Affinage

KDM1A

Lysine-specific histone demethylase 1A · UniProt O60341

Length
852 aa
Mass
92.9 kDa
Annotated
2026-04-28
100 papers in source corpus 39 papers cited in narrative 39 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

KDM1A (LSD1) is an FAD-dependent amine oxidase that demethylates mono- and di-methylated histone H3K4 (transcriptional repression) and H3K9 (transcriptional activation), and also demethylates non-histone substrates including DNMT1, HIV Tat-K51, and FKBP8, functioning as the catalytic core of the LSD1/CoREST/HDAC corepressor complex whose activity on nucleosomal substrates requires CoREST-mediated DNA and histone contacts (PMID:15620353, PMID:16079795, PMID:19098913, PMID:32396821). Beyond its demethylase activity, LSD1 exerts critical scaffolding functions—blocking P300/CBP-mediated H3K27 acetylation at enhancers independently of catalysis, and promoting FBXW7 degradation as a pseudosubstrate—while its genomic targeting is dictated by context-specific transcription factors (androgen receptor, MYCN, Blimp-1, SIX3) and cofactors that assemble it into distinct activating or repressing complexes (PMID:37607921, PMID:31152129, PMID:17392792, PMID:26062444). Neuron-specific alternative splicing generates the LSD1+8a isoform that shifts substrate preference from H3K4 to H3K9 demethylation through interaction with supervillin, while post-translational modifications including K63-linked ubiquitination (removed by OTUD7B), KAT8-mediated K117 acetylation, and lactylation regulate LSD1 stability, complex integrity, and genomic occupancy (PMID:25684206, PMID:34050636, PMID:35970393, PMID:40132584). LSD1 is essential for silencing endogenous retroviruses and maintaining genomic integrity during early embryogenesis, the maternal-to-zygotic transition, and multiple lineage decisions including hematopoietic, muscle, intestinal, and neuronal differentiation, and participates in the DNA damage response downstream of RNF168 (PMID:21357675, PMID:26814574, PMID:34324630, PMID:24217620).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 2004 High

    The foundational question of whether histone methylation is reversible was answered by demonstrating that LSD1 specifically removes H3K4me1/2 via FAD-dependent oxidation, establishing the first histone demethylase and a new paradigm for epigenetic regulation.

    Evidence In vitro demethylase assay with mass spectrometric detection of formaldehyde product, RNAi knockdown causing H3K4me accumulation and gene derepression in human cells

    PMID:15620353

    Open questions at the time
    • Mechanism of substrate selection among different lysine methylation states unknown
    • Whether LSD1 acts on non-H3K4 substrates not tested
    • In vivo relevance in development not yet addressed
  2. 2005 High

    The puzzle of how a H3K4 demethylase (repressor) could also activate transcription was resolved by showing that LSD1 demethylates H3K9me1/2 at androgen receptor target genes upon ligand stimulation, establishing dual substrate specificity directed by interaction partners.

    Evidence Reciprocal Co-IP of LSD1 with androgen receptor, ChIP demonstrating H3K9me loss at AR targets, pargyline blockade of AR-dependent transcription

    PMID:16079795

    Open questions at the time
    • Structural basis for H3K9 vs. H3K4 substrate switching not determined
    • Whether other nuclear receptors similarly redirect LSD1 specificity untested
  3. 2007 High

    How LSD1 could simultaneously participate in gene activation and repression programs in the same tissue was explained by showing it assembles into distinct complexes—CoREST-CtBP for repression vs. a separate co-activator complex—with context-dependent switching controlled by ZEB1 during pituitary development.

    Evidence Mouse genetic model of pituitary organogenesis, Co-IP identifying distinct LSD1 complexes, ChIP at target promoters

    PMID:17392792

    Open questions at the time
    • Identity of the co-activator complex components not fully resolved
    • Whether complex switching generalizes beyond pituitary lineage unclear
  4. 2008 High

    Whether LSD1 acts on non-histone substrates was answered by demonstrating that LSD1 demethylates DNMT1, thereby stabilizing DNMT1 protein and maintaining global DNA methylation—linking histone demethylation to DNA methylation maintenance.

    Evidence In vitro demethylase assay on DNMT1 peptide, LSD1 knockout ES cells showing DNMT1 destabilization and progressive DNA hypomethylation

    PMID:19098913

    Open questions at the time
    • Whether LSD1-DNMT1 axis operates in all cell types or is context-specific not established
    • Additional non-histone substrates not yet surveyed
  5. 2010 High

    The functional significance of neuron-specific LSD1 splicing was established by identifying exon 8a-containing isoforms that are required for neurite maturation and have reduced transcriptional repressor activity, demonstrating tissue-specific fine-tuning of LSD1 function through alternative splicing.

    Evidence RT-PCR isoform analysis during cortical development, isoform-specific siRNA knockdown blocking neurite morphogenesis, in vitro demethylase and reporter assays

    PMID:20164337

    Open questions at the time
    • Molecular basis for reduced repressor activity of 8a isoform not resolved
    • Cofactor requirements for isoform-specific activity unknown
  6. 2010 High

    Biophysical characterization of the LSD1-CoREST interface revealed a high-affinity (Kd ~16 nM) 1:1 complex mediated by the CoREST linker region and LSD1 tower domain, providing the structural framework for understanding how CoREST enables nucleosomal substrate access.

    Evidence Isothermal titration calorimetry with CoREST truncation series

    PMID:21142040

    Open questions at the time
    • Full structural model of how CoREST contacts the nucleosome not yet available
    • Whether the tower-linker interface is druggable not addressed
  7. 2011 High

    A genome-wide role for LSD1 in silencing endogenous retroviruses was uncovered, showing that LSD1 demethylates H3K4 and promotes H3K9 methylation at MERVL elements, with loss causing embryonic arrest—connecting LSD1 to transposable element control and early development.

    Evidence Mouse KO with ChIP-seq at MERVL and neighboring loci, ES cell rescue experiments

    PMID:21357675

    Open questions at the time
    • How LSD1 is specifically targeted to ERVs vs. other genomic repeats unclear
    • Whether MERVL derepression directly causes gastrulation arrest or is correlative not fully resolved
  8. 2013 High

    LSD1 was placed in the DNA damage response by demonstrating its RNF168-dependent recruitment to damage sites, where H3K4me2 demethylation is required for 53BP1 and BRCA1 foci formation, particularly in S/G2 phase.

    Evidence Live cell imaging of LSD1 recruitment to laser-induced damage, Co-IP with RNF168, ChIP at damage loci, siRNA causing radiation sensitivity

    PMID:24217620

    Open questions at the time
    • Whether LSD1 demethylase activity or scaffolding is the critical function at damage sites not distinguished
    • Structural basis of RNF168-LSD1 interaction not determined
  9. 2015 High

    The mechanism underlying neuron-specific LSD1+8a substrate switching was resolved: the 8a isoform lacks intrinsic H3K4me2 activity but gains H3K9me2 demethylation capacity through interaction with the cofactor supervillin (SVIL), which co-localizes at target promoters.

    Evidence In vitro demethylase assay comparing isoforms, Co-IP identifying SVIL, ChIP co-localization, siRNA phenocopy

    PMID:25684206

    Open questions at the time
    • How SVIL binding alters LSD1 active site geometry not structurally resolved
    • Whether SVIL is the sole determinant of H3K9 specificity in neurons not excluded
  10. 2016 High

    The requirement for maternally provided LSD1 in the earliest stages of mammalian development was established: maternal LSD1 is essential for the maternal-to-zygotic transition, and its partial loss disrupts imprinted gene methylation, causing perinatal lethality.

    Evidence Conditional maternal KO in mouse oocytes, DNA methylation and imprinted gene expression analysis

    PMID:26814574

    Open questions at the time
    • Which specific targets of maternal LSD1 are required for MZT competence not identified
    • Whether demethylase vs. scaffolding activity is required at this stage not tested
  11. 2017 Medium

    Multiple studies established that context-specific transcription factors (MYCN, SIX3, and others) recruit LSD1 to defined genomic targets, demonstrating that LSD1's repressive output depends on its interaction partners rather than intrinsic targeting.

    Evidence Co-IP and ChIP co-occupancy of LSD1 with MYCN at CDKN1A/CLU, AP-MS identification of LSD1/NuRD(MTA3)/SIX3 complex, ChIP at MyoD core enhancer in conditional KO muscle progenitors

    PMID:26062444 PMID:28228264 PMID:29463994

    Open questions at the time
    • Comprehensive map of all transcription factors that direct LSD1 genomic occupancy not available
    • Relative contribution of each partner to LSD1 occupancy genome-wide not quantified
  12. 2018 High

    LSD1 was connected to innate immune evasion in cancer: its loss derepresses endogenous retroviral elements, generates cytoplasmic dsRNA, and activates type I interferon signaling, sensitizing tumors to anti-PD-1 checkpoint therapy.

    Evidence CRISPR KO with RNA-seq, dsRNA detection, interferon pathway assays, in vivo tumor models with checkpoint blockade

    PMID:29937226

    Open questions at the time
    • Whether all tumor types exhibit this ERV-dsRNA-interferon axis upon LSD1 loss not determined
    • Relative contribution of LSD1 catalytic vs. scaffolding activity in ERV silencing in cancer not dissected
  13. 2019 High

    A demethylase-independent oncogenic mechanism was uncovered: LSD1 binds FBXW7 as a pseudosubstrate, blocks FBXW7 dimerization, and promotes its autophagic/proteasomal degradation, abrogating FBXW7 tumor suppressor function.

    Evidence Reciprocal Co-IP, ubiquitylation and dimerization assays, catalytic-dead LSD1 mutant retaining full FBXW7-destabilizing activity

    PMID:31152129

    Open questions at the time
    • Structural basis of pseudosubstrate binding to FBXW7 not resolved
    • Whether this mechanism operates in non-cancer contexts not tested
  14. 2020 High

    The crystal structure of LSD1/CoREST on a nucleosome revealed that CoREST bridges both DNA and histone surfaces while the LSD1 catalytic domain contacts extranucleosomal DNA ~100 Å from the core, explaining the longstanding requirement for CoREST in nucleosomal demethylation.

    Evidence X-ray crystallography of LSD1/CoREST bound to 191-bp nucleosome, mutagenesis showing K661A mutant retains nucleosomal activity

    PMID:32396821

    Open questions at the time
    • How LSD1 accesses the H3 tail from its distal position not mechanistically clear
    • Whether nucleosome remodeling is required for productive demethylation in vivo not addressed
  15. 2021 High

    K63-linked ubiquitination was identified as a key regulatory switch for LSD1 complex integrity: OTUD7B removes K63-Ub at K226/K277, and without deubiquitination, LSD1 dissociates from CoREST and undergoes p62-mediated proteolysis, reducing genome-wide occupancy.

    Evidence Co-IP, ubiquitination site mapping, genome-wide ChIP showing reduced LSD1 occupancy upon OTUD7B depletion

    PMID:34050636

    Open questions at the time
    • The E3 ligase that installs K63-Ub on LSD1 not identified
    • Whether other deubiquitinases compensate for OTUD7B loss in specific tissues not tested
  16. 2021 High

    LSD1 was shown to function as a lineage gatekeeper in hematopoiesis: its loss in erythroid progenitors causes erythroid-to-myeloid fate conversion through de-repression of PU.1 and CEBPα, rescuable by blocking either transcription factor.

    Evidence Conditional KO using Gata1-creERT2, epistasis rescue by PU.1/RUNX1 inhibition, replicated in human HSCs

    PMID:34324630

    Open questions at the time
    • Whether LSD1 directly demethylates PU.1/CEBPα loci or acts indirectly not fully resolved
    • How LSD1 selectively maintains erythroid identity while being broadly expressed not explained
  17. 2023 High

    The relative importance of LSD1's catalytic vs. scaffolding functions was definitively dissected: catalytic inactivation has mild effects, whereas protein loss causes widespread enhancer de-repression via unopposed P300/CBP-mediated H3K27 acetylation, establishing that LSD1's primary role at enhancers is blocking acetyltransferase access.

    Evidence Catalytic point-mutant knock-in compared to protein deletion, genome-wide ChIP-seq for H3K27ac and P300, RNA-seq

    PMID:37607921

    Open questions at the time
    • Whether the scaffolding function depends on LSD1's interaction with specific cofactors or is intrinsic to the protein not resolved
    • Relative contribution of catalytic vs. scaffolding function in different developmental contexts not systematically assessed
  18. 2025 Medium

    Lactylation was identified as a novel post-translational modification of LSD1 that stabilizes it by preventing TRIM21-mediated degradation, promotes FosL1 interaction, and redirects LSD1 to repress ferroptosis genes in drug-resistant melanoma.

    Evidence Lactylation detection, Co-IP of lactylated LSD1 with FosL1 and TRIM21, ChIP-seq of lactylated LSD1, ferroptosis assays

    PMID:40132584

    Open questions at the time
    • The specific lactylation sites on LSD1 and whether they are conserved across species not mapped
    • Whether lactylation regulates LSD1 in non-cancer physiological contexts not tested
    • Independent replication awaited

Open questions

Synthesis pass · forward-looking unresolved questions
  • Major open questions include: the structural basis for how transcription factor partners redirect LSD1 substrate specificity, the relative contribution of catalytic vs. scaffolding functions across different developmental and disease contexts, and whether additional post-translational modifications beyond ubiquitination, acetylation, and lactylation regulate LSD1 in a tissue-specific manner.
  • No systematic structure-function analysis of LSD1 partnered with different transcription factors
  • Catalytic vs. scaffolding dissection limited to one cellular system
  • Full PTM map of endogenous LSD1 across tissues not available

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016491 oxidoreductase activity 7 GO:0042393 histone binding 6 GO:0140096 catalytic activity, acting on a protein 6 GO:0140110 transcription regulator activity 5 GO:0098772 molecular function regulator activity 3
Localization
GO:0005634 nucleus 7 GO:0000228 nuclear chromosome 3 GO:0005829 cytosol 1
Pathway
R-HSA-4839726 Chromatin organization 7 R-HSA-1266738 Developmental Biology 6 R-HSA-74160 Gene expression (Transcription) 6 R-HSA-1643685 Disease 3 R-HSA-168256 Immune System 3 R-HSA-5357801 Programmed Cell Death 2 R-HSA-73894 DNA Repair 1
Partners
ARFBXW7KAT8MYCNOTUD7BPRDM1RCOR1SVIL
Complex memberships
LSD1/CoREST/CtBPLSD1/CoREST/HDACLSD1/NuRD(MTA3)

Evidence

Reading pass · 39 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2004 LSD1 (KDM1A) is a histone demethylase that specifically demethylates histone H3 lysine 4 (H3K4me1/2) via an FAD-dependent oxidative mechanism, generating formaldehyde as a byproduct. RNAi knockdown causes increased H3K4 methylation and derepression of target genes, establishing LSD1 as a transcriptional corepressor. In vitro demethylase assay, RNAi knockdown, chromatin immunoprecipitation, mass spectrometry Cell High 15620353
2005 LSD1 interacts with the androgen receptor in vitro and in vivo, and demethylates H3K9me1/2 (a repressive mark) at androgen receptor target gene promoters upon ligand stimulation, thereby activating transcription. Pargyline inhibits this demethylation and blocks androgen-receptor-dependent transcription. Co-immunoprecipitation, chromatin immunoprecipitation, in vitro interaction assay, siRNA knockdown, pharmacological inhibition Nature High 16079795
2008 LSD1 demethylates DNMT1 protein (a non-histone substrate) in vitro, counteracting Set7/9-mediated methylation of DNMT1. Loss of LSD1 in ES cells leads to increased DNMT1 methylation, reduced DNMT1 stability, and progressive loss of global DNA methylation. In vitro demethylase assay, targeted gene deletion in ES cells, western blot for protein stability, in vivo methylation analysis Nature genetics High 19098913
2007 LSD1 functions in both gene activation and repression programs depending on its associated complex: the LSD1-CoREST-CtBP complex mediates repression, while a distinct LSD1-containing co-activator complex mediates activation during pituitary organogenesis. ZEB1 expression recruits the LSD1-CoREST-CtBP complex to repress previously LSD1-activated genes. Genetic mouse model, reporter assays, co-immunoprecipitation, chromatin immunoprecipitation Nature High 17392792
2007 S. pombe LSD1 homologs (spLsd1 and spLsd2) form a stable complex that demethylates H3K9me in vitro. Loss of spLsd1 increases H3K9 methylation at euchromatic promoters and boundary regions, suppressed by removal of H3K9 methylase Clr4, placing spLsd1 downstream in heterochromatin regulation. In vitro demethylase assay, genetic deletion, epistasis with H3K9 methylase mutant, chromatin immunoprecipitation Molecular cell High 17434129
2011 LSD1/KDM1A represses endogenous retroviral elements (MuERV-L/MERVL) and neighboring cellular genes through H3K4 demethylation and H3K9 methylation. Loss of KDM1A in ES cells increases H3K4 methylation and H3K27 acetylation at MERVL elements and adjacent genes, causing embryonic arrest at gastrulation. Mouse genetic deletion, genome-wide epigenetic profiling (ChIP-seq), ES cell rescue experiments Genes & development High 21357675
2011 LSD1/KDM1 demethylates monomethylated lysine 51 (K51me1) of HIV Tat protein in a K51-specific manner. This demethylation is required for subsequent K50 acetylation and activation of HIV transcription. LSD1 and its cofactor CoREST associate with the HIV promoter in vivo. Mass spectrometry on immunoprecipitated Tat, modification-specific antibodies, ChIP, shRNA knockdown, pharmacological inhibition PLoS pathogens High 21876670
2012 KDM1A sustains oncogenic gene expression programs at MLL-AF9-bound genomic loci in leukemia stem cells, preventing differentiation and apoptosis. Pharmacological inhibition using tranylcypromine analogs phenocopies KDM1A knockdown in murine and human AML cells without affecting normal hematopoietic stem and progenitor cells. Mouse MLL-AF9 leukemia model, shRNA knockdown, pharmacological inhibition, in vivo transplantation assays, gene expression analysis Cancer cell High 22464800
2013 LSD1/KDM1A is recruited to sites of DNA damage in an RNF168 E3 ubiquitin ligase-dependent manner. At damage sites, LSD1 demethylates H3K4me2, and its loss impairs 53BP1 and BRCA1 complex recruitment (preferentially in late S/G2) due to compromised histone ubiquitylation, placing LSD1 downstream of RNF168 in the DNA damage response pathway. Live cell imaging of recruitment to damage sites, co-immunoprecipitation, ChIP at damage loci, siRNA knockdown, gamma-irradiation sensitivity assay The Journal of cell biology High 24217620
2015 A neuron-specific LSD1 isoform, LSD1+8a (containing exon 8a within the amine oxidase domain), lacks intrinsic H3K4me2 demethylase activity but mediates H3K9me2 demethylation at target promoters through interaction with the novel cofactor supervillin (SVIL). SVIL co-localizes with LSD1+8a at target promoters and its knockdown mimics LSD1+8a loss. In vitro demethylase assay comparing isoforms, Co-immunoprecipitation identifying SVIL, ChIP, siRNA knockdown, neuronal differentiation assay Molecular cell High 25684206
2010 Alternative splicing of LSD1 in neurons generates isoforms containing exon E8a (neuro-specific) whose expression increases during cortical development. Neuro-specific LSD1 isoforms have comparable in vitro demethylase activity but reduced transcriptional repressor activity on a reporter gene. Knockdown of neuro-specific but not ubiquitous isoforms inhibits neurite maturation. RT-PCR isoform analysis, in vitro demethylase assay, reporter gene assay, siRNA isoform-specific knockdown, neurite morphogenesis assay The Journal of neuroscience High 20164337
2020 The crystal structure of the LSD1/CoREST complex bound to a 191-bp nucleosome reveals that the LSD1 catalytic domain binds extranucleosomal DNA and is positioned ~100 Å from the nucleosome core. CoREST makes critical contacts with both histone and DNA components, explaining its essential role in enabling LSD1 to demethylate nucleosomal (not just peptide) substrates. The commonly used LSD1(K661A) catalytically inactive mutant retains substantial H3K4 demethylase activity on nucleosome substrates. X-ray crystallography of LSD1/CoREST-nucleosome complex, in vitro demethylase assay with nucleosome substrate, mutagenesis Molecular cell High 32396821
2010 LSD1 knockdown in 3T3-L1 preadipocytes markedly reduces adipogenesis, associated with decreased H3K4me2 and increased H3K9me2 at the CEBPA promoter. LSD1 maintains a permissive chromatin state at adipogenic gene promoters by opposing the H3K9 methyltransferase SETDB1. siRNA knockdown, chromatin immunoprecipitation for H3K4me2 and H3K9me2 at CEBPA promoter, differentiation assay The Journal of biological chemistry Medium 20656681
2010 Thermodynamic characterization by isothermal titration calorimetry shows LSD1 and CoREST bind with a Kd of ~16 nM in a 1:1 stoichiometry. The central binding determinant lies in CoREST residues 293-380 (the 'linker' region), which forms a triple-helical bundle with the LSD1 coiled-coil tower domain. Isothermal titration calorimetry, structure-guided CoREST truncation analysis Biochemistry High 21142040
2016 LSD1 inactivation in adult mice leads to hippocampal and cortical neurodegeneration with re-activation of stem cell genes in degenerating neurons. LSD1 is mislocalized to pathological protein aggregates in Alzheimer's disease and frontotemporal dementia cases. Inducible conditional knockout in adult mice, transcriptome analysis, immunohistochemistry in human neurodegenerative disease tissue Nature communications Medium 28993646
2016 Maternally provided LSD1/KDM1A 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 LSD1 loss leads to alterations in DNA methylation and expression at imprinted genes, manifesting as perinatal lethality and behavioral abnormalities. Conditional maternal knockout in mice, DNA methylation analysis, imprinted gene expression analysis eLife High 26814574
2018 LSD1 ablation in cancer cells increases expression of endogenous retroviral elements, decreases RISC component expression, leading to dsRNA stress, type 1 interferon activation, and anti-tumor T cell immunity. This mechanism enables response to anti-PD-1 checkpoint blockade. CRISPR knockout, RNA-seq, dsRNA detection, interferon signaling assays, in vivo tumor models with checkpoint blockade Cell High 29937226
2019 LSD1 binds to the NOTCH1 locus and suppresses NOTCH1 expression and downstream signaling. LSD1 inhibition reactivates NOTCH signaling, suppresses ASCL1 and neuroendocrine gene expression, and reduces SCLC tumorigenesis. ChIP showing LSD1 occupancy at NOTCH1 locus, pharmacological inhibition and shRNA knockdown, gene expression analysis, in vivo PDX models Science signaling High 30723171
2019 LSD1 directly binds FBXW7 as a pseudosubstrate in a demethylase-independent manner, preventing FBXW7 dimerization and promoting FBXW7 self-ubiquitylation, leading to FBXW7 degradation via p62/SQSTM1-mediated autophagy and proteasome. This destabilizes FBXW7 and abrogates its tumor suppressor functions. Co-immunoprecipitation, ubiquitylation assay, dimerization assay, proteasome/autophagy pathway analysis, catalytic mutant LSD1 Proceedings of the National Academy of Sciences of the United States of America High 31152129
2021 OTUD7B deubiquitinates LSD1 at K226/K277 residues, removing K63-linked polyubiquitination. K63-ubiquitinated LSD1 dissociates from the CoREST complex and is targeted for p62-mediated proteolysis. OTUD7B deficiency disrupts LSD1/CoREST complex integrity and reduces genome-wide LSD1 occupancy. Co-immunoprecipitation, ubiquitination site mapping, proteolysis assay, genome-wide ChIP, cell cycle analysis Advanced science High 34050636
2017 LSD1 directly regulates PLK1 transcription by binding to the PLK1 promoter. LSD1 inhibition causes G2-M arrest and downregulation of PLK1 pathway genes, and exogenous PLK1 overexpression rescues the LSD1 inhibition-mediated PLK1 pathway suppression. ChIP showing LSD1 at PLK1 promoter, siRNA/pharmacological inhibition, rescue by PLK1 overexpression, gene expression profiling Molecular cancer research Medium 30760542
2017 LSD1 binds MYCN both in vitro and in vivo; this interaction requires the MYCN BoxIII domain. LSD1 co-localizes with MYCN at the CDKN1A and CLU tumor suppressor gene promoters and cooperates with MYCN to repress their expression. LSD1 association with these promoters is dependent on MYCN. Co-immunoprecipitation (in vitro and in vivo), ChIP at CDKN1A and CLU promoters, siRNA and pharmacological inhibition Oncotarget Medium 26062444
2017 LSD1 binds the promoter of Sestrin2 (SESN2), a regulator of mTORC1. LSD1 inhibition or knockdown derepresses SESN2 expression, which suppresses mTORC1 activity and promotes autophagy in neuroblastoma cells. SESN2 overexpression mimics and SESN2 loss reduces LSD1 inhibition-induced autophagy. ChIP at SESN2 promoter, pharmacological and siRNA inhibition of LSD1, SESN2 knockdown/overexpression, mTORC1 activity assay Oncogene Medium 28783174
2017 LSD1 is recruited to the MyoD core enhancer upon muscle differentiation, where it demethylates H3K9me to facilitate RNA polymerase II recruitment and transcription of a non-coding enhancer RNA (CEeRNA) required for MyoD expression. Conditional Lsd1 inactivation in muscle progenitors delays MyoD expression during embryogenesis. ChIP of LSD1 at MyoD core enhancer, H3K9 methylation ChIP, Pol II ChIP, conditional knockout in mice, enhancer RNA detection Cell reports High 28228264
2018 LSD1 is required for B cell proliferation and differentiation into plasmablasts. LSD1-deficient plasmablasts show increased H3K4me1 and chromatin accessibility at naive B cell active enhancers, including binding sites for Blimp-1, PU.1, and IRF4, consistent with a role for LSD1 in decommissioning enhancers during differentiation. Conditional knockout in mice, ATAC-seq, H3K4me1 ChIP, gene expression analysis, flow cytometry Journal of immunology Medium 30232138
2019 Blimp-1 recruits LSD1 to the Pdcd1 (PD-1) gene locus during acute but not chronic LCMV infection, facilitating removal of H3K4me marks and repression of PD-1 expression. LSD1-deficient CD8 T cells fail to remethylate the Pdcd1 locus and maintain elevated PD-1 expression. Conditional KO in CD8 T cells, Co-immunoprecipitation of Blimp-1 and LSD1, ChIP at Pdcd1 locus, in vivo LCMV infection model Journal of immunology Medium 31811020
2017 LSD1 independently of its demethylase activity stabilizes ERRα protein by protecting it from ubiquitination, thereby increasing ERRα protein levels in breast cancer cells. Demethylase-inactive LSD1 mutant, ubiquitination assay, protein stability assay PloS one Medium 29190800
2018 Lsd1 ablation or inhibition in Pax7-positive satellite cells delays muscle regeneration and redirects cell fate toward brown adipocytes. Lsd1 directly regulates key myogenic transcription factor genes and prevents brown adipocyte differentiation by repressing the pro-adipogenic transcription factor Glis1. Conditional Lsd1 knockout in Pax7+ cells, pharmacological inhibition, gene expression and chromatin analysis, cell fate tracing Nature communications High 29371665
2020 Conditional LSD1 knockout in intestinal epithelium blocks Paneth cell differentiation. Mechanistically, LSD1 enzymatically represses a set of fetal/neonatal gene expression programs; without LSD1, these genes are de-repressed and the epithelium acquires superior regenerative capacity after irradiation. Conditional knockout in mouse intestinal epithelium, organoid cultures, transcriptome analysis, irradiation regeneration assay Science advances Medium 32917713
2023 Catalytic inactivation of LSD1 has mild impact on gene expression and cellular differentiation, whereas loss of LSD1 protein de-represses enhancers globally by increasing H3K27ac (catalyzed by P300/CBP) and P300 occupancy at LSD1-targeted enhancers. This demonstrates a demethylase-independent role of LSD1 in enhancer repression through exclusion of P300/CBP. Catalytic point mutant knock-in vs. protein deletion, ChIP-seq for H3K27ac and P300, RNA-seq, CRISPR-based genetic dissection Nature communications High 37607921
2022 KDM1A demethylates FKBP8 (a non-histone cytoplasmic substrate), and this demethylation stabilizes BCL2 protein. KDM1A cytoplasmic localization and protein stability are promoted by acetylation at lysine-117 by acetyltransferase KAT8, and K117 acetylation enhances FKBP8 demethylation activity. Co-immunoprecipitation, in vitro demethylation assay, acetylation site mapping, KAT8 identification, BCL2 stability assay, subcellular fractionation The Journal of biological chemistry Medium 35970393
2025 Lactylation of LSD1 (induced by re-accumulated lactate in BRAFi/MEKi-resistant melanoma cells) promotes LSD1 interaction with FosL1, prevents TRIM21-mediated LSD1 degradation, and enhances LSD1 genomic enrichment. Lactylated LSD1 co-directs gene transcription with FosL1 to repress ferroptosis by interfering with TFRC-mediated iron uptake. Lactylation detection, Co-immunoprecipitation (LSD1-FosL1 and TRIM21), ChIP-seq of lactylated LSD1, ubiquitination/degradation assay, gene expression and ferroptosis assays Developmental cell Medium 40132584
2018 LSD1 interacts with androgen receptor and co-binds the CENPE promoter in castration-resistant prostate cancer (CRPC). LSD1 epigenetic reprogramming in CRPC activates CENPE and other cell-cycle genes, dependent on co-loss of RB1. ChIP of LSD1 and AR at CENPE promoter, genetic and pharmacological inhibition, CRPC patient sample analysis Cancer research Medium 28916652
2015 LSD1/KDM1A is recruited to the SESN2 promoter and represses its expression; in addition, LSD1 acts together with UBE4B in a protein quality control pathway mediated through regulation of p53, a shared substrate of both enzymes, that controls proteasomal and autophagic degradation of misfolded proteins. C. elegans genetic screen, mammalian cell KD, p53 target gene analysis, proteasomal/autophagic assays PLoS biology Medium 25837623
2017 LSD1 interacts with EZH2 (H3K27 methyltransferase, component of PRC2), as shown by Co-IP and GST pulldown in MCF-7 cells. The LSD1-EZH2 interaction stabilizes LSD1 binding to the IRF9 promoter, coordinately repressing interferon-stimulated gene expression. Co-immunoprecipitation, GST pulldown, ChIP at IRF9 promoter, siRNA knockdown of LSD1 and EZH2, proteomics Biomedicine & pharmacotherapy Medium 28152483
2018 BRMS1 is an integral component of the LSD1/CoREST corepressor complex, identified by affinity purification and mass spectrometry. BRMS1 together with LSD1 is required for repression of metastasis-related target genes and inhibition of breast cancer cell migration and invasion. Affinity purification and mass spectrometry, Co-IP, RNA-seq, migration/invasion assays American journal of cancer research Medium 30416854
2018 SIX3 recruits the LSD1/NuRD(MTA3) complex to suppress WNT1 and FOXC2 target genes. The complex was identified by affinity purification and mass spectrometry, and genome-wide ChIP-chip analysis identified the cohort of co-occupied targets. Affinity purification and mass spectrometry, co-immunoprecipitation, genome-wide ChIP-chip Theranostics Medium 29463994
2021 LSD1 inactivation in erythroid progenitors blocks erythroid differentiation and induces expansion of granulocyte-monocyte progenitor-like cells (erythroid-to-myeloid fate conversion). This is mediated by de-repression of myeloid transcription factors PU.1 and CEBPα; blocking PU.1 or RUNX1 activity simultaneously with LSD1 inhibition rescues the erythroid phenotype. Conditional Lsd1 KO using Gata1-creERT2, human HSC studies, myeloid TF inhibition rescue, gene expression analysis Blood High 34324630
2024 KDM1A acts as a transcriptional activator of PIAS4, and PIAS4 promotes SUMOylation of SLC7A11 via direct binding. Tanshinone IIA decreases KDM1A expression, suppressing PIAS4 transcription, thereby reducing PIAS4-dependent SUMOylation of SLC7A11 and inducing ferroptosis in breast cancer cells. ChIP of KDM1A at PIAS4 promoter, luciferase reporter, Co-IP of PIAS4-SLC7A11, Ni-beads pull-down for SUMOylation, xenograft models Journal of advanced research Medium 38615741

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2004 Histone demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell 3328 15620353
2005 LSD1 demethylates repressive histone marks to promote androgen-receptor-dependent transcription. Nature 1412 16079795
2008 The lysine demethylase LSD1 (KDM1) is required for maintenance of global DNA methylation. Nature genetics 645 19098913
2018 LSD1 Ablation Stimulates Anti-tumor Immunity and Enables Checkpoint Blockade. Cell 547 29937226
2012 The histone demethylase KDM1A sustains the oncogenic potential of MLL-AF9 leukemia stem cells. Cancer cell 480 22464800
2007 Opposing LSD1 complexes function in developmental gene activation and repression programmes. Nature 472 17392792
2018 ORY-1001, a Potent and Selective Covalent KDM1A Inhibitor, for the Treatment of Acute Leukemia. Cancer cell 255 29502954
2015 A specific LSD1/KDM1A isoform regulates neuronal differentiation through H3K9 demethylation. Molecular cell 224 25684206
2011 Endogenous retroviruses and neighboring genes are coordinately repressed by LSD1/KDM1A. Genes & development 216 21357675
2019 Targeting NOTCH activation in small cell lung cancer through LSD1 inhibition. Science signaling 180 30723171
2013 The histone LSD1 demethylase in stemness and cancer transcription programs. Biochimica et biophysica acta 170 23684752
2016 LSD1: biologic roles and therapeutic targeting. Epigenomics 168 27479862
2019 Re-programing Chromatin with a Bifunctional LSD1/HDAC Inhibitor Induces Therapeutic Differentiation in DIPG. Cancer cell 147 31631026
2010 Alternative splicing of the histone demethylase LSD1/KDM1 contributes to the modulation of neurite morphogenesis in the mammalian nervous system. The Journal of neuroscience : the official journal of the Society for Neuroscience 147 20164337
2010 Structurally designed trans-2-phenylcyclopropylamine derivatives potently inhibit histone demethylase LSD1/KDM1 . Biochemistry 140 20568732
2010 Histone demethylase LSD1 regulates adipogenesis. The Journal of biological chemistry 140 20656681
2013 The histone demethylase LSD1/KDM1A promotes the DNA damage response. The Journal of cell biology 111 24217620
2017 Advances toward LSD1 inhibitors for cancer therapy. Future medicinal chemistry 107 28722477
2018 Pharmacological Inhibition of LSD1 for Cancer Treatment. Molecules (Basel, Switzerland) 106 30518104
2020 Biological roles of LSD1 beyond its demethylase activity. Cellular and molecular life sciences : CMLS 93 32193608
2020 Crystal Structure of the LSD1/CoREST Histone Demethylase Bound to Its Nucleosome Substrate. Molecular cell 91 32396821
2019 LSD1/KDM1A, a Gate-Keeper of Cancer Stemness and a Promising Therapeutic Target. Cancers 90 31756917
2016 Pharmacological inhibition of LSD1 for the treatment of MLL-rearranged leukemia. Journal of hematology & oncology 88 26970896
2007 S. pombe LSD1 homologs regulate heterochromatin propagation and euchromatic gene transcription. Molecular cell 86 17434129
2011 Activation of HIV transcription by the viral Tat protein requires a demethylation step mediated by lysine-specific demethylase 1 (LSD1/KDM1). PLoS pathogens 84 21876670
2020 Natural products as LSD1 inhibitors for cancer therapy. Acta pharmaceutica Sinica. B 83 32837872
2017 LSD1-Mediated Epigenetic Reprogramming Drives CENPE Expression and Prostate Cancer Progression. Cancer research 82 28916652
2021 Roles of lysine-specific demethylase 1 (LSD1) in homeostasis and diseases. Journal of biomedical science 79 34082769
2016 Irreversible LSD1 Inhibitors: Application of Tranylcypromine and Its Derivatives in Cancer Treatment. Current topics in medicinal chemistry 76 26881714
2018 Germline Lysine-Specific Demethylase 1 (LSD1/KDM1A) Mutations Confer Susceptibility to Multiple Myeloma. Cancer research 73 29559475
2017 Lysine-specific demethylase LSD1 regulates autophagy in neuroblastoma through SESN2-dependent pathway. Oncogene 72 28783174
2012 Targeting the PELP1-KDM1 axis as a potential therapeutic strategy for breast cancer. Breast cancer research : BCR 72 22812534
2015 Preclinical activity of combined HDAC and KDM1A inhibition in glioblastoma. Neuro-oncology 70 25795306
2016 Maternally provided LSD1/KDM1A enables the maternal-to-zygotic transition and prevents defects that manifest postnatally. eLife 67 26814574
2015 KDM1 histone lysine demethylases as targets for treatments of oncological and neurodegenerative disease. Epigenomics 67 26111032
2009 New roles of flavoproteins in molecular cell biology: histone demethylase LSD1 and chromatin. The FEBS journal 65 19624733
2019 LSD1 destabilizes FBXW7 and abrogates FBXW7 functions independent of its demethylase activity. Proceedings of the National Academy of Sciences of the United States of America 64 31152129
2017 LSD1 protects against hippocampal and cortical neurodegeneration. Nature communications 64 28993646
2016 Histone demethylase LSD1 controls the phenotypic plasticity of cancer cells. Cancer science 63 27375009
2016 Therapeutic opportunities in Ewing sarcoma: EWS-FLI inhibition via LSD1 targeting. Oncotarget 59 26848860
2021 OTUD7B Deubiquitinates LSD1 to Govern Its Binding Partner Specificity, Homeostasis, and Breast Cancer Metastasis. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 55 34050636
2018 Lsd1 regulates skeletal muscle regeneration and directs the fate of satellite cells. Nature communications 54 29371665
2015 KDM1 class flavin-dependent protein lysine demethylases. Biopolymers 54 25787087
2018 Therapeutic Targeting of KDM1A/LSD1 in Ewing Sarcoma with SP-2509 Engages the Endoplasmic Reticulum Stress Response. Molecular cancer therapeutics 50 29997151
2015 Lysine-specific demethylase (LSD1/KDM1A) and MYCN cooperatively repress tumor suppressor genes in neuroblastoma. Oncotarget 50 26062444
2018 KDM1A microenvironment, its oncogenic potential, and therapeutic significance. Epigenetics & chromatin 47 29921310
2018 The Histone Demethylase LSD1 Regulates B Cell Proliferation and Plasmablast Differentiation. Journal of immunology (Baltimore, Md. : 1950) 46 30232138
2019 Synthesis, structure-activity relationship studies and biological characterization of new [1,2,4]triazolo[1,5-a]pyrimidine-based LSD1/KDM1A inhibitors. European journal of medicinal chemistry 42 30780087
2017 LSD1 Controls Timely MyoD Expression via MyoD Core Enhancer Transcription. Cell reports 41 28228264
2017 Epigenetic regulation of epithelial to mesenchymal transition by the Lysine-specific demethylase LSD1/KDM1A. Biochimica et biophysica acta. Gene regulatory mechanisms 41 28720390
2020 Leukemia Cell of Origin Influences Apoptotic Priming and Sensitivity to LSD1 Inhibition. Cancer discovery 40 32606137
2015 Regulation of protein quality control by UBE4B and LSD1 through p53-mediated transcription. PLoS biology 37 25837623
2021 LSD1: Expanding Functions in Stem Cells and Differentiation. Cells 35 34831474
2015 KDM1A triggers androgen-induced miRNA transcription via H3K4me2 demethylation and DNA oxidation. The Prostate 35 25728837
2021 Superior efficacy of co-targeting GFI1/KDM1A and BRD4 against AML and post-MPN secondary AML cells. Blood cancer journal 34 34016956
2018 Pharmacological inhibition of LSD1 activity blocks REST-dependent medulloblastoma cell migration. Cell communication and signaling : CCS 34 30227871
2024 Tanshinone IIA destabilizes SLC7A11 by regulating PIAS4-mediated SUMOylation of SLC7A11 through KDM1A, and promotes ferroptosis in breast cancer. Journal of advanced research 33 38615741
2019 PD-1 Expression during Acute Infection Is Repressed through an LSD1-Blimp-1 Axis. Journal of immunology (Baltimore, Md. : 1950) 33 31811020
2018 The Homeotic Protein SIX3 Suppresses Carcinogenesis and Metastasis through Recruiting the LSD1/NuRD(MTA3) Complex. Theranostics 33 29463994
2016 Inhibitors of LSD1 as a potential therapy for acute myeloid leukemia. Expert opinion on investigational drugs 33 27077938
2016 LSD1 Histone Demethylase Assays and Inhibition. Methods in enzymology 32 27372757
2024 Targeting LSD1 in cancer: Molecular elucidation and recent advances. Cancer letters 31 38969160
2023 Demethylase-independent roles of LSD1 in regulating enhancers and cell fate transition. Nature communications 30 37607921
2022 Targeting histone demethylase LSD1 for treatment of deficits in autism mouse models. Molecular psychiatry 30 35296809
2008 NF-Y substitutes H2A-H2B on active cell-cycle promoters: recruitment of CoREST-KDM1 and fine-tuning of H3 methylations. Nucleic acids research 30 18940868
2017 CACUL1 reciprocally regulates SIRT1 and LSD1 to repress PPARγ and inhibit adipogenesis. Cell death & disease 29 29233982
2016 The growing structural and functional complexity of the LSD1/KDM1A histone demethylase. Current opinion in structural biology 29 27470128
2020 Capsaicin: A "hot" KDM1A/LSD1 inhibitor from peppers. Bioorganic chemistry 28 32889380
2019 Extra Virgin Olive Oil Contains a Phenolic Inhibitor of the Histone Demethylase LSD1/KDM1A. Nutrients 28 31331073
2012 Integration of ERα-PELP1-HER2 signaling by LSD1 (KDM1A/AOF2) offers combinatorial therapeutic opportunities to circumventing hormone resistance in breast cancer. Breast cancer research : BCR 28 22992372
2025 Lactylation of LSD1 is an acquired epigenetic vulnerability of BRAFi/MEKi-resistant melanoma. Developmental cell 27 40132584
2017 KDM1A/LSD1 regulates the differentiation and maintenance of spermatogonia in mice. PloS one 27 28498828
2020 Alternative splicing of LSD1+8a in neuroendocrine prostate cancer is mediated by SRRM4. Neoplasia (New York, N.Y.) 26 32403054
2017 LSD1 collaborates with EZH2 to regulate expression of interferon-stimulated genes. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 26 28152483
2018 BRMS1 coordinates with LSD1 and suppresses breast cancer cell metastasis. American journal of cancer research 25 30416854
2022 A comprehensive comparative study on LSD1 in different cancers and tumor specific LSD1 inhibitors. European journal of medicinal chemistry 24 35820351
2017 ERRα protein is stabilized by LSD1 in a demethylation-independent manner. PloS one 24 29190800
2022 Lysine-Specific Demethylase 1 (LSD1) epigenetically controls osteoblast differentiation. PloS one 23 35255108
2021 KDM1A and KDM3A promote tumor growth by upregulating cell cycle-associated genes in pancreatic cancer. Experimental biology and medicine (Maywood, N.J.) 23 34171978
2019 Dual inhibitors of LSD1 and spermine oxidase. MedChemComm 23 31191868
2015 LSD1 is Required for Hair Cell Regeneration in Zebrafish. Molecular neurobiology 23 26008620
2022 Dual LSD1 and HDAC6 Inhibition Induces Doxorubicin Sensitivity in Acute Myeloid Leukemia Cells. Cancers 22 36497494
2021 An erythroid-to-myeloid cell fate conversion is elicited by LSD1 inactivation. Blood 22 34324630
2019 Catalytic inhibition of KDM1A in Ewing sarcoma is insufficient as a therapeutic strategy. Pediatric blood & cancer 22 31207107
2022 The Role of LSD1 and LSD2 in Cancers of the Gastrointestinal System: An Update. Biomolecules 21 35327654
2022 Lysine demethylase KDM1A promotes cell growth via FKBP8-BCL2 axis in hepatocellular carcinoma. The Journal of biological chemistry 20 35970393
2020 LSD1 represses a neonatal/reparative gene program in adult intestinal epithelium. Science advances 20 32917713
2013 A hypomorphic lsd1 allele results in heart development defects in mice. PloS one 20 23637775
2017 An Overview on Screening Methods for Lysine Specific Demethylase 1 (LSD1) Inhibitors. Current medicinal chemistry 19 28486922
2010 Thermodynamic characterization of the binding interaction between the histone demethylase LSD1/KDM1 and CoREST. Biochemistry 19 21142040
2024 Strategies that regulate LSD1 for novel therapeutics. Acta pharmaceutica Sinica. B 18 38572094
2019 LSD1 Inhibition Attenuates Tumor Growth by Disrupting PLK1 Mitotic Pathway. Molecular cancer research : MCR 18 30760542
2019 Propionate promotes intestinal lipolysis and metabolic benefits via AMPK/LSD1 pathway in mice. The Journal of endocrinology 18 31505463
2024 LSD1 promotes the FSH responsive follicle formation by regulating autophagy and repressing Wt1 in the granulosa cells. Science bulletin 17 38302330
2023 Pharmacological inhibition of KDM1A/LSD1 enhances estrogen receptor beta-mediated tumor suppression in ovarian cancer. Cancer letters 17 37714256
2022 Biological and therapeutic role of LSD1 in Alzheimer's diseases. Frontiers in pharmacology 17 36386192
2019 Somatic deletion of KDM1A/LSD1 gene is associated to advanced colorectal cancer stages. Journal of clinical pathology 17 31471467
2023 Targeting lysine-specific demethylase 1 (KDM1A/LSD1) impairs colorectal cancer tumorigenesis by affecting cancer cells stemness, motility, and differentiation. Cell death discovery 16 37385999
2022 Aberrant expression of KDM1A inhibits ferroptosis of lung cancer cells through up-regulating c-Myc. Scientific reports 16 36357457
2019 Lysine-Specific Demethylase 1 (LSD1/KDM1A) Is a Novel Target Gene of c-Myc. Biological & pharmaceutical bulletin 16 30828079