Lysine-specific histone demethylase 1A

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. Acts by oxidizing the substrate by FAD to generate the corresponding imine that is subsequently hydrolyzed. Acts as a corepressor by mediating demethylation of H3K4me, a specific tag for epigenetic transcriptional activation. Demethylates both mono- (H3K4me1) and di-methylated (H3K4me2). 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. 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. 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. Demethylates methylated 'Lys-42' and methylated 'Lys-117' of SOX2. 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. Facilitates epithelial-to-mesenchymal transition by acting as an effector of SNAI1-mediated transcription repression of epithelial markers E-cadherin/CDH1, CDN7 and KRT8. Required for the maintenance of the silenced state of the SNAI1 target genes E-cadherin/CDH1 and CDN7. Required for the repression of GIPR expression.

Classification

Family (Pfam)

PF01593 Amino_oxidase, PF04433 SWIRM

InterPro

Amino_oxidase, FAD/NAD-bd_sf, Flavin_monoamine_oxidase, Hist_Lys-spec_deMease, Homeodomain-like_sf, SWIRM, WH-like_DNA-bd_sf

Functional cluster

Homeobox & Zinc-Finger Transcription Factors

Experimental structures · PDB · 127

• 2COM NMR
• 2DW4 X-ray 2.30A
• 2EJR X-ray 2.70A
• 2H94 X-ray 2.90A
• 2HKO X-ray 2.80A
• 2IW5 X-ray 2.57A
• 2L3D NMR
• 2UXN X-ray 2.72A
• 2UXX X-ray 2.74A
• 2V1D X-ray 3.10A
• 2X0L X-ray 3.00A
• 2XAF X-ray 3.25A
• … and 115 more

A predicted model is available from AlphaFold.

Gene Ontology · 58

• GO:0000785 chromatin
• GO:0000781 chromosome, telomeric region
• GO:1990391 DNA repair complex
• GO:0035097 histone methyltransferase complex
• GO:0005654 nucleoplasm
• GO:0005634 nucleus
• GO:0032991 protein-containing complex
• GO:0005667 transcription regulator complex
• GO:0003682 chromatin binding
• GO:0140297 DNA-binding transcription factor binding
• GO:0019899 enzyme binding
• GO:0140682 FAD-dependent H3K4me/H3K4me3 demethylase activity
• GO:0050660 flavin adenine dinucleotide binding
• GO:0032452 histone demethylase activity
• GO:0032453 histone H3K4 demethylase activity
• GO:0032454 histone H3K9 demethylase activity
• GO:0140683 histone H3K9me/H3K9me2 demethylase activity
• GO:0035575 histone H4K20 demethylase activity
• GO:0042802 identical protein binding
• GO:0043426 MRF binding
• GO:0050681 nuclear androgen receptor binding
• GO:0016491 oxidoreductase activity
• GO:0002039 p53 binding
• GO:1990841 promoter-specific chromatin binding
• GO:0140457 protein demethylase activity
• GO:0061629 RNA polymerase II-specific DNA-binding transcription factor binding
• GO:0061752 telomeric repeat-containing RNA binding
• GO:0003713 transcription coactivator activity
• GO:0003714 transcription corepressor activity
• GO:0071320 cellular response to cAMP
• GO:0071480 cellular response to gamma radiation
• GO:0034644 cellular response to UV
• GO:0021987 cerebral cortex development
• GO:0140861 DNA repair-dependent chromatin remodeling
• GO:0006351 DNA-templated transcription
• GO:0040029 epigenetic regulation of gene expression
• GO:0046098 guanine metabolic process
• GO:0055001 muscle cell development
• GO:0043518 negative regulation of DNA damage response, signal transduction by p53 class mediator
• GO:0045892 negative regulation of DNA-templated transcription
• GO:1902254 negative regulation of intrinsic apoptotic signaling pathway by p53 class mediator
• GO:1902166 negative regulation of intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator
• GO:0000122 negative regulation of transcription by RNA polymerase II
• GO:0160217 negative regulation of transcription initiation-coupled chromatin remodeling
• GO:0042551 neuron maturation
• GO:0048812 neuron projection morphogenesis
• GO:0120162 positive regulation of cold-induced thermogenesis
• GO:0010718 positive regulation of epithelial to mesenchymal transition
• GO:2000179 positive regulation of neural precursor cell proliferation
• GO:0002052 positive regulation of neuroblast proliferation
• GO:0031398 positive regulation of protein ubiquitination
• GO:2000648 positive regulation of stem cell proliferation
• GO:0045944 positive regulation of transcription by RNA polymerase II
• GO:0060765 regulation of androgen receptor signaling pathway
• GO:0010569 regulation of double-strand break repair via homologous recombination
• GO:0032880 regulation of protein localization
• GO:0006357 regulation of transcription by RNA polymerase II
• GO:0060992 response to fungicide

Disease associations

• palatal anomalies-widely spaced teeth-facial dysmorphism-developmental delay syndrome MONDO:0014751
• ACTH-independent macronodular adrenal hyperplasia 3 MONDO:0700299

Drugs targeting this protein · 1

• BOMEDEMSTAT inhibitor

Related proteins · sequence + function similarity

• Lysine-specific histone demethylase 1A 0.99
• Lysine-specific histone demethylase 1A 0.99
• Possible lysine-specific histone demethylase 1 0.67
• Lysine-specific histone demethylase 2 0.64
• Lysine-specific histone demethylase 1B 0.62
• Spermine oxidase 0.62
• Spermine oxidase 0.61
• Probable ATP-dependent RNA helicase DHX37 0.60
• Choline dehydrogenase, mitochondrial 0.59
• Choline dehydrogenase, mitochondrial 0.59
• Probable polyamine oxidase 4 0.59
• Choline dehydrogenase, mitochondrial 0.58

Co-cited proteins · studied together in the literature

• Lysine-specific histone demethylase 1A 5 shared papers
• REST corepressor 1 6 shared papers
• Zinc finger protein SNAI1 4 shared papers
• Supervillin 1 shared papers
• PHD finger protein 21A 3 shared papers
• Lysine-specific histone demethylase 1A 2 shared papers
• Ubiquitin carboxyl-terminal hydrolase 38 1 shared papers
• Transcription factor HIVEP2 1 shared papers
• Lethal(3)malignant brain tumor-like protein 3 3 shared papers
• Lethal(3)malignant brain tumor-like protein 3 2 shared papers
• SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily E member 1-related 2 shared papers
• PHD finger protein 20-like protein 1 1 shared papers

Literature · 55 cited papers

• KDM1A inactivation causes hereditary food-dependent Cushing syndrome. Genet. Med. · 2022
• Loss of KDM1A in GIP-dependent primary bilateral macronodular adrenal hyperplasia with Cushing's syndrome: a multicentre, retrospective, cohort study. Lancet Diabetes Endocrinol. · 2021
• The SAM domain-containing protein 1 (SAMD1) acts as a repressive chromatin regulator at unmethylated CpG islands. Sci. Adv. · 2021
• The deubiquitinase USP38 affects cellular functions through interacting with LSD1. Biol. Res. · 2018
• Methylated DNMT1 and E2F1 are targeted for proteolysis by L3MBTL3 and CRL4-DCAF5 ubiquitin ligase. Nat. Commun. · 2018
• LSD1 demethylase and the methyl-binding protein PHF20L1 prevent SET7 methyltransferase-dependent proteolysis of the stem-cell protein SOX2. J. Biol. Chem. · 2018
• RBPJ/CBF1 interacts with L3MBTL3/MBT1 to promote repression of Notch signaling via histone demethylase KDM1A/LSD1. EMBO J. · 2017
• Site-specific mapping of the human SUMO proteome reveals co-modification with phosphorylation. Nat. Struct. Mol. Biol. · 2017
• MOF acetylates the histone demethylase LSD1 to suppress epithelial-to-mesenchymal transition. Cell Rep. · 2016
• Gene discovery for Mendelian conditions via social networking: de novo variants in KDM1A cause developmental delay and distinctive facial features. Genet. Med. · 2016
• LSD1n is an H4K20 demethylase regulating memory formation via transcriptional elongation control. Nat. Neurosci. · 2015
• Remaining challenges in cellular flavin cofactor homeostasis and flavoprotein biogenesis. Front. Chem. · 2015
• … and 43 more in the literature graph