KDM1A

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	MGI: 1196256 HomoloGene: 32240 GeneCards: KDM1A
Targeted by Drug
tranylcypromine[1]
Gene ontology Molecular function • DNA binding • telomeric repeat-containing RNA binding • histone demethylase activity (H3-K9 specific) • demethylase activity • histone demethylase activity (H3-dimethyl-K4 specific) • MRF binding • telomeric DNA binding • RNA polymerase II transcription factor binding • flavin adenine dinucleotide binding • transcription factor activity, sequence-specific DNA binding • p53 binding • transcription factor binding • protein binding • androgen receptor binding • ligand-dependent nuclear receptor transcription coactivator activity • histone demethylase activity (H3-K4 specific) • enzyme binding • transcription regulatory region DNA binding • oxidoreductase activity • chromatin binding • histone deacetylase activity • histone demethylase activity Cellular component • DNA repair complex • transcription factor complex • nucleoplasm • protein complex • nuclear chromatin • nucleus • nuclear chromosome, telomeric region Biological process • pituitary gland development • regulation of transcription, DNA-templated • negative regulation of intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator • positive regulation of erythrocyte differentiation • histone H3-K9 demethylation • 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 • in utero embryonic development • negative regulation of transcription from RNA polymerase II promoter • negative regulation of protein binding • negative regulation of sequence-specific DNA binding transcription factor activity • transcription, DNA-templated • regulation of primitive erythrocyte differentiation • multicellular organism development • positive regulation of neural precursor cell proliferation • granulocyte differentiation • negative regulation of histone H3-K4 methylation • 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 histone H3-K9 methylation • cell proliferation • negative regulation of transcription, DNA-templated • oxidation-reduction process • positive regulation of megakaryocyte differentiation • positive regulation of stem cell proliferation • muscle cell development • positive regulation of transcription from RNA polymerase II promoter • positive regulation of hormone biosynthetic process • 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 • covalent chromatin modification Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	23028	99982
Ensembl	ENSG00000004487	ENSMUSG00000036940
UniProt	O60341	Q6ZQ88
RefSeq (mRNA)	NM_001009999 NM_015013	NM_133872
RefSeq (protein)	NP_001009999.1 NP_055828.2	NP_598633.2
Location (UCSC)	Chr 1: 23.02 – 23.08 Mb	Chr 4: 136.55 – 136.6 Mb
PubMed search	[2]	[3]
Wikidata

View/Edit Human

View/Edit Mouse

Lysine-specific histone demethylase 1A (KDM1A) also known as lysine (K)-specific demethylase 1A (LSD1) is a protein in humans that is encoded by the KDM1A gene.^[4] 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).^[5] This enzyme can have roles critical in embryogenesis and tissue-specific differentiation, as well as oocyte growth.^[6] KDM1A was the first histone demethylase to be discovered though more than 30 have been described.^[7]

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.

Interactions

KDM1A has many different binding partners, which may be necessary for its demethylation activity.^[8]

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.^[9][10] Deletion of the gene for KDM1A can have effects on the growth and differentiation of embryonic stem cells.^[11] Deletion in mouse embryos is lethal; embryos do not progress beyond Day 7.5.^[12][13] KDM1A is also thought to play a role in cancer, as poorer outcomes can be correlated with higher expression of this gene.^[14][15] Therefore, the inhibition of KDM1A may be a possible treatment for cancer.^{[16][17][18][19]}

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.^[20][21] All documented mutations are missense substitutions.^[22][23][24] One of the affected families has created a public website in order to identify further cases.^[25]

See also

• Histone methylation

References

1. "Drugs that physically interact with Lysine-specific histone demethylase 1A view/edit references on wikidata".
2. "Human PubMed Reference:".
3. "Mouse PubMed Reference:".
4. "Entrez Gene: Lysine (K)-specific demethylase 1A".
5. 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.
6. 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.
7. 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.
8. 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.
9. 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.
10. "Disruptions to embryonic reprogramming alter adult mouse behavior". phys.org. Retrieved 2016-06-01.
11. Amente S, Lania L, Majello B (October 2013). "The histone LSD1 demethylase in stemness and cancer transcription programs". Biochimica et Biophysica Acta. 1829 (10): 981–6. doi:10.1016/j.bbagrm.2013.05.002. PMID 23684752.
12. 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.
13. 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.
14. 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.
15. 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.
16. 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.
17. 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.
18. 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. PMID 22867098.
19. 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.
20. "Needle in the genetic haystack: How a new UW website is helping families, scientists". The Seattle Times. 2016-05-07. Retrieved 2016-05-27.
21. "Stirrings of Hope for Families Isolated by Rarest of Genetic Conditions". KQED Future of You. Retrieved 2016-06-01.
22. 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.
23. 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. PMID 26656649.
24. 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. doi:10.1093/hmg/ddw120. PMID 27094131.
25. "Milo's Journey".

External links

• lysine specific demethylase 1, human at the US National Library of Medicine Medical Subject Headings (MeSH)

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