KDM1A (lysine demethylase 1A)

Gene

• Entrez ID: 23028
• Gene name: Lysine demethylase 1A
• Gene symbol: KDM1A
• Synonyms: AOF2, BHC110, CPRF, KDM1, LSD1
• Chromosome: 1
• Chromosome location: 1p36.12
• Summary: This gene encodes a nuclear protein containing a SWIRM domain, a FAD-binding motif, and an amine oxidase domain. This protein is a component of several histone deacetylase complexes, though it silences genes by functioning as a histone demethylase. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2009]

SNPs

SNP ID	Visualize variation	Clinical significance	Consequence
rs864309714	T>C	Pathogenic	Missense variant, coding sequence variant
rs864309715	G>A	Pathogenic	Missense variant, coding sequence variant
rs864309716	A>G	Pathogenic	Missense variant, coding sequence variant
rs1553129293	G>T	Likely-pathogenic	Coding sequence variant, stop gained
rs1553130904	A>G	Likely-pathogenic	Coding sequence variant, missense variant

miRNA

miRTarBase ID	miRNA	Experiments	Reference
MIRT004579	hsa-miR-137	Luciferase reporter assay, Microarray, qRT-PCR, Western blot	20682795
MIRT004579	hsa-miR-137	Luciferase reporter assay	23400681
MIRT004579	hsa-miR-137	Luciferase reporter assay	24084696
MIRT020665	hsa-miR-155-5p	Proteomics	18668040
MIRT037998	hsa-miR-500a-5p	CLASH	23622248
MIRT046281	hsa-miR-23b-3p	CLASH	23622248
MIRT054713	hsa-miR-329-3p	Luciferase reporter assay, qRT-PCR, Western blot	24316513
MIRT735512	hsa-miR-708-5p	Luciferase reporter assay, qRT-PCR, Western blot	26833707

Gene ontology (GO)

GO ID	Ontology	Definition	Evidence	Reference
GO:0000122	Process	Negative regulation of transcription by RNA polymerase II	IBA	21873635
GO:0000122	Process	Negative regulation of transcription by RNA polymerase II	IMP	17805299
GO:0000122	Process	Negative regulation of transcription by RNA polymerase II	ISS
GO:0000380	Process	Alternative mRNA splicing, via spliceosome	IEA
GO:0000781	Component	Chromosome, telomeric region	IDA	24529708
GO:0000785	Component	Chromatin	IDA	17277772
GO:0000785	Component	Chromatin	ISS	20833138
GO:0001085	Function	RNA polymerase II transcription factor binding	ISS
GO:0002039	Function	P53 binding	IPI	17805299
GO:0002052	Process	Positive regulation of neuroblast proliferation	IMP	23400681
GO:0003682	Function	Chromatin binding	IBA	21873635
GO:0003682	Function	Chromatin binding	IDA	16079795, 20228790, 24217620
GO:0005515	Function	Protein binding	IPI	16169070, 17043677, 17537733, 19497860, 19703393, 20228790, 20389281, 20448663, 20467437, 20562920, 21258344, 21516116, 23022380, 23455924, 23592795, 23752268, 24529708, 24726434, 25609649, 26226427, 28420882, 31413325, 32296183, 32814053
GO:0005634	Component	Nucleus	IDA	16079795, 19497860
GO:0005654	Component	Nucleoplasm	IDA
GO:0005654	Component	Nucleoplasm	TAS
GO:0005667	Component	Transcription regulator complex	ISS
GO:0006357	Process	Regulation of transcription by RNA polymerase II	IMP	16079795
GO:0006482	Process	Protein demethylation	IMP	17805299
GO:0007596	Process	Blood coagulation	TAS
GO:0008134	Function	Transcription factor binding	IBA	21873635
GO:0008134	Function	Transcription factor binding	IDA	20833138
GO:0010569	Process	Regulation of double-strand break repair via homologous recombination	IMP	24217620
GO:0010976	Process	Positive regulation of neuron projection development	IEA
GO:0016491	Function	Oxidoreductase activity	IBA	21873635
GO:0016491	Function	Oxidoreductase activity	IDA	15620353
GO:0019899	Function	Enzyme binding	IPI	17277772
GO:0021987	Process	Cerebral cortex development	IEA
GO:0030374	Function	Nuclear receptor coactivator activity	IMP	16079795
GO:0032091	Process	Negative regulation of protein binding	IMP	17805299
GO:0032451	Function	Demethylase activity	IMP	17805299
GO:0032452	Function	Histone demethylase activity	EXP	16079795, 18066052
GO:0032452	Function	Histone demethylase activity	IDA	19497860
GO:0032453	Function	Histone demethylase activity (H3-K4 specific)	IDA	15620353
GO:0032454	Function	Histone demethylase activity (H3-K9 specific)	IDA	16079795, 20228790
GO:0032454	Function	Histone demethylase activity (H3-K9 specific)	TAS
GO:0032991	Component	Protein-containing complex	IDA	24217620
GO:0033169	Process	Histone H3-K9 demethylation	IDA	16079795, 20228790
GO:0033184	Process	Positive regulation of histone ubiquitination	IMP	24217620
GO:0034644	Process	Cellular response to UV	IDA	24217620
GO:0034648	Function	Histone demethylase activity (H3-dimethyl-K4 specific)	IBA	21873635
GO:0034648	Function	Histone demethylase activity (H3-dimethyl-K4 specific)	IDA	20228790
GO:0034720	Process	Histone H3-K4 demethylation	IDA	15620353, 20228790, 24217620
GO:0035563	Process	Positive regulation of chromatin binding	IEA
GO:0042162	Function	Telomeric DNA binding	IDA	24529708
GO:0042551	Process	Neuron maturation	IEA
GO:0043392	Process	Negative regulation of DNA binding	IC	17805299
GO:0043426	Function	MRF binding	IDA	20833138
GO:0043433	Process	Negative regulation of DNA-binding transcription factor activity	IDA	19497860
GO:0043433	Process	Negative regulation of DNA-binding transcription factor activity	IMP	17805299
GO:0043518	Process	Negative regulation of DNA damage response, signal transduction by p53 class mediator	IMP	17805299
GO:0045793	Process	Positive regulation of cell size	IEA
GO:0045892	Process	Negative regulation of transcription, DNA-templated	IDA	19497860
GO:0045944	Process	Positive regulation of transcription by RNA polymerase II	IBA	21873635
GO:0045944	Process	Positive regulation of transcription by RNA polymerase II	IDA	20833138
GO:0046098	Process	Guanine metabolic process	IEA
GO:0050660	Function	Flavin adenine dinucleotide binding	IBA	21873635
GO:0050660	Function	Flavin adenine dinucleotide binding	IDA	15620353
GO:0050681	Function	Androgen receptor binding	IDA	16079795
GO:0051091	Process	Positive regulation of DNA-binding transcription factor activity	IDA	20833138
GO:0051572	Process	Negative regulation of histone H3-K4 methylation	ISS
GO:0051573	Process	Negative regulation of histone H3-K9 methylation	ISS
GO:0055001	Process	Muscle cell development	ISS	20833138
GO:0060992	Process	Response to fungicide	IEA
GO:0061752	Function	Telomeric repeat-containing RNA binding	IDA	24529708
GO:0071320	Process	Cellular response to cAMP	IEA
GO:0071480	Process	Cellular response to gamma radiation	IMP	24217620
GO:0120162	Process	Positive regulation of cold-induced thermogenesis	ISS	27566776
GO:1902166	Process	Negative regulation of intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator	IMP	17805299
GO:1903827	Process	Regulation of cellular protein localization	IMP	24217620
GO:1990391	Component	DNA repair complex	IDA	24217620
GO:1990841	Function	Promoter-specific chromatin binding	ISS
GO:2000179	Process	Positive regulation of neural precursor cell proliferation	ISS
GO:2000648	Process	Positive regulation of stem cell proliferation	ISS

Other IDs

• MIM: 609132
• HGNC: 29079
• e!Ensembl: ENSG00000004487

Protein

• UniProt ID: O60341
• Protein name: Lysine-specific histone demethylase 1A (EC 1.14.99.66) (BRAF35-HDAC complex protein BHC110) (Flavin-containing amine oxidase domain-containing protein 2) ([histone H3]-dimethyl-L-lysine(4) FAD-dependent demethylase 1A)
• Protein 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:16140033, PubMed:16079794, PubMed:16079795, PubMed:16223729). Acts by oxidizing the substrate by FAD to generate the corresponding imine that is subsequently hydrolyzed (PubMed:15620353, PubMed:15811342, PubMed:16079794, PubMed:21300290). Acts as a corepressor by mediating demethylation of H3K4me, a specific tag for epigenetic transcriptional activation. Demethylates both mono- (H3K4me1) and di-methylated (H3K4me2) H3K4me (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:16140033, PubMed:16079794, 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. 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. Effector of SNAI1-mediated transcription repression of E-cadherin/CDH1, CDN7 and KRT8. Required for the maintenance of the silenced state of the SNAI1 target genes E-cadherin/CDH1 and CDN7 (PubMed:20389281).
• PDB: 2COM, 2DW4, 2EJR, 2H94, 2HKO, 2IW5, 2L3D, 2UXN, 2UXX, 2V1D, 2X0L, 2XAF, 2XAG, 2XAH, 2XAJ, 2XAQ, 2XAS, 2Y48, 2Z3Y, 2Z5U, 3ABT, 3ABU, 3ZMS, 3ZMT, 3ZMU, 3ZMV, 3ZMZ, 3ZN0, 3ZN1, 4BAY, 4CZZ, 4KUM, 4UV8, 4UV9, 4UVA, 4UVB, 4UVC, 4UXN, 4XBF, 5AFW, 5H6Q, 5H6R, 5IT3, 5L3B, 5L3C, 5L3D, 5L3E, 5L3F, 5L3G, 5LBQ, 5LGN
• Family and domains:

  Pfam

  Accession	ID	Position in sequence	Description	Type
  PF04433	SWIRM	177 → 264	SWIRM domain	Domain
  PF01593	Amino_oxidase	288 → 826	Flavin containing amine oxidoreductase	Domain

• Sequence:

  MLSGKKAAAAAAAAAAAATGTEAGPGTAGGSENGSEVAAQPAGLSGPAEVGPGAVGERTP
  RKKEPPRASPPGGLAEPPGSAGPQAGPTVVPGSATPMETGIAETPEGRRTSRRKRAKVEY
  REMDESLANLSEDEYYSEEERNAKAEKEKKLPPPPPQAPPEEENESEPEEPSGVEGAAFQ
  SRLPHDRMTSQEAACFPDIISGPQQTQKVFLFIRNRTLQLWLDNPKIQLTFEATLQQLEA
  PYNSDTVLVHRVHSYLERHGLINFGIYKRIKPLPTKKTGKVIIIGSGVSGLAAARQLQSF
  GMDVTLLEARDRVGGRVATFRKGNYVADLGAMVVTGLGGNPMAVVSKQVNMELAKIKQKC
  PLYEANGQAVPKEKDEMVEQEFNRLLEATSYLSHQLDFNVLNNKPVSLGQALEVVIQLQE
  KHVKDEQIEHWKKIVKTQEELKELLNKMVNLKEKIKELHQQYKEASEVKPPRDITAEFLV
  KSKHRDLTALCKEYDELAETQGKLEEKLQELEANPPSDVYLSSRDRQILDWHFANLEFAN
  ATPLSTLSLKHWDQDDDFEFTGSHLTVRNGYSCVPVALAEGLDIKLNTAVRQVRYTASGC
  EVIAVNTRSTSQTFIYKCDAVLCTLPLGVLKQQPPAVQFVPPLPEWKTSAVQRMGFGNLN
  KVVLCFDRVFWDPSVNLFGHVGSTTASRGELFLFWNLYKAPILLALVAGEAAGIMENISD
  DVIVGRCLAILKGIFGSSAVPQPKETVVSRWRADPWARGSYSYVAAGSSGNDYDLMAQPI
  TPGPSIPGAPQPIPRLFFAGEHTIRNYPATVHGALLSGLREAGRIADQFLGAMYTLPRQA
  TPGVPAQQSPSM

• Sequence length: 852

Pathways

KEGG:

Thermogenesis

Reactome:

HDACs deacetylate histones
HDMs demethylate histones
Activated PKN1 stimulates transcription of AR (androgen receptor) regulated genes KLK2 and KLK3
Estrogen-dependent gene expression
NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux
Factors involved in megakaryocyte development and platelet production

Associated diseases

Causal
Disease name	Disease term	dbSNP ID	References
Developmental delay	Global developmental delay	rs28941770, rs199469464, rs281865469, rs143747297, rs398123009, rs587777428, rs786205133, rs606231459, rs797044854, rs797045027, rs864309504, rs878853160, rs886039902, rs886042046, rs886041291, rs886041382, rs1057518991, rs1057518699, rs753254213, rs748294403, rs762552974, rs1135401795, rs1553121073, rs1553122926, rs1364690005, rs1554086554, rs1554210415, rs1554168326, rs1554776342, rs1553873247, rs1567860112, rs779009256, rs1557447255, rs1564568350, rs780011005, rs1597464953, rs1200336864, rs1569513017, rs1587459606, rs1570332505, rs748888652, rs1575155995, rs2087029320, rs1589669105, rs1601769604, rs1184981709, rs749201074	26656649
Lung carcinoma	Non-Small Cell Lung Carcinoma	rs1805076, rs121909071, rs121913530, rs112445441, rs121913529, rs121913535, rs121913297, rs121913279, rs104886003, rs397516975, rs11554290, rs121913364, rs121913351, rs121913369, rs121913355, rs121912470, rs121913273, rs121913281, rs121913348, rs727503093, rs121913353, rs397516890, rs397516896, rs121913378, rs397516897, rs397516977, rs397516978, rs397516979, rs397516980, rs397516981, rs397516982, rs121913240, rs17851045, rs397517086, rs121913428, rs397517094, rs397517098, rs397517106, rs121913465, rs397517108, rs397517111, rs397517112, rs397517114, rs397517116, rs1554350366, rs397517127, rs397517200, rs397517202, rs121913283, rs121913370, rs121913357, rs727503106, rs121913238, rs727503108, rs397517040, rs397516976, rs1555618025, rs1057519729, rs1584238193	22493729
Melanoma	melanoma	rs121913315, rs121913323, rs137853080, rs137853081, rs121909232, rs121913388, rs104894094, rs1563902635, rs104894095, rs104894097, rs104894098, rs104894099, rs104894109, rs137854599, rs11547328, rs104894340, rs398123152, rs587780668, rs587782083, rs587782206, rs587782792, rs180177042, rs121913381, rs730881675, rs730881674, rs730881677, rs730881673, rs1800586, rs768966657, rs587778189, rs786204195, rs121913321, rs45476696, rs864622636, rs864622263, rs869025340, rs876660436, rs876658534, rs876658556, rs878853647, rs878853644, rs878853650, rs886041162, rs121913389, rs1057519852, rs121913384, rs121913387, rs1060501266, rs1060501263, rs1060501262, rs749714198, rs1060501265, rs559848002, rs1064794292, rs1131691187, rs1131691186, rs199907548, rs1554654052, rs1554656411, rs1554656624, rs1554653915, rs1554653956, rs1554656253, rs1554654224, rs754806883, rs1057520039, rs1563889584, rs1563889685, rs1287464120, rs1563888944, rs1563892715, rs1563889847, rs141798398, rs1587332338, rs1587340291, rs11552823, rs561034503, rs138677674, rs1819962958, rs1820531050	29438700
Colonic neoplasms	Malignant tumor of colon, Colonic Neoplasms	rs267607789, rs774277300, rs781222233, rs1060502734, rs1060503333, rs1339238483	25043185
Cleft palate, psychomotor retardation, and distinctive facial features	CLEFT PALATE, PSYCHOMOTOR RETARDATION, AND DISTINCTIVE FACIAL FEATURES, Palatal anomalies-widely spaced teeth-facial dysmorphism-developmental delay syndrome	rs864309714, rs864309715, rs864309716	26656649, 24838796, 23020937

Unknown
Disease name	Disease term	dbSNP ID	References
Brachycephaly	Brachycephaly
Camptodactyly of fingers	Clinodactyly of the 5th finger
Dwarfism	Dwarfism
Exotropia	Exotropia
Frontal bossing	Frontal bossing
Hypoplasia of corpus callosum	Hypoplasia of corpus callosum
Hypoplasia of thumb	Hypoplasia of thumb
Motor delay	Clumsiness - motor delay
Primary tethered cord syndrome	Tethered Cord Syndrome
Prostatic cancer, castration-resistant	Prostatic Cancer, Castration-Resistant		29581250
Prostatic neoplasms, castration-resistant	Prostatic Neoplasms, Castration-Resistant		29581250
Syringomyelia	Syringomyelia
T-cell lymphoma	T-Cell Lymphoma		29438700