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.[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]
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.[5]
Interactions
KDM1A has many different binding partners, which may be necessary for its demethylation activity.[6]
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.[7][8] Deletion of the gene for KDM1A can have effects on the growth and differentiation of embryonic stem cells.[9] Deletion in mouse embryos is lethal; embryos do not progress beyond Day 7.5.[10][11] KDM1A is also thought to play a role in cancer, as poorer outcomes can be correlated with higher expression of this gene.[12][13] Therefore, the inhibition of KDM1A may be a possible treatment for cancer.[14][15][16][17]
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.[18][19] All documented mutations are missense substitutions.[20][21][22] One of the affected families has created a public website in order to identify further cases.[23]
↑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. PMID23612539.
↑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. PMID20863703.
↑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. PMID15620353.
↑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. PMID19703393.
↑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. PMID23684752.
↑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. PMID19098913.
↑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. PMID17392792.
↑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. PMID17145880.
↑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. PMID20042638.
↑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. PMID17504018.
↑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. PMID22339659.
↑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. PMID24838796.
.svg){kind=link}