KDM1A

Lysine-specific histone demethylase 1A (LSD1) also known as lysine (K)-specific demethylase 1A (KDM1A) is a protein in humans that is encoded by the KDM1A gene.[5] LSD1 is a flavin-dependent monoamine oxidase, which can demethylate mono- and di-methylated lysines, specifically histone 3, lysines 4 and 9 (H3K4 and H3K9).[6] This enzyme can have roles critical in embryogenesis and tissue-specific differentiation, as well as oocyte growth.[7] KDM1A was the first histone demethylase to be discovered though more than 30 have been described.[8]

KDM1A
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2COM, 2DW4, 2EJR, 2H94, 2HKO, 2IW5, 2L3D, 2UXN, 2UXX, 2V1D, 2X0L, 2XAF, 2XAG, 2XAH, 2XAJ, 2XAQ, 2XAS, 2Y48, 2Z3Y, 2Z5U, 3ABT, 3ZMS, 3ZMT, 3ZMU, 3ZMV, 3ZMZ, 3ZN0, 3ZN1, 4BAY, 4CZZ, 4KUM, 4UV8, 4UV9, 4UVA, 4UVB, 4UVC, 4UXN, 5AFW, 5L3D, 5L3B, 5IT3, 5L3C, 4XBF
Identifiers
Aliases	KDM1A, AOF2, BHC110, KDM1, LSD1, CPRF, lysine demethylase 1A
External IDs	OMIM: 609132 MGI: 1196256 HomoloGene: 32240 GeneCards: KDM1A
Gene location (Human) Chr. Chromosome 1 (human)[1] Band 1p36.12 Start 23,019,443 bp[1] End 23,083,689 bp[1]
Gene location (Mouse) Chr. Chromosome 4 (mouse)[2] Band 4 D3|4 68.8 cM Start 136,550,540 bp[2] End 136,602,723 bp[2]
Gene ontology Molecular function • DNA binding • telomeric repeat-containing RNA binding • demethylase activity • telomeric DNA binding • flavin adenine dinucleotide binding • p53 binding • GO:0001948 protein binding • androgen receptor binding • ligand-dependent nuclear receptor transcription coactivator activity • histone demethylase activity (H3-K4 specific) • oxidoreductase activity • chromatin binding • histone deacetylase activity • histone demethylase activity • enzyme binding • histone demethylase activity (H3-dimethyl-K4 specific) • MRF binding • transcription factor binding • histone demethylase activity (H3-K9 specific) • RNA polymerase II transcription factor binding Cellular component • DNA repair complex • nucleoplasm • nuclear chromatin • cell nucleus • nuclear chromosome, telomeric region • transcription regulator complex • macromolecular complex Biological process • regulation of transcription, DNA-templated • negative regulation of intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator • regulation of double-strand break repair via homologous recombination • cellular response to UV • histone H3-K4 demethylation • regulation of transcription from RNA polymerase II promoter • negative regulation of DNA binding • protein demethylation • positive regulation of sequence-specific DNA binding transcription factor activity • regulation of cellular protein localization • blood coagulation • negative regulation of protein binding • negative regulation of sequence-specific DNA binding transcription factor activity • transcription, DNA-templated • multicellular organism development • negative regulation of DNA damage response, signal transduction by p53 class mediator • positive regulation of histone ubiquitination • cellular response to gamma radiation • negative regulation of transcription, DNA-templated • oxidation-reduction process • positive regulation of transcription from RNA polymerase II promoter • alternative mRNA splicing, via spliceosome • cerebral cortex development • positive regulation of cell size • response to organic cyclic compound • guanine metabolic process • cellular response to cAMP • positive regulation of chromatin binding • histone deacetylation • positive regulation of neuron projection development • neuron maturation • response to fungicide • negative regulation of transcription from RNA polymerase II promoter • histone H3-K9 demethylation • muscle cell development • chromatin organization • positive regulation of neuroblast proliferation • negative regulation of histone H3-K4 methylation • negative regulation of histone H3-K9 methylation • positive regulation of cold-induced thermogenesis • positive regulation of neural precursor cell proliferation • positive regulation of stem cell proliferation Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	23028	99982
Ensembl	ENSG00000004487	ENSMUSG00000036940
UniProt	O60341	Q6ZQ88
RefSeq (mRNA)	NM_001009999 NM_015013 NM_001363654	NM_133872 NM_001347221 NM_001356567
RefSeq (protein)	NP_001009999 NP_055828 NP_001350583	NP_001334150 NP_598633 NP_001343496
Location (UCSC)	Chr 1: 23.02 – 23.08 Mb	Chr 4: 136.55 – 136.6 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

Structure

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.

Function

LSD1 (lysine-specific demethylase 1), also known as KDM1, is the first of several protein lysine demethylases discovered. Through a FAD-dependent oxidative reaction, LSD1 specifically removes histone H3K4me2 to H3K4me1 or H3K4me0. When forming a complex with androgen receptor (and possibly other nuclear hormone receptors), LSD1 changes its substrates to H3K9me2. It's now known LSD1 complex mediates a coordinated histone modification switch through enzymatic activities as well as histone modification readers in the complex.

Function of KDM1A gene can be effectively examined by siRNA knockdown based on an independent validation.[9]

Interactions

KDM1A has many different binding partners, which may be necessary for its demethylation activity.[10] In acute myeloid leukemia (AML), GFI1B was definitively demonstrated to maintain an interaction with KDM1A that is necessary for the proliferation of the disease.[11]

Clinical significance

KDM1A appears to play an important role in the epigenetic "reprogramming" that occurs when sperm and egg come together to make a zygote.[12][13] Deletion of the gene for KDM1A can have effects on the growth and differentiation of embryonic stem cells.[14] Deletion in mouse embryos is lethal; embryos do not progress beyond Day 7.5.[15][16] KDM1A is also thought to play a role in cancer, as poorer outcomes can be correlated with higher expression of this gene.[17][18] Therefore, the inhibition of KDM1A may be a possible treatment for cancer.[19][20][21][22]

Mutations

De novo mutations to KDM1A have been reported in three patients, each with developmental delays believed to be attributable in part to the mutations.[23][24] All documented mutations are missense substitutions.[25][26][27] One of the affected families has created a public website in order to identify further cases.[28]

See also

• Histone methylation

References

1. GRCh38: Ensembl release 89: ENSG00000004487 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000036940 - Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. "Entrez Gene: Lysine (K)-specific demethylase 1A".
6. Rudolph T, Beuch S, Reuter G (August 2013). "Lysine-specific histone demethylase LSD1 and the dynamic control of chromatin". (review). Biological Chemistry. 394 (8): 1019–28. doi:10.1515/hsz-2013-0119. PMID 23612539.
7. Pedersen MT, Helin K (November 2010). "Histone demethylases in development and disease". (review). Trends in Cell Biology. 20 (11): 662–71. doi:10.1016/j.tcb.2010.08.011. PMID 20863703.
8. Shi Y, Lan F, Matson C, Mulligan P, Whetstine JR, Cole PA, Casero RA, Shi Y (December 2004). "Histone demethylation mediated by the nuclear amine oxidase homolog LSD1". Cell. 119 (7): 941–53. doi:10.1016/j.cell.2004.12.012. PMID 15620353.
9. Munkácsy G, Sztupinszki Z, Herman P, Bán B, Pénzváltó Z, Szarvas N, Győrffy B (September 2016). "Validation of RNAi Silencing Efficiency Using Gene Array Data shows 18.5% Failure Rate across 429 Independent Experiments". Molecular Therapy. Nucleic Acids. 5 (9): e366. doi:10.1038/mtna.2016.66. PMC 5056990. PMID 27673562.
10. Wang Y, Zhang H, Chen Y, Sun Y, Yang F, Yu W, Liang J, Sun L, Yang X, Shi L, Li R, Li Y, Zhang Y, Li Q, Yi X, Shang Y (August 2009). "LSD1 is a subunit of the NuRD complex and targets the metastasis programs in breast cancer". Cell. 138 (4): 660–72. doi:10.1016/j.cell.2009.05.050. PMID 19703393.
11. Vinyard ME, Su C, Siegenfeld AP, Waterbury AL, Freedy AM, Gosavi PM, Park Y, Kwan EE, Senzer BD, Doench JG, Bauer DE, Pinello L, Liau BB (May 2019). "CRISPR-suppressor scanning reveals a nonenzymatic role of LSD1 in AML". Nature Chemical Biology. 15 (5): 529–539. doi:10.1038/s41589-019-0263-0. PMC 7679026. PMID 30992567.
12. Ancelin K, Syx L, Borensztein M, Ranisavljevic N, Vassilev I, Briseño-Roa L, Liu T, Metzger E, Servant N, Barillot E, Chen CJ, Schüle R, Heard E (2016-02-02). "Maternal LSD1/KDM1A is an essential regulator of chromatin and transcription landscapes during zygotic genome activation". eLife. 5. doi:10.7554/eLife.08851. PMC 4829419. PMID 26836306.
13. "Disruptions to embryonic reprogramming alter adult mouse behavior". phys.org. Retrieved 2016-06-01.
14. Amente S, Lania L, Majello B (October 2013). "The histone LSD1 demethylase in stemness and cancer transcription programs". Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms. 1829 (10): 981–6. doi:10.1016/j.bbagrm.2013.05.002. PMID 23684752.
15. Wang J, Hevi S, Kurash JK, Lei H, Gay F, Bajko J, Su H, Sun W, Chang H, Xu G, Gaudet F, Li E, Chen T (January 2009). "The lysine demethylase LSD1 (KDM1) is required for maintenance of global DNA methylation". Nature Genetics. 41 (1): 125–9. doi:10.1038/ng.268. PMID 19098913.
16. Wang J, Scully K, Zhu X, Cai L, Zhang J, Prefontaine GG, Krones A, Ohgi KA, Zhu P, Garcia-Bassets I, Liu F, Taylor H, Lozach J, Jayes FL, Korach KS, Glass CK, Fu XD, Rosenfeld MG (April 2007). "Opposing LSD1 complexes function in developmental gene activation and repression programmes". Nature. 446 (7138): 882–7. doi:10.1038/nature05671. PMID 17392792.
17. Kahl P, Gullotti L, Heukamp LC, Wolf S, Friedrichs N, Vorreuther R, Solleder G, Bastian PJ, Ellinger J, Metzger E, Schüle R, Buettner R (December 2006). "Androgen receptor coactivators lysine-specific histone demethylase 1 and four and a half LIM domain protein 2 predict risk of prostate cancer recurrence". Cancer Research. 66 (23): 11341–7. doi:10.1158/0008-5472.CAN-06-1570. PMID 17145880.
18. Lim S, Janzer A, Becker A, Zimmer A, Schüle R, Buettner R, Kirfel J (March 2010). "Lysine-specific demethylase 1 (LSD1) is highly expressed in ER-negative breast cancers and a biomarker predicting aggressive biology". Carcinogenesis. 31 (3): 512–20. doi:10.1093/carcin/bgp324. PMID 20042638.
19. Stavropoulos P, Hoelz A (June 2007). "Lysine-specific demethylase 1 as a potential therapeutic target". (review). Expert Opinion on Therapeutic Targets. 11 (6): 809–20. doi:10.1517/14728222.11.6.809. PMID 17504018.
20. Chen Y, Jie W, Yan W, Zhou K, Xiao Y (2012). "Lysine-specific histone demethylase 1 (LSD1): A potential molecular target for tumor therapy". (review). Critical Reviews in Eukaryotic Gene Expression. 22 (1): 53–9. doi:10.1615/critreveukargeneexpr.v22.i1.40. PMID 22339659.
21. Crea F, Sun L, Mai A, Chiang YT, Farrar WL, Danesi R, Helgason CD (2012). "The emerging role of histone lysine demethylases in prostate cancer". (review). Molecular Cancer. 11: 52. doi:10.1186/1476-4598-11-52. PMC 3441810. PMID 22867098.
22. Lynch JT, Harris WJ, Somervaille TC (December 2012). "LSD1 inhibition: a therapeutic strategy in cancer?". (review). Expert Opinion on Therapeutic Targets. 16 (12): 1239–49. doi:10.1517/14728222.2012.722206. PMID 22957941.
23. "Needle in the genetic haystack: How a new UW website is helping families, scientists". The Seattle Times. 2016-05-07. Retrieved 2016-05-27.
24. "Stirrings of Hope for Families Isolated by Rarest of Genetic Conditions". KQED Future of You. Retrieved 2016-06-01.
25. Tunovic S, Barkovich J, Sherr EH, Slavotinek AM (July 2014). "De novo ANKRD11 and KDM1A gene mutations in a male with features of KBG syndrome and Kabuki syndrome". American Journal of Medical Genetics. Part A. 164A (7): 1744–9. doi:10.1002/ajmg.a.36450. PMID 24838796.
26. Chong JX, Yu JH, Lorentzen P, Park KM, Jamal SM, Tabor HK, Rauch A, Saenz MS, Boltshauser E, Patterson KE, Nickerson DA, Bamshad MJ (August 2016). "Gene discovery for Mendelian conditions via social networking: de novo variants in KDM1A cause developmental delay and distinctive facial features". Genetics in Medicine. 18 (8): 788–95. doi:10.1038/gim.2015.161. PMC 4902791. PMID 26656649.
27. Pilotto S, Speranzini V, Marabelli C, Rusconi F, Toffolo E, Grillo B, Battaglioli E, Mattevi A (April 2016). "LSD1/KDM1A mutations associated to a newly described form of intellectual disability impair demethylase activity and binding to transcription factors". Human Molecular Genetics. 25 (12): 2578–2587. doi:10.1093/hmg/ddw120. PMID 27094131.
28. "Milo's Journey".

External links

• lysine+specific+demethylase+1,+human at the US National Library of Medicine Medical Subject Headings (MeSH)
• Overview of all the structural information available in the PDB for UniProt: O60341 (Lysine-specific histone demethylase 1A) at the PDBe-KB.

This article incorporates text from the United States National Library of Medicine, which is in the public domain.