sarcoma with SP-2509 Engages the Endoplasmic Reticulum Stress Response.","date":"2018","source":"Molecular cancer therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/29997151","citation_count":52,"is_preprint":false},{"pmid":"23248157","id":"PMC_23248157","title":"KDM1 is a novel therapeutic target for the treatment of gliomas.","date":"2013","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/23248157","citation_count":50,"is_preprint":false},{"pmid":"26062444","id":"PMC_26062444","title":"Lysine-specific demethylase (LSD1/KDM1A) and MYCN cooperatively repress tumor suppressor genes in neuroblastoma.","date":"2015","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/26062444","citation_count":50,"is_preprint":false},{"pmid":"29921310","id":"PMC_29921310","title":"KDM1A microenvironment, its oncogenic potential, and therapeutic significance.","date":"2018","source":"Epigenetics & chromatin","url":"https://pubmed.ncbi.nlm.nih.gov/29921310","citation_count":48,"is_preprint":false},{"pmid":"34906447","id":"PMC_34906447","title":"KDM1A inactivation causes hereditary food-dependent Cushing syndrome.","date":"2021","source":"Genetics in medicine : official journal of the American College of Medical Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/34906447","citation_count":47,"is_preprint":false},{"pmid":"27019002","id":"PMC_27019002","title":"LSD1 inhibitors: a patent review (2010-2015).","date":"2016","source":"Expert opinion on therapeutic patents","url":"https://pubmed.ncbi.nlm.nih.gov/27019002","citation_count":43,"is_preprint":false},{"pmid":"28228264","id":"PMC_28228264","title":"LSD1 Controls Timely MyoD Expression via MyoD Core Enhancer Transcription.","date":"2017","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/28228264","citation_count":42,"is_preprint":false},{"pmid":"36652263","id":"PMC_36652263","title":"Lysine-specific histone demethylase 1A (KDM1A/LSD1) inhibition attenuates DNA double-strand break repair and augments the efficacy of temozolomide in glioblastoma.","date":"2023","source":"Neuro-oncology","url":"https://pubmed.ncbi.nlm.nih.gov/36652263","citation_count":42,"is_preprint":false},{"pmid":"30780087","id":"PMC_30780087","title":"Synthesis, structure-activity relationship studies and biological characterization of new [1,2,4]triazolo[1,5-a]pyrimidine-based LSD1/KDM1A inhibitors.","date":"2019","source":"European journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/30780087","citation_count":42,"is_preprint":false},{"pmid":"32606137","id":"PMC_32606137","title":"Leukemia Cell of Origin Influences Apoptotic Priming and Sensitivity to LSD1 Inhibition.","date":"2020","source":"Cancer discovery","url":"https://pubmed.ncbi.nlm.nih.gov/32606137","citation_count":41,"is_preprint":false},{"pmid":"28720390","id":"PMC_28720390","title":"Epigenetic regulation of epithelial to mesenchymal transition by the Lysine-specific demethylase LSD1/KDM1A.","date":"2017","source":"Biochimica et biophysica acta. Gene regulatory mechanisms","url":"https://pubmed.ncbi.nlm.nih.gov/28720390","citation_count":41,"is_preprint":false},{"pmid":"26512114","id":"PMC_26512114","title":"LSD1/KDM1A promotes hematopoietic commitment of hemangioblasts through downregulation of Etv2.","date":"2015","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/26512114","citation_count":38,"is_preprint":false},{"pmid":"38615741","id":"PMC_38615741","title":"Tanshinone IIA destabilizes SLC7A11 by regulating PIAS4-mediated SUMOylation of SLC7A11 through KDM1A, and promotes ferroptosis in breast cancer.","date":"2024","source":"Journal of advanced research","url":"https://pubmed.ncbi.nlm.nih.gov/38615741","citation_count":37,"is_preprint":false},{"pmid":"34831474","id":"PMC_34831474","title":"LSD1: Expanding Functions in Stem Cells and Differentiation.","date":"2021","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/34831474","citation_count":37,"is_preprint":false},{"pmid":"34016956","id":"PMC_34016956","title":"Superior efficacy of co-targeting GFI1/KDM1A and BRD4 against AML and post-MPN secondary AML cells.","date":"2021","source":"Blood cancer journal","url":"https://pubmed.ncbi.nlm.nih.gov/34016956","citation_count":35,"is_preprint":false},{"pmid":"25728837","id":"PMC_25728837","title":"KDM1A triggers androgen-induced miRNA transcription via H3K4me2 demethylation and DNA oxidation.","date":"2015","source":"The Prostate","url":"https://pubmed.ncbi.nlm.nih.gov/25728837","citation_count":35,"is_preprint":false},{"pmid":"29618057","id":"PMC_29618057","title":"LSD1 mediates metabolic reprogramming by glucocorticoids during myogenic differentiation.","date":"2018","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/29618057","citation_count":34,"is_preprint":false},{"pmid":"29463994","id":"PMC_29463994","title":"The Homeotic Protein SIX3 Suppresses Carcinogenesis and Metastasis through Recruiting the LSD1/NuRD(MTA3) Complex.","date":"2018","source":"Theranostics","url":"https://pubmed.ncbi.nlm.nih.gov/29463994","citation_count":34,"is_preprint":false},{"pmid":"38969160","id":"PMC_38969160","title":"Targeting LSD1 in cancer: Molecular elucidation and recent advances.","date":"2024","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/38969160","citation_count":33,"is_preprint":false},{"pmid":"37607921","id":"PMC_37607921","title":"Demethylase-independent roles of LSD1 in regulating enhancers and cell fate transition.","date":"2023","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/37607921","citation_count":33,"is_preprint":false},{"pmid":"27372757","id":"PMC_27372757","title":"LSD1 Histone Demethylase Assays and Inhibition.","date":"2016","source":"Methods in enzymology","url":"https://pubmed.ncbi.nlm.nih.gov/27372757","citation_count":33,"is_preprint":false},{"pmid":"27077938","id":"PMC_27077938","title":"Inhibitors of LSD1 as a potential therapy for acute myeloid leukemia.","date":"2016","source":"Expert opinion on investigational drugs","url":"https://pubmed.ncbi.nlm.nih.gov/27077938","citation_count":33,"is_preprint":false},{"pmid":"29270148","id":"PMC_29270148","title":"Tranylcypromine Causes Neurotoxicity and Represses BHC110/LSD1 in Human-Induced Pluripotent Stem Cell-Derived Cerebral Organoids Model.","date":"2017","source":"Frontiers in neurology","url":"https://pubmed.ncbi.nlm.nih.gov/29270148","citation_count":32,"is_preprint":false},{"pmid":"40132584","id":"PMC_40132584","title":"Lactylation of LSD1 is an acquired epigenetic vulnerability of BRAFi/MEKi-resistant melanoma.","date":"2025","source":"Developmental cell","url":"https://pubmed.ncbi.nlm.nih.gov/40132584","citation_count":31,"is_preprint":false},{"pmid":"38014919","id":"PMC_38014919","title":"LSD1 in drug discovery: From biological function to clinical application.","date":"2023","source":"Medicinal research reviews","url":"https://pubmed.ncbi.nlm.nih.gov/38014919","citation_count":31,"is_preprint":false},{"pmid":"31216473","id":"PMC_31216473","title":"GR and LSD1/KDM1A-Targeted Gene Activation Requires Selective H3K4me2 Demethylation at Enhancers.","date":"2019","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/31216473","citation_count":30,"is_preprint":false},{"pmid":"18940868","id":"PMC_18940868","title":"NF-Y substitutes H2A-H2B on active cell-cycle promoters: recruitment of CoREST-KDM1 and fine-tuning of H3 methylations.","date":"2008","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/18940868","citation_count":30,"is_preprint":false},{"pmid":"27470128","id":"PMC_27470128","title":"The growing structural and functional complexity of the LSD1/KDM1A histone demethylase.","date":"2016","source":"Current opinion in structural biology","url":"https://pubmed.ncbi.nlm.nih.gov/27470128","citation_count":29,"is_preprint":false},{"pmid":"32889380","id":"PMC_32889380","title":"Capsaicin: A \"hot\" KDM1A/LSD1 inhibitor from peppers.","date":"2020","source":"Bioorganic chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/32889380","citation_count":29,"is_preprint":false},{"pmid":"22992372","id":"PMC_22992372","title":"Integration of ERα-PELP1-HER2 signaling by LSD1 (KDM1A/AOF2) offers combinatorial therapeutic opportunities to circumventing hormone resistance in breast cancer.","date":"2012","source":"Breast cancer research : BCR","url":"https://pubmed.ncbi.nlm.nih.gov/22992372","citation_count":28,"is_preprint":false},{"pmid":"28498828","id":"PMC_28498828","title":"KDM1A/LSD1 regulates the differentiation and maintenance of spermatogonia in mice.","date":"2017","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/28498828","citation_count":28,"is_preprint":false},{"pmid":"26111147","id":"PMC_26111147","title":"Decreased Expression of CoREST1 and CoREST2 Together with LSD1 and HDAC1/2 during Neuronal Differentiation.","date":"2015","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/26111147","citation_count":28,"is_preprint":false},{"pmid":"28152483","id":"PMC_28152483","title":"LSD1 collaborates with EZH2 to regulate expression of interferon-stimulated genes.","date":"2017","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/28152483","citation_count":26,"is_preprint":false},{"pmid":"35255108","id":"PMC_35255108","title":"Lysine-Specific Demethylase 1 (LSD1) epigenetically controls osteoblast differentiation.","date":"2022","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/35255108","citation_count":25,"is_preprint":false},{"pmid":"35820351","id":"PMC_35820351","title":"A comprehensive comparative study on LSD1 in different cancers and tumor specific LSD1 inhibitors.","date":"2022","source":"European journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/35820351","citation_count":25,"is_preprint":false},{"pmid":"30416854","id":"PMC_30416854","title":"BRMS1 coordinates with LSD1 and suppresses breast cancer cell metastasis.","date":"2018","source":"American journal of cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/30416854","citation_count":25,"is_preprint":false},{"pmid":"34171978","id":"PMC_34171978","title":"KDM1A and KDM3A promote tumor growth by upregulating cell cycle-associated genes in pancreatic cancer.","date":"2021","source":"Experimental biology and medicine (Maywood, N.J.)","url":"https://pubmed.ncbi.nlm.nih.gov/34171978","citation_count":24,"is_preprint":false},{"pmid":"26008620","id":"PMC_26008620","title":"LSD1 is Required for Hair Cell Regeneration in Zebrafish.","date":"2015","source":"Molecular neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/26008620","citation_count":24,"is_preprint":false},{"pmid":"39353440","id":"PMC_39353440","title":"The transcription regulators ZNF750 and LSD1/KDM1A dampen inflammation on the skin's surface by silencing pattern recognition receptors.","date":"2024","source":"Immunity","url":"https://pubmed.ncbi.nlm.nih.gov/39353440","citation_count":22,"is_preprint":false},{"pmid":"33414108","id":"PMC_33414108","title":"KDM1A maintains genome-wide homeostasis of transcriptional enhancers.","date":"2021","source":"Genome research","url":"https://pubmed.ncbi.nlm.nih.gov/33414108","citation_count":22,"is_preprint":false},{"pmid":"36497494","id":"PMC_36497494","title":"Dual LSD1 and HDAC6 Inhibition Induces Doxorubicin Sensitivity in Acute Myeloid Leukemia Cells.","date":"2022","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/36497494","citation_count":22,"is_preprint":false},{"pmid":"35327654","id":"PMC_35327654","title":"The Role of LSD1 and LSD2 in Cancers of the Gastrointestinal System: An Update.","date":"2022","source":"Biomolecules","url":"https://pubmed.ncbi.nlm.nih.gov/35327654","citation_count":21,"is_preprint":false},{"pmid":"23637775","id":"PMC_23637775","title":"A hypomorphic lsd1 allele results in heart development defects in mice.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23637775","citation_count":21,"is_preprint":false},{"pmid":"35970393","id":"PMC_35970393","title":"Lysine demethylase KDM1A promotes cell growth via FKBP8-BCL2 axis in hepatocellular carcinoma.","date":"2022","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/35970393","citation_count":21,"is_preprint":false},{"pmid":"21142040","id":"PMC_21142040","title":"Thermodynamic characterization of the binding interaction between the histone demethylase LSD1/KDM1 and CoREST.","date":"2010","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21142040","citation_count":20,"is_preprint":false},{"pmid":"38572094","id":"PMC_38572094","title":"Strategies that regulate LSD1 for novel therapeutics.","date":"2024","source":"Acta pharmaceutica Sinica. B","url":"https://pubmed.ncbi.nlm.nih.gov/38572094","citation_count":19,"is_preprint":false},{"pmid":"37152294","id":"PMC_37152294","title":"The KDM5B and KDM1A lysine demethylases cooperate in regulating androgen receptor expression and signalling in prostate cancer.","date":"2023","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/37152294","citation_count":19,"is_preprint":false},{"pmid":"38302330","id":"PMC_38302330","title":"LSD1 promotes the FSH responsive follicle formation by regulating autophagy and repressing Wt1 in the granulosa cells.","date":"2024","source":"Science bulletin","url":"https://pubmed.ncbi.nlm.nih.gov/38302330","citation_count":18,"is_preprint":false},{"pmid":"37714256","id":"PMC_37714256","title":"Pharmacological inhibition of KDM1A/LSD1 enhances estrogen receptor beta-mediated tumor suppression in ovarian cancer.","date":"2023","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/37714256","citation_count":18,"is_preprint":false},{"pmid":"30760542","id":"PMC_30760542","title":"LSD1 Inhibition Attenuates Tumor Growth by Disrupting PLK1 Mitotic Pathway.","date":"2019","source":"Molecular cancer research : MCR","url":"https://pubmed.ncbi.nlm.nih.gov/30760542","citation_count":18,"is_preprint":false},{"pmid":"38965385","id":"PMC_38965385","title":"Uncoupling histone modification crosstalk by engineering lysine demethylase LSD1.","date":"2024","source":"Nature chemical biology","url":"https://pubmed.ncbi.nlm.nih.gov/38965385","citation_count":17,"is_preprint":false},{"pmid":"39237615","id":"PMC_39237615","title":"The scaffolding function of LSD1 controls DNA methylation in mouse ESCs.","date":"2024","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/39237615","citation_count":17,"is_preprint":false},{"pmid":"39725699","id":"PMC_39725699","title":"MSC-derived exosomal circMYO9B accelerates diabetic wound healing by promoting angiogenesis through the hnRNPU/CBL/KDM1A/VEGFA axis.","date":"2024","source":"Communications biology","url":"https://pubmed.ncbi.nlm.nih.gov/39725699","citation_count":17,"is_preprint":false},{"pmid":"31471467","id":"PMC_31471467","title":"Somatic deletion of KDM1A/LSD1 gene is associated to advanced colorectal cancer stages.","date":"2019","source":"Journal of clinical pathology","url":"https://pubmed.ncbi.nlm.nih.gov/31471467","citation_count":17,"is_preprint":false},{"pmid":"36386192","id":"PMC_36386192","title":"Biological and therapeutic role of LSD1 in Alzheimer's diseases.","date":"2022","source":"Frontiers in pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/36386192","citation_count":17,"is_preprint":false},{"pmid":"32882276","id":"PMC_32882276","title":"The R251Q mutation of LSD1 promotes invasion and migration of luminal breast cancer cells.","date":"2020","source":"International journal of biological macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/32882276","citation_count":17,"is_preprint":false},{"pmid":"35240522","id":"PMC_35240522","title":"KDM1A/LSD1 as a promising target in various diseases treatment by regulating autophagy network.","date":"2022","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/35240522","citation_count":16,"is_preprint":false},{"pmid":"35414135","id":"PMC_35414135","title":"LSD1 is required for euchromatic origin firing and replication timing.","date":"2022","source":"Signal transduction and targeted therapy","url":"https://pubmed.ncbi.nlm.nih.gov/35414135","citation_count":16,"is_preprint":false},{"pmid":"37385999","id":"PMC_37385999","title":"Targeting lysine-specific demethylase 1 (KDM1A/LSD1) impairs colorectal cancer tumorigenesis by affecting cancer cells stemness, motility, and differentiation.","date":"2023","source":"Cell death discovery","url":"https://pubmed.ncbi.nlm.nih.gov/37385999","citation_count":16,"is_preprint":false},{"pmid":"36357457","id":"PMC_36357457","title":"Aberrant expression of KDM1A inhibits ferroptosis of lung cancer cells through up-regulating c-Myc.","date":"2022","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/36357457","citation_count":16,"is_preprint":false},{"pmid":"30828079","id":"PMC_30828079","title":"Lysine-Specific Demethylase 1 (LSD1/KDM1A) Is a Novel Target Gene of c-Myc.","date":"2019","source":"Biological & pharmaceutical bulletin","url":"https://pubmed.ncbi.nlm.nih.gov/30828079","citation_count":16,"is_preprint":false},{"pmid":"34673129","id":"PMC_34673129","title":"KDM1A inhibition augments the efficacy of rapamycin for the treatment of endometrial cancer.","date":"2021","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/34673129","citation_count":16,"is_preprint":false},{"pmid":"36595522","id":"PMC_36595522","title":"Novel dual LSD1/HDAC6 inhibitor for the treatment of cancer.","date":"2023","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/36595522","citation_count":15,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":46584,"output_tokens":6921,"usd":0.121784,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":16002,"output_tokens":5640,"usd":0.110505,"stage2_stop_reason":"end_turn"},"total_usd":0.232289,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2004,\n      \"finding\": \"LSD1/KDM1A functions as a histone demethylase that specifically demethylates histone H3 lysine 4 (H3K4me1/2) via a FAD-dependent oxidation reaction that generates formaldehyde; RNAi inhibition of LSD1 causes increased H3K4 methylation and derepression of target genes, establishing LSD1 as a transcriptional corepressor.\",\n      \"method\": \"In vitro demethylase assay, RNAi knockdown, formaldehyde detection\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro enzymatic reconstitution with product identification (formaldehyde), validated by RNAi in cells, foundational paper replicated extensively\",\n      \"pmids\": [\"15620353\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"LSD1/KDM1A interacts with the androgen receptor (AR) in vitro and in vivo, and in the context of AR-dependent transcription demethylates histone H3 at lysine 9 (H3K9me1/2) to relieve repressive marks and activate AR target genes; pargyline inhibits this H3K9 demethylation activity.\",\n      \"method\": \"Co-immunoprecipitation, chromatin immunoprecipitation (ChIP), in vitro binding, siRNA knockdown, reporter assays\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, ChIP, functional rescue, replicated in multiple subsequent studies\",\n      \"pmids\": [\"16079795\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"LSD1/KDM1A demethylates and stabilizes DNMT1 protein in vitro and in vivo; Set7/9 methylates DNMT1 and LSD1 reverses this methylation, thereby preventing DNMT1 proteasomal degradation and maintaining global DNA methylation levels.\",\n      \"method\": \"In vitro demethylation assay, Co-IP, conditional knockout in mouse ES cells, western blot for DNMT1 stability\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro biochemical reconstitution (methylation/demethylation), genetic KO in ES cells, multiple orthogonal methods\",\n      \"pmids\": [\"19098913\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Alternative splicing of LSD1/KDM1A generates neuro-specific isoforms (containing exon E8a) that show reduced repressor activity on reporter genes compared to ubiquitous isoforms; knockdown of neuro-specific variants inhibits neurite maturation while knockdown of ubiquitous isoforms has no morphogenic effect, indicating isoform-specific functions.\",\n      \"method\": \"Reporter gene assay, siRNA knockdown, immunofluorescence, morphometric analysis of neurite outgrowth\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional reporter assay plus cellular KD phenotype, single lab, two methods\",\n      \"pmids\": [\"20164337\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"LSD1/KDM1A binds CoREST with high affinity (Kd ~16 nM) in a 1:1 stoichiometry; the central binding determinant is the CoREST linker region (residues 293–380) that contacts the LSD1 tower domain in a triple-helical bundle, an interaction required for demethylation of nucleosomal substrates.\",\n      \"method\": \"Isothermal titration calorimetry (ITC), structure-driven truncation analysis\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — rigorous thermodynamic measurements with defined stoichiometry and truncation mapping, single lab but quantitative\",\n      \"pmids\": [\"21142040\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"LSD1/KDM1A represses endogenous retroviral elements (MERVL) and adjacent genes in mouse embryos and ES cells; loss of KDM1A leads to increased H3K4 methylation, increased H3K27 acetylation, and decreased H3K9 methylation at MERVL elements and flanking ZGA genes, causing embryonic arrest at gastrulation.\",\n      \"method\": \"Mouse genetic knockout, genome-wide epigenetic profiling (ChIP-seq), ES cell analysis\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with defined molecular phenotype, genome-wide ChIP-seq, multiple orthogonal methods\",\n      \"pmids\": [\"21357675\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"LSD1/KDM1A demethylates HIV Tat at K51 (monomethylation), acting as a Tat-specific demethylase; LSD1 and its cofactor CoREST associate with the HIV promoter in vivo, and this demethylation is required for subsequent K50 acetylation and full activation of HIV transcription in latently infected T cells.\",\n      \"method\": \"Mass spectrometry on immunoprecipitated Tat, modification-specific antibodies, ChIP, shRNA knockdown, monoamine oxidase inhibitor treatment\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mass spectrometry identification of modification, ChIP, RNAi, chemical inhibition; multiple orthogonal methods in single study\",\n      \"pmids\": [\"21876670\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"LSD1/KDM1A is recruited directly to DNA damage sites in an RNF168-dependent manner; LSD1 demethylates H3K4me2 at damage sites, and its loss reduces histone ubiquitylation in late S/G2, impairs 53BP1 and BRCA1 complex recruitment, increases homologous recombination, and causes hypersensitivity to γ-irradiation.\",\n      \"method\": \"Live cell imaging to DNA damage sites, Co-IP (LSD1–RNF168), ChIP, siRNA knockdown, γ-H2AX foci, HR reporter assay\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct recruitment imaging, Co-IP, ChIP, functional HR reporter, multiple complementary methods\",\n      \"pmids\": [\"24217620\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"The LSD1+8a neuro-specific isoform cannot intrinsically demethylate H3K4me2; instead it mediates H3K9me2 demethylation in collaboration with supervillin (SVIL), a newly identified LSD1+8a interacting protein; SVIL co-localizes at LSD1+8a-bound promoters, and SVIL knockdown mimics LSD1+8a loss (increased H3K9me2, impaired neuronal differentiation).\",\n      \"method\": \"In vitro demethylase assay, Co-IP, ChIP-seq, siRNA knockdown, histone mass spectrometry\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro enzymatic assay distinguishing substrate specificity, Co-IP, ChIP, parallel KD phenotypes; multiple orthogonal methods\",\n      \"pmids\": [\"25684206\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"LSD1/KDM1A promotes hematopoietic commitment of hemangioblasts in zebrafish by suppressing expression of Etv2, an endothelial regulator; knockdown of Etv2 rescues hematopoietic defects in lsd1 mutant embryos, placing LSD1 upstream of Etv2 in the hematopoietic fate decision.\",\n      \"method\": \"Zebrafish genetic mutant, morpholino knockdown epistasis rescue, in situ hybridization\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis rescue in vivo (zebrafish), single lab\",\n      \"pmids\": [\"26512114\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"EHMT2 dimethylates KDM1A at K114 (K114me2), and CHD1 is a reader of this mark; co-crystal structure of the KDM1A K114me2 peptide–CHD1 complex was solved; genome-wide analyses show chromatin colocalization of KDM1A K114me2, CHD1, and AR in prostate tumor cells, linking this modification to androgen-dependent transcription and TMPRSS2-ERG gene fusion.\",\n      \"method\": \"Mass spectrometry, Co-crystal structure (X-ray crystallography), ChIP-seq, Co-IP\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure, mass spectrometry validation of methylation, ChIP-seq genome-wide, Co-IP; multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"26751641\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"KDM1A-mediated H3K4me2 demethylation at the MyoD core enhancer is required for RNA Pol II recruitment and transcription of the non-coding enhancer RNA (CEeRNA) that drives MyoD expression; conditional LSD1 inactivation in muscle progenitors delays MyoD expression in embryonic limb buds.\",\n      \"method\": \"ChIP, siRNA knockdown in myoblasts, conditional mouse knockout, reporter assays for enhancer RNA\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP, genetic KO, functional readout of enhancer RNA; single lab, two orthogonal methods\",\n      \"pmids\": [\"28228264\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"In adult mice, inducible deletion of LSD1/KDM1A leads to paralysis and widespread hippocampal and cortical neurodegeneration with learning/memory defects; loss of LSD1 induces transcription of stem cell genes and neurodegeneration-associated pathways, and LSD1 is mislocalized to pathological protein aggregates in Alzheimer's disease and frontotemporal dementia brain tissue.\",\n      \"method\": \"Inducible conditional knockout, behavioral testing, immunofluorescence, RNA-seq, brain tissue staining from AD/FTD cases\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — inducible genetic KO with defined neurodegeneration phenotype, RNA-seq, single lab\",\n      \"pmids\": [\"28993646\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Maternally provided LSD1/KDM1A in the oocyte is required for the maternal-to-zygotic transition in mice; loss of maternal LSD1 causes embryonic arrest at the 1–2 cell stage; partial maternal loss results in altered DNA methylation and expression at imprinted genes and perinatal/behavioral phenotypes.\",\n      \"method\": \"Conditional oocyte-specific knockout in mice, bisulfite sequencing, RNA-seq, behavioral assays\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with defined stage-specific phenotype, bisulfite sequencing, single lab\",\n      \"pmids\": [\"26814574\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"LSD1/KDM1A physically associates with GFI1 in medulloblastoma cells; GFI1 proteins engineered to be unable to recruit LSD1 cannot drive tumorigenesis; genetic ablation of LSD1 impairs tumor growth in vivo, demonstrating that the GFI1–LSD1 interaction is required for GFI1-mediated transformation and repression of neuronal differentiation genes.\",\n      \"method\": \"Co-immunoprecipitation, structure-guided mutagenesis of GFI1-LSD1 interface, mouse genetic ablation, in vivo tumor models\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP, mutagenesis abolishing interaction, in vivo genetic ablation; multiple orthogonal methods\",\n      \"pmids\": [\"30659187\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"LSD1 ablation in cancer cells increases endogenous retroviral element (ERV) expression and decreases RISC components, leading to dsRNA accumulation, type I interferon activation, and enhanced anti-tumor T cell immunity; this mechanism underlies sensitization to anti-PD-1 checkpoint blockade.\",\n      \"method\": \"Genetic ablation (CRISPR/shRNA), RNA-seq, flow cytometry for immune infiltration, in vivo tumor models with checkpoint blockade\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO, RNA-seq, in vivo immune and tumor models; multiple orthogonal methods\",\n      \"pmids\": [\"29937226\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Glucocorticoid signaling induces expression of the ubiquitin E3 ligase JADE-2, which mediates proteasomal degradation of LSD1/KDM1A; loss of LSD1 activity during myogenic differentiation de-represses oxidative metabolism genes accompanied by increased H3K4 methylation at those loci, revealing a glucocorticoid–LSD1–metabolism axis.\",\n      \"method\": \"Western blot (proteasome inhibitors, JADE-2 siRNA), ChIP-seq, RNA-seq, metabolic assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic link between JADE-2 and LSD1 degradation via siRNA, ChIP-seq; single lab\",\n      \"pmids\": [\"29618057\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"KDM1A inhibition in DIPG cells increases H3K27me3 levels at differentiation genes and simultaneously increases H3K27ac and H3K4me1, driving therapeutic differentiation; a CRISPR screen identified KDM1A knockout as sensitizing DIPG cells to HDAC inhibitors.\",\n      \"method\": \"CRISPR screen, ChIP-seq, western blot for histone marks, cell death/differentiation assays, xenograft models\",\n      \"journal\": \"Cancer cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR screen and ChIP-seq; single lab, mechanistic pathway placement\",\n      \"pmids\": [\"31631026\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"KDM1A binds GR as an integral complex component; in cell-free assays GR modulates KDM1A-catalyzed H3K4 progressive demethylation by limiting removal to H3K4me2 while leaving H3K4me1; in cells KDM1A removes H3K4me2 at GR binding sites, and blocking KDM1A catalysis prevents GR chromatin binding and dysregulates GR target genes.\",\n      \"method\": \"Biochemical purification of nuclear GR complex, cell-free demethylation assay, ChIP-seq, pharmacological inhibition\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstituted demethylase assay plus ChIP-seq; multiple orthogonal methods, single lab\",\n      \"pmids\": [\"31216473\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"LSD1 inhibition in Merkel cell carcinoma disrupts the LSD1–CoREST complex leading to displacement and proteasomal degradation of HMG20B/BRAF35, a complex member essential for MCC proliferation; this is accompanied by derepression of neuronal lineage transcription factors.\",\n      \"method\": \"Pharmacological inhibition, Co-IP, western blot for HMG20B degradation, proteasome inhibitor rescue, RNA-seq\",\n      \"journal\": \"EMBO molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, degradation rescued by proteasome inhibitor, RNA-seq; single lab, two orthogonal methods\",\n      \"pmids\": [\"33026191\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"KDM1A maintains genome-wide optimal enhancer activity in mouse ESCs and postmitotic neurons by counterbalancing H3K4 methylation; KDM1A loss leads to increased H3K4 methylation, increased H3K27 acetylation, and elevated eRNA and target gene expression at KDM1A-occupied enhancers.\",\n      \"method\": \"Conditional/inducible KO in mESCs and neurons, ChIP-seq (H3K4me1/2, H3K27ac), eRNA measurement, RNA-seq\",\n      \"journal\": \"Genome research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO in two cell types, genome-wide ChIP-seq, eRNA assay; multiple orthogonal methods\",\n      \"pmids\": [\"33414108\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"KDM1A interacts with and demethylates the cytoplasmic non-histone substrate FKBP8; FKBP8 demethylation enhances its ability to stabilize BCL2, promoting liver cancer cell survival; cytoplasmic KDM1A localization and stability is promoted by KAT8-mediated acetylation at lysine-117.\",\n      \"method\": \"Co-IP, in vitro demethylation assay, western blot, KAT8 overexpression/knockdown, xenograft tumor models\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and in vitro demethylation assay; single lab, two orthogonal methods\",\n      \"pmids\": [\"35970393\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"LSD1/KDM1A interacts with the DNA replication machinery and is required for euchromatic origin firing; LSD1 loss causes a genome-wide switch from early to late replication; mechanistically, LSD1 facilitates loading of TICRR onto pre-replication complexes and subsequent CDC45 recruitment during origin firing.\",\n      \"method\": \"Co-IP with replication factors, DNA fiber assay, ChIP-seq, siRNA/KO, origin firing assays\",\n      \"journal\": \"Signal transduction and targeted therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, DNA fiber assay, ChIP-seq; single lab, mechanistic pathway placement\",\n      \"pmids\": [\"35414135\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Catalytic inactivation of LSD1 has only mild effects on gene expression and cellular differentiation, whereas complete loss of LSD1 protein de-represses enhancers globally by increasing H3K27ac via P300/CBP; it is the gain of P300/CBP-catalyzed H3K27ac, not loss of CoREST complex from chromatin, that drives transcription derepression and differentiation defects.\",\n      \"method\": \"CRISPR catalytic-dead knockin vs. knockout, ChIP-seq (H3K27ac, P300), RNA-seq, differentiation assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — isogenic catalytic-dead knockin vs KO dissects catalytic vs scaffolding role; genome-wide ChIP-seq and RNA-seq; multiple orthogonal methods\",\n      \"pmids\": [\"37607921\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The LSD1 Y391K mutant is insensitive to H3K14 acetylation-mediated inhibition of H3K4 demethylase activity; K562 cells with Y391K CRISPR knockin show decreased expression of genes associated with cellular adhesion and myeloid leukocyte activation, and these genes display higher H3K14ac and lower H3K4me1, demonstrating functional crosstalk between H3K14ac and H3K4 demethylation by LSD1.\",\n      \"method\": \"CRISPR knockin of engineered mutant (Y391K), ChIP-seq, RNA-seq, in vitro demethylase assay\",\n      \"journal\": \"Nature chemical biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — engineered mutant validated by in vitro assay, CRISPR knockin in cells, ChIP-seq and RNA-seq; rigorous multi-method single study\",\n      \"pmids\": [\"38965385\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"LSD1 controls DNA methylation in mouse ESCs via a scaffolding (demethylase-independent) mechanism: LSD1 and catalytically-impaired LSD1 both stabilize UHRF1 and DNMT1 by interacting with HDAC1 and USP7, facilitating deacetylation and deubiquitination of DNMT1/UHRF1; loss of LSD1 (but not catalytic mutant) reduces DNMT1/UHRF1 levels and causes global hypomethylation.\",\n      \"method\": \"Conditional KO, catalytically-impaired knockin (LSD1MUT), Co-IP with HDAC1/USP7, bisulfite sequencing, western blot\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — isogenic catalytic-dead knockin distinguishes scaffolding from enzymatic function, biochemical Co-IP, bisulfite sequencing; multiple orthogonal methods\",\n      \"pmids\": [\"39237615\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ZNF750 recruits KDM1A/LSD1 to silence pattern recognition receptor genes (TLR3, IFIH1/MDA5, DDX58/RIG1) in differentiated keratinocytes; loss of ZNF750 or KDM1A results in sustained PRR expression and excessive skin inflammation resembling psoriasis that can be restored by TLR3 silencing.\",\n      \"method\": \"Conditional KO in mice, ChIP (ZNF750/KDM1A co-occupancy), siRNA knockdown, inflammatory phenotype assays\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-occupancy ChIP, genetic KO with defined inflammatory phenotype, epistasis rescue; single lab\",\n      \"pmids\": [\"39353440\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In BRAFi/MEKi-resistant melanoma, re-accumulated lactate induces lactylation of LSD1; lactylated LSD1 interacts with FosL1, preventing LSD1 degradation by E3 ligase TRIM21 and enhancing genomic enrichment of LSD1; lactylated LSD1-FosL1 co-directs transcription to repress ferroptosis by interfering with TFRC-mediated iron uptake.\",\n      \"method\": \"Mass spectrometry identification of LSD1 lactylation, Co-IP (LSD1–FosL1, LSD1–TRIM21), ChIP-seq, cell viability assays, murine drug-resistant tumor models\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mass spectrometry, Co-IP, ChIP-seq; single lab, mechanistic pathway placement\",\n      \"pmids\": [\"40132584\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"KDM1A/LSD1 is a FAD-dependent amine oxidase that demethylates mono- and di-methylated H3K4 (repressing transcription) or H3K9 (activating transcription), depending on context and binding partners; it operates in multiprotein complexes (e.g., CoREST-HDAC, AR, GR, NuRD, GFI1) that direct its substrate specificity, and additionally exerts demethylase-independent scaffolding functions—stabilizing DNMT1/UHRF1 via HDAC1/USP7 and blocking P300-driven enhancer acetylation—while also demethylating non-histone substrates (DNMT1, FKBP8, HIV Tat K51) and being regulated post-translationally by EHMT2-mediated K114 methylation, KAT8-mediated K117 acetylation, lactylation, and JADE-2-mediated proteasomal degradation, collectively making it a multifunctional epigenetic regulator of development, differentiation, DNA replication, DNA damage response, and immunity.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"KDM1A/LSD1 is a FAD-dependent histone demethylase that serves as a central, context-dependent epigenetic regulator of transcription, development, and genome maintenance [#0]. Its canonical activity removes mono- and di-methyl marks from histone H3 lysine 4 (H3K4me1/2), generating formaldehyde and repressing target genes, while in association with the androgen receptor it instead demethylates H3K9me1/2 to activate transcription, illustrating that bound partners redirect its substrate specificity [#0, #1]. Substrate choice and activity are governed by an extensive interaction network: high-affinity binding to CoREST through the LSD1 tower domain enables nucleosomal demethylation [#4], while assembly with the glucocorticoid receptor restrains processivity to leave H3K4me1 and licenses receptor chromatin binding [#18], and recruitment by sequence-specific factors such as GFI1, ZNF750, and FosL1 directs repression of differentiation, immune, and ferroptosis programs [#14, #26, #27]. Genome-wide, KDM1A counterbalances H3K4 methylation at enhancers to keep enhancer activity and eRNA output in check [#20], and isogenic catalytic-dead versus null comparisons show that much of its enhancer control is demethylase-independent\\u2014loss of the protein, not loss of catalysis, drives P300/CBP-mediated H3K27 acetylation and derepression [#23]. This scaffolding role extends to DNA methylation maintenance, where KDM1A stabilizes DNMT1 and UHRF1 by engaging HDAC1 and USP7, independent of its enzymatic function [#2, #25]. Beyond chromatin, KDM1A demethylates non-histone substrates including DNMT1, HIV Tat at K51, and cytoplasmic FKBP8, and it participates directly in DNA replication origin firing and the RNF168-dependent DNA damage response [#2, #6, #21, #22, #7]. It is regulated post-translationally by EHMT2-mediated K114 methylation read by CHD1, KAT8-mediated K117 acetylation, lactylation, and JADE-2\\u2013 and TRIM21\\u2013directed proteasomal degradation [#10, #21, #27, #16]. Through these activities KDM1A governs embryonic and maternal-to-zygotic transitions, hematopoietic and myogenic differentiation, neuronal maturation, retroelement silencing with antitumor immunity, and serves as a therapeutic target across several cancers [#5, #13, #9, #11, #8, #15].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Established that an amine-oxidase enzyme could remove methyl marks from histones, defining LSD1 as the first histone demethylase and a transcriptional corepressor.\",\n      \"evidence\": \"In vitro FAD-dependent demethylase assay with formaldehyde detection plus RNAi derepression of targets\",\n      \"pmids\": [\"15620353\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define how substrate specificity is directed in vivo\", \"Cofactor and complex requirements for nucleosomal substrates unresolved\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Showed that partner binding can switch LSD1's substrate from H3K4 to H3K9, converting it from a repressor to a coactivator in androgen receptor signaling.\",\n      \"evidence\": \"Co-IP, ChIP, in vitro binding, siRNA and reporter assays with AR; pargyline inhibition\",\n      \"pmids\": [\"16079795\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for the H3K4-to-H3K9 specificity switch not defined\", \"Whether other nuclear receptors use the same mechanism unknown at the time\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Extended LSD1 activity beyond histones, showing it demethylates and stabilizes DNMT1 to maintain global DNA methylation.\",\n      \"evidence\": \"In vitro demethylation assay, Co-IP, conditional KO in mouse ES cells, DNMT1 stability western blot\",\n      \"pmids\": [\"19098913\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not separate enzymatic from scaffolding contributions to DNMT1 stability\", \"Other non-histone substrates not yet surveyed\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Defined the molecular architecture of LSD1-CoREST binding and identified tissue-specific isoforms with distinct activities, beginning to explain context-dependent function.\",\n      \"evidence\": \"ITC and truncation mapping of CoREST linker-tower interaction; reporter and siRNA analysis of neuro-specific exon E8a isoforms\",\n      \"pmids\": [\"21142040\", \"20164337\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Isoform substrate specificity mechanism not yet resolved\", \"How CoREST binding alters catalysis on nucleosomes not fully defined\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Demonstrated LSD1's developmental requirement for retroelement and zygotic-gene silencing and its role in demethylating a viral non-histone substrate.\",\n      \"evidence\": \"Mouse KO with ChIP-seq at MERVL/ZGA loci; mass spectrometry of Tat K51 with ChIP and chemical inhibition\",\n      \"pmids\": [\"21357675\", \"21876670\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Recruitment machinery to retroelements not fully mapped\", \"Generality of non-histone demethylation across substrates unknown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Placed LSD1 in the DNA damage response, showing damage-site recruitment and a role in repair pathway choice.\",\n      \"evidence\": \"Live-cell imaging of recruitment, RNF168 Co-IP, ChIP, HR reporter and \\u03b3-irradiation sensitivity\",\n      \"pmids\": [\"24217620\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct catalytic substrate at damage sites versus scaffolding role not separated\", \"Link between H3K4me2 removal and ubiquitylation mechanistically incomplete\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Resolved how a non-catalytic isoform achieves a distinct activity through a new partner and placed LSD1 in a hematopoietic fate decision.\",\n      \"evidence\": \"In vitro demethylase assays, Co-IP, ChIP-seq of LSD1+8a with SVIL; zebrafish epistasis rescue with Etv2\",\n      \"pmids\": [\"25684206\", \"26512114\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of SVIL-conferred H3K9 activity unresolved\", \"Mammalian relevance of the Etv2 axis not established in this work\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Uncovered post-translational regulation of LSD1 by methylation (with a reader) and degradation, and broadened its roles to myogenesis, neurodegeneration, and the maternal-to-zygotic transition.\",\n      \"evidence\": \"Co-crystal of K114me2-CHD1, mass spectrometry, ChIP-seq; JADE-2 degradation assays; conditional/inducible and oocyte-specific KO mice with RNA-seq/bisulfite\",\n      \"pmids\": [\"26751641\", \"29618057\", \"28228264\", \"28993646\", \"26814574\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Interplay among K114 methylation, degradation, and complex assembly not integrated\", \"Causality of LSD1 mislocalization in human neurodegeneration not established\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Established that disrupting specific LSD1 protein-protein interfaces, not just catalysis, is required for oncogenic programs.\",\n      \"evidence\": \"Co-IP, structure-guided GFI1-LSD1 interface mutagenesis, in vivo genetic ablation in medulloblastoma models\",\n      \"pmids\": [\"30659187\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the catalytic contribution to GFI1-driven repression\", \"Generalizability beyond medulloblastoma not tested here\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Connected LSD1 loss to retroelement-driven innate immune activation, defining a route to enhance checkpoint-blockade immunotherapy.\",\n      \"evidence\": \"CRISPR/shRNA ablation, RNA-seq, immune infiltration flow cytometry, in vivo tumor models with anti-PD-1\",\n      \"pmids\": [\"29937226\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Catalytic versus scaffolding basis of ERV derepression not dissected\", \"Direct LSD1 targets driving the dsRNA response not fully mapped\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showed partner-dependent tuning of LSD1 processivity by the glucocorticoid receptor and placed LSD1 inhibition as a differentiation therapy in pediatric glioma.\",\n      \"evidence\": \"Reconstituted GR-complex cell-free demethylation assay and ChIP-seq; CRISPR screen and ChIP-seq in DIPG\",\n      \"pmids\": [\"31216473\", \"31631026\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of GR-imposed processivity limit not defined\", \"Whether DIPG effects are catalytic or scaffolding not resolved here\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Revealed that LSD1 inhibition can act by destabilizing CoREST-complex members, linking pharmacology to complex integrity.\",\n      \"evidence\": \"Pharmacological inhibition, Co-IP, HMG20B degradation with proteasome rescue, RNA-seq in Merkel cell carcinoma\",\n      \"pmids\": [\"33026191\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab, two orthogonal methods\", \"Mechanism of inhibitor-induced complex disassembly not structurally defined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined LSD1 as a genome-wide enhancer rheostat that constrains H3K4 methylation and eRNA output in stem cells and neurons.\",\n      \"evidence\": \"Conditional/inducible KO in mESCs and neurons with H3K4me1/2 and H3K27ac ChIP-seq, eRNA and RNA-seq\",\n      \"pmids\": [\"33414108\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not isolate catalytic from scaffolding contribution at enhancers\", \"Determinants of enhancer-specific occupancy unresolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Extended LSD1 function to cytoplasmic non-histone substrate demethylation and to direct participation in replication origin firing.\",\n      \"evidence\": \"Co-IP and in vitro FKBP8 demethylation with KAT8 K117 acetylation; replication-factor Co-IP, DNA fiber and origin-firing assays\",\n      \"pmids\": [\"35970393\", \"35414135\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab evidence with two orthogonal methods each\", \"Direct versus indirect role in TICRR/CDC45 loading not fully resolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Dissected catalytic from scaffolding function, establishing that protein presence\\u2014via suppression of P300/CBP-driven H3K27ac\\u2014rather than demethylase activity drives enhancer repression and differentiation control.\",\n      \"evidence\": \"Isogenic catalytic-dead knockin versus knockout with H3K27ac/P300 ChIP-seq, RNA-seq, differentiation assays\",\n      \"pmids\": [\"37607921\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How LSD1 protein physically blocks P300/CBP not structurally defined\", \"Loci where catalysis remains essential not enumerated\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Consolidated the scaffolding paradigm for DNA methylation, mapped histone-acetylation crosstalk regulating catalysis, and added an immune-silencing partner.\",\n      \"evidence\": \"Catalytic-impaired knockin with HDAC1/USP7 Co-IP and bisulfite sequencing; Y391K knockin with H3K14ac crosstalk ChIP-seq; ZNF750-KDM1A co-occupancy and KO inflammatory phenotype\",\n      \"pmids\": [\"39237615\", \"38965385\", \"39353440\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological signals controlling H3K14ac-mediated inhibition unclear\", \"Recruitment hierarchy among ZNF750, CoREST, and LSD1 not fully resolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed metabolic regulation of LSD1 by lactylation that stabilizes the protein and redirects it to repress ferroptosis in drug-resistant tumors.\",\n      \"evidence\": \"Mass spectrometry of LSD1 lactylation, Co-IP (FosL1, TRIM21), ChIP-seq, viability assays, murine resistant-tumor models\",\n      \"pmids\": [\"40132584\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab mechanistic placement\", \"Lactylation site stoichiometry and direct effect on catalysis not defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how LSD1's many post-translational modifications, isoforms, and partner complexes are integrated to set the balance between catalytic and scaffolding functions at any given locus.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified structural model coupling modification state to complex assembly and substrate choice\", \"Catalytic versus scaffolding contributions not systematically mapped genome-wide across cell types\", \"Rules governing recruitment by competing sequence-specific factors unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 2, 6, 8, 18, 21, 24]},\n      {\"term_id\": \"GO:0016491\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 1, 20, 23]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [0, 4]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [23, 25]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 1, 5, 20]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [21]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 1, 20, 23]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [0, 5, 20, 23]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"R-HSA-69306\", \"supporting_discovery_ids\": [22]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [5, 9, 11, 13]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [15, 26]}\n    ],\n    \"complexes\": [\"CoREST-HDAC\", \"androgen receptor complex\", \"glucocorticoid receptor complex\"],\n    \"partners\": [\"RCOR1\", \"AR\", \"NR3C1\", \"DNMT1\", \"GFI1\", \"HDAC1\", \"USP7\", \"UHRF1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}