组蛋白去甲基化酶LSD1及其生物学功能

doi:10.3724/SP.J.1005.2010.00331

遗传 ›› 2010, Vol. 32 ›› Issue (4): 331-338.doi: 10.3724/SP.J.1005.2010.00331

组蛋白去甲基化酶LSD1及其生物学功能

邵根宝, 黄晓佳, 龚爱华, 张志坚, 陆荣柱, 桑建荣

江苏大学医学院基础医学研究所, 镇江 212013

收稿日期:2009-08-16 修回日期:2009-10-20 出版日期:2010-04-20 发布日期:2010-04-15
通讯作者: 邵根宝 E-mail:genbaoshao@163.com
基金资助:
江苏省高校自然科学研究项目(编号：09KJB310002)和江苏大学高级人才基金项目(编号：07JDG066, 08JDG005, 08JDG033)资助

Histone demethylase LSD1 and its biological functions

SHAO Gen-Bao, HUANG Xiao-Jia, GONG Ai-Hua, ZHANG Zhi-Jian, LU Rong-Zhu, SANG Jian-Rong

Institute of Basic Medical Science, School of Medicine, Jiangsu University, Zhenjiang 212013, China

Received:2009-08-16 Revised:2009-10-20 Online:2010-04-20 Published:2010-04-15
Contact: SHAO Gen-Bao E-mail:genbaoshao@163.com

摘要/Abstract

摘要： 赖氨酸特异性组蛋白去甲基化酶1(Lysine specific demethylase 1, LSD1) 的发现, 表明组蛋白的甲基化修饰是一个动态可调节的过程。结构分析显示, LSD1 是一个黄素腺嘌呤二核苷酸(Flavin adenine dinulcleotide, FAD) 依赖性胺氧化酶, 它能够特异性脱去单甲基化和二甲基化组蛋白H3第4位赖氨酸(H3K4) 和H3K9 位点上的甲基基团。功能研究显示, LSD1 定位于细胞核内, 调控着基因转录的激活和抑制, 被誉为细胞深处的基因“开关”, 在胚胎发育和肿瘤发生过程中起着重要的作用。文章主要综述了LSD1 的结构、作用机制及其调控作用研究的新进展。

关键词: LSD1, 组蛋白去甲基化酶, 基因转录调控, 肿瘤抑制, 胚胎发育

Abstract: Discovery of histone lysine specific demethylase 1 (LSD1) indicates that even histone methylation is reversible. Structural analysis shows that LSD1 is a flavin-dependent amine oxidase, which is able to catalyze the specific removal of methyl groups from mono- and dimethylated Lys4 and Lys9 of histone H3. Functional studies demonstrate that LSD1 regulates activation and inhibition of gene transcription in the nucleus, which is known as the innermost gene switch of cells. LSD1 plays important roles in embryonic development and tumorigenesis. Here, we review recent insights into the structure and chemical mechanism of LSD1, and its regulatory roles in development and cancer.

Key words: gene transcriptional regulation, cancer suppression, embryonic development, LSD1, histone demethylase

邵根宝，黄晓佳，龚爱华，张志坚，陆荣柱，桑建荣. 组蛋白去甲基化酶LSD1及其生物学功能[J]. 遗传, 2010, 32(4): 331-338.

SHAO Gen-Bao, HUANG Xiao-Jia, GONG Ai-Hua, ZHANG Zhi-Jian, LIU Rong-Zhu, SANG Jian-Rong. Histone demethylase LSD1 and its biological functions[J]. HEREDITAS, 2010, 32(4): 331-338.

参考文献

[1] Kornberg RD, Lorch Y. Twenty-five years of the nu-cleosome, fundamental particle of the eukaryote chromo-some. Cell, 1999, 98(3): 285−294. [2] Kouzarides T. Chromatin modifications and their function. Cell, 2007, 128(4): 693−705. [3] Shahbazian MD, Grunstein M. Functions of site-specific histone acetylation and deacetylation. Annu Rev Biochem, 2007, 76(2): 75−100. [4] Marmorstein R, Trievel RC. Histone modifying enzymes: structures, mechanisms, and specificities. Biochim Biophys Acta, 2009, 1789(1): 58−68. [5] Zhang Y. Transcriptional regulation by histone ubiquitination and deubiquitination. Genes Dev, 2003, 17(22): 2733−2740. [6] Shi Y, Lan F, Matson C, Mulligan P, Whetstine JR, Cole PA, Casero RA, Shi Y. Histone demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell, 2004, 119(7): 941−953. [7] Chen Y, Yang Y, Wang F, Wan K, Yamane K, Zhang Y, Lei M. Crystal structure of human histone lysine-specific de-methylase 1 (LSD1). Proc Natl Acad Sci USA, 2006, 103(38): 13956−13961. [8] Anand R, Marmorstein R. Structure and mechanism of ly-sine-specific demethylase enzymes. J Biol Chem, 2007, 282(49): 35425−35429. [9] 阮建彬, 臧建业. 组蛋白去甲基化酶LSD1 的结构和功能研究进展. 中国科学技术大学学报, 2008, 38(8): 930−940. [10] Lee MG, Wynder C, Bochar DA, Hakimi MA, Cooch N, Shiekhattar R. Functional interplay between histone de-methylase and deacetylase enzymes. Mol Cell Biol, 2006, 26(17): 6395−6402. [11] Yang M, Gocke CB, Luo X, Borek D, Tomchick DR, Machius M, Otwinowski Z, Yu H. Structural basis for CoREST dependent demethylation of nucleosomes by the human LSD1 histone demethylase. Mol Cell, 2006, 23(3): 377−387. [12] Lan F, Nottke AC, Shi Y. Mechanisms involved in the regulation of histone lysine demethylases. Curr Opin Cell Biol, 2008, 20(3): 316−325. [13] Nottke A, Colaiacovo MP, Shi Y. Developmental roles of the histone lysine demethylases. Development, 2009, 136(6): 879−889. [14] 高文龙, 刘红林. DOT1—— 一类新的组蛋白赖氨酸甲基转移酶. 遗传, 2007, 29(12): 1449−1454. [15] Karytinos A, Forneris F, Profumo A, Ciossani G, Battaglioli E, Binda C, Mattevi A. A novel mammalian flavin-dependent histone demethylase. J Biol Chem, 2009, 284(26): 17775−17782. [16] Rudolph T, Yonezawa M, Lein S, Heidrich K, Kubicek S, Schafer C, Phalke S, Walther M, Schmidt A, Jenuwein T, Reuter G. Heterochromatin formation in Drosophila is ini-tiated through active removal of H3K4 methylation by the LSD1 homolog SU(VAR)3-3. Mol Cell, 2007, 26(1): 103−115. [17] Eimer S, Lakowski B, Donhauser R, Baumeister R. Loss of spr-5 bypasses the requirement for the C. elegans pre-senilin sel-12 by derepressing hop-1. EMBO J, 2002, 21(21): 5787−5796. [18] Huang J, Sengupta R, Espejo AB, Lee MG, Dorsey JA, Richter M, Opravil S, Shiekhattar R, Bedford MT, Jenuwein T, Berger SL. p53 is regulated by the lysine de-methylase LSD1. Nature, 2007, 449(7158): 105−108. [19] Nicholson TB, Chen T. LSD1 demethylates histone and non-histone proteins. Epigenetics, 2009, 4(3): 129−132. [20] Jiang D, Yang W, He Y, Amasino RM. Arabidopsis rela-tives of the human lysine-specific Demethylase1 repress the expression of FWA and FLOWERING LOCUS C and thus promote the floral transition. Plant Cell, 2007, 19(10): 2975−2987. [21] Wang L, Pei Z, Tian Y, He C. OsLSD1, a rice zinc finger protein, regulates programmed cell death and callus dif-ferentiation. Mol Plant Microbe Interact, 2005, 18(5): 375−384. [22] Tsukada Y, Fang J, Erdjument-Bromage H, Warren ME, Borchers CH,Tempst P, Zhang Y. Histone demethylation by a family of JmjC domain-containing proteins. Nature, 2006, 439(7078): 811−816. [23] Yamane K, Toumazou C, Tsukada Y, Erdjument-Bromage H, Tempst P, Wong J, Zhang Y. JHDM2A, a JmjC-containing H3K9 demethylase, facilitates transcrip-tion activation by androgen receptor. Cell, 2006, 125(3): 483−495. [24] Whetstine JR, Nottke A, Lan F, Huarte M, Smolikov S, Chen Z, Spooner E, Li E, Zhang G, Colaiacovo M, Shi Y. Reversal of histone lysine trimethylation by the JMJD2 family of his-tone demethylases. Cell, 2006, 125(3): 467−481. [25] Christensen J, Agger K, Cloos PA, Pasini D, Rose S, Sennels L, Rappsilber J, Hansen KH, Salcini AE, Helin K. RBP2 belongs to a family of demethylases, specific for tri-and dimethylated lysine 4 on histone 3. Cell, 2007, 128(6): 1063−1076. [26] Iwase S, Lan F, Bayliss P, de la Torre-Ubieta L, Huarte M, Qi HH, Whetstine JR, Bonni A, Roberts TM, Shi Y. The X-linked mental retardation gene SMCX/JARID1C de-fines a family of histone H3 lysine 4 demethylases. Cell, 2007, 128(6): 1077−1088. [27] Klose RJ, Yan Q, Tothova Z, Yamane K, Erdjument- Bromage H, Tempst P, Gilliland DG, Zhang Y, Kaelin WG Jr. The retinoblastoma binding protein RBP2 is an H3K4 demethylase. Cell, 2007, 128(5): 889−900. [28] Liang G, Klose RJ, Gardner KE, Zhang Y. Yeast Jhd2p is a histone H3 Lys4 trimethyl demethylase. Nat Struct Mol Biol, 2007, 14(3): 243−245. [29] Agger K, Cloos PA, Christensen J, Pasini D, Rose S, Rappsilber J, Issaeva I, Canaani E, Salcini AE, Helin K. UTX and JMJD3 are histone H3K27 demethylases in-volved in HOX gene regulation and development. Nature, 2007, 449(7163): 731−734. [30] Lan F, Bayliss PE, Rinn JL, Whetstine JR, Wang JK, Chen S, Iwase S, Alpatov R, Issaeva I, Canaani E, Roberts TM, Chang HY, Shi Y. A histone H3 lysine 27 demethylase regulates animal posterior development. Nature, 2007, 449(7163): 689−694. [31] Huang Y, Greene E, Murray Stewart T, Goodwin AC, Baylin SB, Woster PM, Casero RA Jr. Inhibition of ly-sine-specific demethylase 1 by polyamine analogues re-sults in reexpression of aberrantly silenced genes. Proc Natl Acad Sci USA, 2007, 104(19): 8023−8028. [32] Metzger E, Wissmann M, Yin N, Muller JM, Schneider R, Peters AH, Gunther T, Buettner R, Schule R. LSD1 de-methylates repressive histone marks to promote androgen receptor-dependent transcription. Nature, 2005, 437(7057): 436−439. [33] Garcia-Bassets I, Kwon YS, Telese F, Prefontaine GG, Hutt KR, Cheng CS, Ju BG, Ohgi KA, Wang J, Escoubet- Lozach L, Rose DW, Glass CK, Fu XD, Rosenfeld MG. Histone methylation-dependent mechanisms impose ligand dependency for gene activation by nuclear recep-tors. Cell, 2007, 128(3): 505−518. [34] Ooi SK, Qiu C, Bernstein E, Li K, Jia D, Yang Z, Erdjument-Bromage H, Tempst P, Lin SP, Allis CD, Cheng X, Bestor TH. DNMT3L connects unmethylated lysine 4 of histone H3 to de novo methylation of DNA. Nature, 2007, 448(7154): 714−717. [35] 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. The ly-sine demethylase LSD1 (KDM1) is required for mainte-nance of global DNA methylation. Nat Genet, 2009, 411): 125−129. [36] Lan F, Collins RE, De Cegli R, Alpatov R, Horton JR, Shi X, Gozani O, Cheng X, Shi Y. Recognition of unmethylated histone H3 lysine 4 links BHC80 to LSD1-mediated gene repression. Nature, 2007, 448(7154): 718−722. [37] Shi YJ, Matson C, Lan F, Iwase S, Baba T, Shi Y. Regula-tion of LSD1 histone demethylase activity by its associ-ated factors. Mol Cell, 2005, 19(6): 857−864. [38] Ouyang J, Shi Y, Valin A, Xuan Y, Gill G. Direct binding of CoREST1 to SUMO-2/3 contributes to gene-specific repression by the LSD1/CoREST1/HDAC complex. Mol Cell, 2009, 34(2): 145−154. [39] Forneris F, Binda C, Vanoni MA, Battaglioli E, Mattevi A. Human histone demethylase LSD1 reads the histone code. J Biol Chem, 2005, 280(50): 41360−41365. [40] Forneris F, Binda C, Dall’Aglio A, Fraaije MW, Battaglioli E, Mattevi A. A highly specific mechanism of histone H3-K4 recognition by histone demethylase LSD1. J Biol Chem, 2006, 281(46): 35289−35295. [41] Forneris F, Binda C, Battaglioli E, Mattevi A. LSD1: oxida-tive chemistry for multifaceted functions in chromatin regula-tion. Trends Biochem Sci, 2008, 33(4): 181−189. [42] Lee MG, Wynder C, Cooch N, Shiekhattar R. An essential role for CoREST in nucleosomal histone 3 lysine 4 de-methylation. Nature, 2005, 437(7057): 432−435. [43] Ooi L, Wood IC. Chromatin crosstalk in development and disease: lessons from REST. Nat Rev Genet, 2007, 8(7): 544−554. [44] Saleque S, Kim J, Rooke HM, Orkin SH. Epigenetic regulation of hematopoietic differentiation by Gfi-1 and Gfi-1b is mediated by the cofactors CoREST and LSD1. Mol Cell, 2007, 27(4): 562−572. [45] 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. Opposing LSD1 complexes function in developmental gene activation and repression programmes. Nature, 2007, 446(7138): 882−887. [46] McGraw S, Vigneault C, Sirard MA. Temporal expression of factors involved in chromatin remodeling and in gene regulation during early bovine in vitro embryo development. Reproduction, 2007, 133(3): 597−608. [47] Di Stefano L, Ji JY, Moon NS, Herr A, Dyson N. Mutation of Drosophila Lsd1 disrupts H3-K4 methylation, resulting in tissue-specific defects during development. Curr Biol, 2007, 17(9): 808−812. [48] Shao GB, Ding HM, Gong AH. Role of histone methyla-tion in zygotic genome activation in the preimplantation mouse embryo. In Vitro Cell Dev Biol Anim, 2008, 44(3-4): 115−120. [49] Shao GB, Ding HM, Gong AH, Xiao DS. Inheritance of histone H3 methylation in reprogramming of somatic nu-clei following nuclear transfer. J Reprod Dev, 2008, 54(3): 233−238. [50] Loh YH, Zhang W, Chen X, George J, Ng HH. Jmjd1a and Jmjd2c histone H3 Lys 9 demethylases regulate self-renewal in embryonic stem cells. Genes Dev, 2007, 21(20): 2545−2557. [51] Katz DJ, Edwards TM, Reinke V, Kelly WG. A C. elegans LSD1 demethylase contributes to germline immortality by reprogramming epigenetic memory. Cell, 2009, 137(2): 308−320. [52] Jie Z, Li T, Jia-Yun H, Qiu J, Ping-Yao Z, Houyan S. Trans-2-phenylcyclopropylamine induces nerve cells apoptosis in zebrafish mediated by depression of LSD1 activity. Brain Res Bull, 2009, 80(1-2): 79−84. [53] 夏志强, 何奕昆, 鲍时来, 种康. 植物开花的组蛋白甲基化调控分子机理. 植物学通报, 2007, 24(3): 275−283. [54] Liu F, Quesada V, Crevillen P, Baurle I, Swiezewski S, Dean C. The Arabidopsis RNA-binding protein FCA re-quires a lysine-specific demethylase 1 homolog to down-regulate FLC. Mol Cell, 2007, 28(3): 398−407. [55] Baurle I, Dean C. Differential interactions of the autono-mous pathway RRM proteins and chromatin regulators in the silencing of Arabidopsis targets. PLoS One, 2008, 3(7): e2733. [56] 孙昌辉, 邓晓建, 方军, 储成才. 高等植物开花诱导研究进展. 遗传, 2007, 29(10): 1182−1190. [57] Kahl P, Gullotti L, Heukamp LC, Wolf S, Friedrichs N, Vorreuther R, Solleder G, Bastian PJ, Ellinger J, Metzger E, Schule R, Buettner R. Androgen receptor coactivators lysine-specific histone demethylase 1 and four and a half LIM domain protein 2 predict risk of prostate cancer re-currence. Cancer Res, 2006, 66(23): 11341−11347. [58] Schulte JH, Lim S, Schramm A, Friedrichs N, Koster J, Ver-steeg R, Ora I, Pajtler K, Klein-Hitpass L, Kuhfittig-Kulle S, Metzger E, Schule R, Eggert A, Buettner R, Kirfel J. Lysine-specific demethylase 1 is strongly expressed in poorly differentiated neuroblastoma: implications for therapy. Cancer Res, 2009, 69(5): 2065−2071. [59] Tsai WW, Nguyen TT, Shi Y, Barton MC. p53-targeted LSD1 functions in repression of chromatin structure and transcription in vivo. Mol Cell Biol, 2008, 28(17): 5139−5146. [60] 谢萍, 田春艳, 张令强, 安利国, 贺福初. 组蛋白甲基转移酶的研究进展. 遗传, 2007, 29(9): 1035−1041. [61] 李想, 张飞雄. 组蛋白甲基化的研究进展. 遗传, 2004, 26(2): 244−248. [62] Zhu Q, Liu C, Ge Z, Fang X, Zhang X, Straat K, Bjorkholm M, Xu D. Lysine-specific demethylase 1 (LSD1) is required for the transcriptional repression of the telomerase reverse transcriptase (hTERT) gene. PLoS ONE, 2008, 3(1): e1446.

编辑推荐

Metrics

www.chinagene.cn
备案号：京ICP备09063187号-4
总访问:,今日访问:,当前在线:

组蛋白去甲基化酶LSD1及其生物学功能

Histone demethylase LSD1 and its biological functions

PDF (PC)

可视化

被引次数

摘要/Abstract

引用本文

使用本文

参考文献

相关文章 15

编辑推荐

Metrics

[1]	柯玉文,刘江. 动物早期胚胎发育中染色质结构的继承和重编程[J]. 遗传, 2018, 40(11): 977-987.
[2]	符梅, 徐克惠, 许文明. Dicer调节生殖功能的研究进展[J]. 遗传, 2016, 38(7): 612-622.
[3]	朱屹然,张美玲,翟志超,赵云蛟,马馨. 生殖细胞及早期胚胎基因组印记的表观调控[J]. 遗传, 2016, 38(2): 103-108.
[4]	李园园, 郭磊, 卢晟盛, 韩之明. 甲状旁腺激素样激素在胚胎发育中的作用[J]. 遗传, 2014, 36(9): 871-878.
[5]	葛少钦, 赵峥辉, 张雪倩, 郝媛. 精子表观遗传修饰及其在胚胎发育过程中的潜在作用[J]. 遗传, 2014, 36(5): 439-446.
[6]	郭晓强，张巧霞，黄卫人，段相林，蔡志明. 染色质重塑因子ARID1A的肿瘤抑制作用[J]. 遗传, 2013, 35(3): 255-261.
[7]	杨晓丹，韩威，刘峰. DNA甲基化与脊椎动物胚胎发育[J]. 遗传, 2012, 34(9): 1108-1113.
[8]	秦伟，胡占英，佟军威，孟杰，游学甫，张靖溥. 三甲双酮对斑马鱼胚胎早期发育的影响[J]. 遗传, 2012, 34(9): 1165-1173.
[9]	赫崇波，朱宝，刘卫东，鲍相渤，李云峰，单忠国，李宏俊. 虾夷扇贝脂多糖诱导的肿瘤坏死因子LITAF基因的克隆及表达分析[J]. 遗传, 2012, 34(6): 736-741.
[10]	秦祖兴，黄高波，罗军，宁淑芳，卢晟盛. TSA和VPA处理对食蟹猴-猪异种体细胞核移植胚胎早期发育的影响[J]. 遗传, 2012, 34(3): 342-347.
[11]	孔庆然，朱江，黄波，郇延军，王峰，石永乾，刘仲凤，武美玲，刘忠华. TSA促进转基因猪体细胞核移植胚胎发育和外源基因表达[J]. 遗传, 2011, 33(7): 749-756.
[12]	宋博研，朱卫国. 组蛋白甲基化修饰效应分子的研究进展[J]. 遗传, 2011, 33(4): 285-292.
[13]	马占福，杨冬，贺福初，姜颖. KRAB型锌指蛋白在高等脊椎动物胚胎发育和肿瘤发生、发展中的调控功能[J]. 遗传, 2010, 32(5): 431-436.
[14]	王蕊，曾宪录. ATP依赖的染色质改构复合物及其作用机制[J]. 遗传, 2010, 32(4): 301-306.
[15]	杜卫华，朱化彬，郝海生，王栋. 体细胞核移植与中心体遗传[J]. 遗传, 2008, 30(8): 1513-966.