KDM1A

Lysine (K)-specific demethylase 1A
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​, 3ABU​, 3ZMS​, 3ZMT​, 3ZMU​, 3ZMV​, 3ZMZ​, 3ZN0​, 3ZN1​, 4BAY​, 4CZZ​, 4KUM​, 4UV8​, 4UV9​, 4UVA​, 4UVB​, 4UVC​, 4UXN​
Identifiers
Symbols	KDM1A ; AOF2; BHC110; KDM1; LSD1
External IDs	OMIM: 609132 HomoloGene: 32240 GeneCards: KDM1A Gene
Gene ontology Molecular function • RNA polymerase II transcription factor binding • p53 binding • chromatin binding • transcription factor activity, sequence-specific DNA binding • protein binding • transcription factor binding • oxidoreductase activity • enzyme binding • ligand-dependent nuclear receptor transcription coactivator activity • demethylase activity • histone demethylase activity • histone demethylase activity (H3-K4 specific) • histone demethylase activity (H3-K9 specific) • histone demethylase activity (H3-dimethyl-K4 specific) • MRF binding • transcription regulatory region DNA binding • flavin adenine dinucleotide binding • androgen receptor binding Cellular component • nuclear chromatin • nucleus • nucleoplasm • transcription factor complex Biological process • negative regulation of transcription from RNA polymerase II promoter • in utero embryonic development • chromatin organization • transcription, DNA-templated • regulation of transcription from RNA polymerase II promoter • protein demethylation • small GTPase mediated signal transduction • blood coagulation • cell proliferation • regulation of primitive erythrocyte differentiation • pituitary gland development • granulocyte differentiation • negative regulation of protein binding • histone H3-K9 demethylation • histone H3-K4 demethylation • negative regulation of DNA binding • negative regulation of sequence-specific DNA binding transcription factor activity • negative regulation of DNA damage response, signal transduction by p53 class mediator • positive regulation of erythrocyte differentiation • positive regulation of megakaryocyte differentiation • negative regulation of transcription, DNA-templated • positive regulation of transcription from RNA polymerase II promoter • positive regulation of hormone biosynthetic process • positive regulation of sequence-specific DNA binding transcription factor activity • negative regulation of histone H3-K4 methylation • negative regulation of histone H3-K9 methylation • muscle cell development • oxidation-reduction process • negative regulation of intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator • 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_133872
RefSeq (protein)	NP_001009999	NP_598633
Location (UCSC)	Chr 1: 23.02 – 23.08 Mb	Chr 4: 136.55 – 136.6 Mb
PubMed search

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.^[1] 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).^[2] This enzyme can have roles critical in embryogenesis and tissue-specific differentiation, as well as oocyte growth.^[3] KDM1A was the first histone demethylase to be discovered though more than 30 have been described.^[4]

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.^[5]

Clinical significance

Deletion of the gene for KDM1A can have effects on the growth and differentiation of embryonic stem cells.^[6] Deletion in mouse embryos is lethal; embryos do no prgress beyond Day 7.5. lethality in knockout mice, who do not produce the KDM1A gene product^[7][8] KDM1A is also thought to play a role in cancer, as poorer outcomes can be correlated with higher expression of this gene.^[9][10] Therefore, the inhibition of KDM1A may be a possible treatment for cancer.^{[11][12][13][14]}

Mutations

De novo mutations to KDM1A have been reported in two patients, both with severe developmental delays believed to be attributable in part to the mutations. Both mutations were missense substitutions.^[15][16] One of the affected families has created a public website in order to identify further cases.^[17]

See also

• Histone methylation

References

1. "Entrez Gene: Lysine (K)-specific demethylase 1A".
2. Rudolph T, Beuch S, Reuter G (Aug 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.
3. Pedersen MT, Helin K (Nov 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.
4. Shi Y, Lan F, Matson C, Mulligan P, Whetstine JR, Cole PA, Casero RA, Shi Y (Dec 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.
5. 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 (Aug 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.
6. Amente S, Lania L, Majello B (Oct 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.
7. 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 (Jan 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.
8. 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 (Apr 2007). "Opposing LSD1 complexes function in developmental gene activation and repression programmes". Nature 446 (7138): 882–7. doi:10.1038/nature05671. PMID 17392792.
9. Kahl P, Gullotti L, Heukamp LC, Wolf S, Friedrichs N, Vorreuther R, Solleder G, Bastian PJ, Ellinger J, Metzger E, Schüle R, Buettner R (Dec 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.
10. Lim S, Janzer A, Becker A, Zimmer A, Schüle R, Buettner R, Kirfel J (Mar 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.
11. Stavropoulos P, Hoelz A (Jun 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.
12. 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.
13. 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.
14. Lynch JT, Harris WJ, Somervaille TC (Dec 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.
15. Tunovic S, Barkovich J, Sherr EH, Slavotinek AM (Jul 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.
16. Rauch A, Wieczorek D, Graf E, Wieland T, Endele S, Schwarzmayr T, Albrecht B, Bartholdi D, Beygo J, Di Donato N, Dufke A, Cremer K, Hempel M, Horn D, Hoyer J, Joset P, Röpke A, Moog U, Riess A, Thiel CT, Tzschach A, Wiesener A, Wohlleber E, Zweier C, Ekici AB, Zink AM, Rump A, Meisinger C, Grallert H, Sticht H, Schenck A, Engels H, Rappold G, Schröck E, Wieacker P, Riess O, Meitinger T, Reis A, Strom TM (Nov 2012). "Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study". Lancet 380 (9854): 1674–82. doi:10.1016/S0140-6736(12)61480-9. PMID 23020937.
17. "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.