Dot1及其同源物的研究进展
|
摘要
Dot1(disruptor of telomeric silencing 1)最初在芽殖酵母中通过遗传筛选基因被发现,缺失则会引起端粒沉默。Dot1和其脊椎动物同源物DOT1L(Dot1-like)都具有催化组蛋白H3第79位赖氨酸(H3K79)甲基化的组蛋白甲基转移酶活性。在人类各种组织中,DOT1L基因启动子区域的CpG岛均呈现极低的DNA甲基化水平,说明DOT1L基因在人体中广泛中等程度表达。DOT1L基因在EBV转化的细胞及睾丸中表达水平升高。Dot1/DOT1L介导的H3K79甲基化参与多种生物学过程,并在小鼠基因损伤实验中发现DOT1L在心功能、红细胞生成、白血病及多种肿瘤的疾病发展中起重要的作用,因而DOT1L已成为针对表观遗传修饰因子的重要药物靶点。本文对Dot1/DOT1L在生理和病理方面的研究进展作一综述。
Dot1(disruptor of telomeric silencing 1)was initially found in budding yeast in a genetic screen for genes,and its deletion confers defects in telomeric silencing.Dot1 and its mammalian homologue,DOT1 L(Dot1-like),possess histone methyltransferase activity toward histone H3 K79(H3 K79).In human tissues,the CpG islands in DOT1 Lgene promoter region show very low levels of DNA methylation,indicating that the DOT1 L gene is widely expressed in the human body.The expression levels of DOT1 Lgene increase in EBV-transformed cells and testis.It has been found that Dot1/DOT1 L-mediated H3 K79 methylation is involved in a variety of biological processes.In addition,gene disruption in mice has revealed that DOT1 L plays an essential role in the development of diseases such as cardiac function,erythropoiesis,leukemia and various tumors.Thus DOT1 L has become an important drug target for epigenetic modification factors.This review focuses on the research progress of Dot1/DOT1 L in physiology and pathology.
Dot1(disruptor of telomeric silencing 1)was initially found in budding yeast in a genetic screen for genes,and its deletion confers defects in telomeric silencing.Dot1 and its mammalian homologue,DOT1 L(Dot1-like),possess histone methyltransferase activity toward histone H3 K79(H3 K79).In human tissues,the CpG islands in DOT1 Lgene promoter region show very low levels of DNA methylation,indicating that the DOT1 L gene is widely expressed in the human body.The expression levels of DOT1 Lgene increase in EBV-transformed cells and testis.It has been found that Dot1/DOT1 L-mediated H3 K79 methylation is involved in a variety of biological processes.In addition,gene disruption in mice has revealed that DOT1 L plays an essential role in the development of diseases such as cardiac function,erythropoiesis,leukemia and various tumors.Thus DOT1 L has become an important drug target for epigenetic modification factors.This review focuses on the research progress of Dot1/DOT1 L in physiology and pathology.
引文
[1]FAROOQ Z,BANDAY S,PANDITA TK,et al.The many faces of histone H3K79 methylation[J].Mutat Res Rev Mutat Res,2016,768:46-52.
[2]NGUYEN AT,ZHANG Y.The diverse functions of Dot1and H3K79 methylation[J].Genes Dev,2011,25(13):1345-1358.
[3]MIN J,FENG Q,LI Z,et al.Structure of the catalytic domain of human DOT1L,a non-SET domain nucleosomal histone methyltransferase[J].Cell,2003,112(5):711-723.
[4]SAWADA K,YANG Z,HORTON JR,et al.Structure of the conserved core of the yeast Dot1p,a nucleosomal histone H3 lysine 79 methyltransferase[J].J Biol Chem,2004,279(41):43296-43306.
[5]VAN LEEUWEN F,GAFKEN PR,GOTTSCHLING DE.Dot1p modulates silencing in yeast by methylation of the nucleosome core[J].Cell,2002,109(6):745-756.
[6]SHANOWER GA,MULLER M,BLANTON JL,et al.Characterization of the grappa gene,the Drosophila histone H3 lysine 79 methyltransferase[J].Genetics,2005,169(1):173-184.
[7]FENG Q,WANG H,NG HH,et al.Methylation of H3-lysine 79 is mediated by a new family of HMTases without a SET domain[J].Curr Biol,2002,12(12):1052-1058.
[8]ZHANG W,HAYASHIZAKI Y,KONE BC.Structure and regulation of the mDot1 gene,a mouse histone H3methyltransferase[J].Biochem J,2004,377(Pt 3):641-651.
[9]JONES B,SU H,BHAT A,et al.The histone H3K79methyltransferase Dot1L is essential for mammalian development and heterochromatin structure[J].PLoS Genet,2008,4(9):e1000190.
[10]OOGA M,SUZUKI MG,AOKI F.Involvement of DOT1L in the remodeling of heterochromatin configuration during early preimplantation development in mice[J].Biol Reprod,2013,89(6):145.
[11]ZHOU Q,LIU K,WU H,et al.Spironolactone rescues Dot1a-Af9-mediated repression of endothelin-1 and improves kidney injury in streptozotocin-induced diabetic rats[J].PLoS One,2012,7(10):e47360.
[12]MATSUURA K,FUJIMOTO K,DAS B,et al.Histone H3K79 methyltransferase Dot1L is directly activated by thyroid hormone receptor during Xenopus metamorphosis[J].Cell Biosci,2012,2(1):25.
[13]KIM W,CHOI M,KIM JE.The histone methyltransferase Dot1/DOT1L as a critical regulator of the cell cycle[J].Cell Cycle,2014,13(5):726-738.
[14]WHITCOMB SJ,FIERZ B,MCGINTY RK,et al.Histone monoubiquitylation position determines specificity and direction of enzymatic cross-talk with histone methyltransferases Dot1L and PRC2[J].J Biol Chem,2012,287(28):23718-23725.
[15]WU L,ZEE BM,WANG Y,et al.The RING finger protein MSL2 in the MOF complex is an E3 ubiquitin ligase for H2B K34 and is involved in crosstalk with H3K4 and K79 methylation[J].Mol Cell,2011,43(1):132-144.
[16]MCGINTY RK,KIM J,CHATTERJEE C,et al.Chemically ubiquitylated histone H2B stimulates hDot1Lmediated intranucleosomal methylation[J].Nature,2008,453(7196):812-816.
[17]NAKANISHI S,LEE JS,GARDNER KE,et al.Histone H2BK123 monoubiquitination is the critical determinant for H3K4 and H3K79 trimethylation by COMPASS and Dot1[J].J Cell Biol,2009,186(3):371-377.
[18]CHATTERJEE C,MCGINTY RK,FIERZ B,et al.Disulfide-directed histone ubiquitylation reveals plasticity in hDot1L activation[J].Nat Chem Biol,2010,6(4):267-269.
[19]CHENG X,COLLINS RE,ZHANG X.Structural and sequence motifs of protein(histone)methylation enzymes[J].Annu Rev Biophys Biomol Struct,2005,34:267-294.
[20]OH S,JEONG K,KIM H,et al.A lysine-rich region in Dot1p is crucial for direct interaction with H2B ubiquitylation and high level methylation of H3K79[J].Biochem Biophys Res Commun,2010,399(4):512-517.
[21]EZHKOVA E,TANSEY WP.Proteasomal ATPases link ubiquitylation of histone H2B to methylation of histone H3[J].Mol Cell,2004,13(3):435-442.
[22]LEE JS,SHUKLA A,SCHNEIDER J,et al.Histone crosstalk between H2B monoubiquitination and H3methylation mediated by COMPASS[J].Cell,2007,131(6):1084-1096.
[23]WOOD A,SCHNEIDER J,DOVER J,et al.The Paf1complex is essential for histone monoubiquitination by the Rad6-Bre1 complex,which signals for histone methylation by COMPASS and Dot1p[J].J Biol Chem,2003,278(37):34739-34742.
[24]KROGAN NJ,DOVER J,WOOD A,et al.The Paf1complex is required for histone H3 methylation by COMPASS and Dot1p:linking transcriptional elongation to histone methylation[J].Mol Cell,2003,11(3):721-729.
[25]KIM SK,JUNG I,LEE H,et al.Human histone H3K79methyltransferase DOT1L protein[corrected]binds actively transcribing RNA polymerase II to regulate gene expression[J].J Biol Chem,2012,287(47):39698-39709.
[26]FIERZ B,CHATTERJEE C,MCGINTY RK,et al.Histone H2B ubiquitylation disrupts local and higherorder chromatin compaction[J].Nat Chem Biol,2011,7(2):113-119.
[27]FINGERMAN IM,LI HC,BRIGGS SD.A charge-based interaction between histone H4 and Dot1 is required for H3K79 methylation and telomere silencing:identification of a new trans-histone pathway[J].Genes Dev,2007,21(16):2018-2029.
[28]ALTAF M,UTLEY RT,LACOSTE N,et al.Interplay of chromatin modifiers on a short basic patch of histone H4tail defines the boundary of telomeric heterochromatin[J].Mol Cell,2007,28(6):1002-1014.
[29]VAQUERO A,SCHER M,LEE D,et al.Human SirT1interacts with histone H1 and promotes formation of facultative heterochromatin[J].Mol Cell,2004,16(1):93-105.
[30]FREDERIKS F,VAN WELSEM T,OUDGENOEG G,et al.Heterologous expression reveals distinct enzymatic activities of two DOT1 histone methyltransferases of Trypanosoma brucei[J].J Cell Sci,2010,123(Pt 23):4019-4023.
[31]SCHULZE JM,JACKSON J,NAKANISHI S,et al.Linking cell cycle to histone modifications:SBF and H2B monoubiquitination machinery and cell-cycle regulation of H3K79 dimethylation[J].Mol Cell,2009,35(5):626-641.
[32]TAKAHASHI YH,SCHULZE JM,JACKSON J,et al.Dot1 and histone H3K79 methylation in natural telomeric and HM silencing[J].Mol Cell,2011,42(1):118-126.
[33]LIN YH,KAKADIA PM,CHEN Y,et al.Global reduction of the epigenetic H3K79 methylation mark and increased chromosomal instability in CALM-AF10-positive leukemias[J].Blood,2009,114(3):651-658.
[34]SWEET SM,LI M,THOMAS PM,et al.Kinetics of reestablishing H3K79 methylation marks in global human chromatin[J].J Biol Chem,2010,285(43):32778-32786.
[35]DE VOS D,FREDERIKS F,TERWEIJ M,et al.Progressive methylation of ageing histones by Dot1functions as a timer[J].EMBO Rep,2011,12(9):956-962.
[36]FOSTER ER,DOWNS JA.Methylation of H3 K4 and K79 is not strictly dependent on H2B K123 ubiquitylation[J].J Cell Biol,2009,184(5):631-638.
[37]STEGER DJ,LEFTEROVA MI,YING L,et al.DOT1L/KMT4 recruitment and H3K79 methylation are ubiquitously coupled with gene transcription in mammalian cells[J].Mol Cell Biol,2008,28(8):2825-2839.
[38]KATAN-KHAYKOVICH Y,STRUHL K.Heterochromatin formation involves changes in histone modifications over multiple cell generations[J].EMBO J,2005,24(12):2138-2149.
[39]SAWADO T,HALOW J,IM H,et al.H3 K79dimethylation marks developmental activation of the betaglobin gene but is reduced upon LCR-mediated high-level transcription[J].Blood,2008,112(2):406-414.
[40]ONTOSO D,KAUPPI L,KEENEY S,et al.Dynamics of DOT1L localization and H3K79 methylation during meiotic prophaseⅠin mouse spermatocytes[J].Chromosoma,2014,123(1-2):147-164.
[41]OOGA M,INOUE A,KAGEYAMA S,et al.Changes in H3K79 methylation during preimplantation development in mice[J].Biol Reprod,2008,78(3):413-424.
[42]TU S,BULLOCH EM,YANG L,et al.Identification of histone demethylases in Saccharomyces cerevisiae[J].J Biol Chem,2007,282(19):14262-14271.
[43]XU W,YANG H,LIU Y,et al.Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of alphaketoglutarate-dependent dioxygenases[J].Cancer Cell,2011,19(1):17-30.
[44]KIM W,KIM R,PARK G,et al.Deficiency of H3K79histone methyltransferase Dot1-like protein(DOT1L)inhibits cell proliferation[J].J Biol Chem,2012,287(8):5588-5599.
[45]WANG CM,TSAI SN,YEW TW,et al.Identification of histone methylation multiplicities patterns in the brain of senescence-accelerated prone mouse 8[J].Biogerontology,2010,11(1):87-102.
[46]BARRY ER,KRUEGER W,JAKUBA CM,et al.ES cell cycle progression and differentiation require the action of the histone methyltransferase Dot1L[J].Stem Cells,2009,27(7):1538-1547.
[47]FENG Y,YANG Y,ORTEGA MM,et al.Early mammalian erythropoiesis requires the Dot1L methyltransferase[J].Blood,2010,116(22):4483-4491.
[48]ILLI B,SCOPECE A,NANNI S,et al.Epigenetic histone modification and cardiovascular lineage programming in mouse embryonic stem cells exposed to laminar shear stress[J].Circ Res,2005,96(5):501-508.
[49]NGUYEN AT,XIAO B,NEPPL RL,et al.DOT1L regulates dystrophin expression and is critical for cardiac function[J].Genes Dev,2011,25(3):263-274.
[50]IM H,PARK C,FENG Q,et al.Dynamic regulation of histone H3 methylated at lysine 79 within a tissue-specific chromatin domain[J].J Biol Chem,2003,278(20):18346-18352.
[51]GONZALEZ A.Osteoarthritis year 2013 in review:genetics and genomics[J].Osteoarthritis Cartilage,2013,21(10):1443-1451.
[52]CASTANO BETANCOURT MC,CAILOTTO F,KERKHOF HJ,et al.Genome-wide association and functional studies identify the DOT1L gene to be involved in cartilage thickness and hip osteoarthritis[J].Proc Natl Acad Sci U S A,2012,109(21):8218-8223.
[53]EVANGELOU E,VALDES AM,CASTANOBETANCOURT MC,et al.The DOT1L rs12982744polymorphism is associated with osteoarthritis of the hip with genome-wide statistical significance in males[J].Ann Rheum Dis,2013,72(7):1264-1265.
[54]MOHAN M,HERZ HM,TAKAHASHI YH,et al.Linking H3K79 trimethylation to Wnt signaling through a novel Dot1-containing complex(DotCom)[J].Genes Dev,2010,24(6):574-589.
[55]HARTMANN C,TABIN CJ.Wnt-14 plays a pivotal role in inducing synovial joint formation in the developing appendicular skeleton[J].Cell,2001,104(3):341-351.
[56]MAHMOUDI T,BOJ SF,HATZIS P,et al.The leukemia-associated Mllt10/Af10-Dot1l are Tcf4/betacatenin coactivators essential for intestinal homeostasis[J].PLoS Biol,2010,8(11):e1000539.
[57]NGUYEN AT,TARANOVA O,HE J,et al.DOT1L,the H3K79 methyltransferase,is required for MLL-AF9-mediated leukemogenesis[J].Blood,2011,117(25):6912-6922.
[58]DAIGLE SR,OLHAVA EJ,THERKELSEN CA,et al.Selective killing of mixed lineage leukemia cells by a potent small-molecule DOT1L inhibitor[J].Cancer Cell,2011,20(1):53-65.
[2]NGUYEN AT,ZHANG Y.The diverse functions of Dot1and H3K79 methylation[J].Genes Dev,2011,25(13):1345-1358.
[3]MIN J,FENG Q,LI Z,et al.Structure of the catalytic domain of human DOT1L,a non-SET domain nucleosomal histone methyltransferase[J].Cell,2003,112(5):711-723.
[4]SAWADA K,YANG Z,HORTON JR,et al.Structure of the conserved core of the yeast Dot1p,a nucleosomal histone H3 lysine 79 methyltransferase[J].J Biol Chem,2004,279(41):43296-43306.
[5]VAN LEEUWEN F,GAFKEN PR,GOTTSCHLING DE.Dot1p modulates silencing in yeast by methylation of the nucleosome core[J].Cell,2002,109(6):745-756.
[6]SHANOWER GA,MULLER M,BLANTON JL,et al.Characterization of the grappa gene,the Drosophila histone H3 lysine 79 methyltransferase[J].Genetics,2005,169(1):173-184.
[7]FENG Q,WANG H,NG HH,et al.Methylation of H3-lysine 79 is mediated by a new family of HMTases without a SET domain[J].Curr Biol,2002,12(12):1052-1058.
[8]ZHANG W,HAYASHIZAKI Y,KONE BC.Structure and regulation of the mDot1 gene,a mouse histone H3methyltransferase[J].Biochem J,2004,377(Pt 3):641-651.
[9]JONES B,SU H,BHAT A,et al.The histone H3K79methyltransferase Dot1L is essential for mammalian development and heterochromatin structure[J].PLoS Genet,2008,4(9):e1000190.
[10]OOGA M,SUZUKI MG,AOKI F.Involvement of DOT1L in the remodeling of heterochromatin configuration during early preimplantation development in mice[J].Biol Reprod,2013,89(6):145.
[11]ZHOU Q,LIU K,WU H,et al.Spironolactone rescues Dot1a-Af9-mediated repression of endothelin-1 and improves kidney injury in streptozotocin-induced diabetic rats[J].PLoS One,2012,7(10):e47360.
[12]MATSUURA K,FUJIMOTO K,DAS B,et al.Histone H3K79 methyltransferase Dot1L is directly activated by thyroid hormone receptor during Xenopus metamorphosis[J].Cell Biosci,2012,2(1):25.
[13]KIM W,CHOI M,KIM JE.The histone methyltransferase Dot1/DOT1L as a critical regulator of the cell cycle[J].Cell Cycle,2014,13(5):726-738.
[14]WHITCOMB SJ,FIERZ B,MCGINTY RK,et al.Histone monoubiquitylation position determines specificity and direction of enzymatic cross-talk with histone methyltransferases Dot1L and PRC2[J].J Biol Chem,2012,287(28):23718-23725.
[15]WU L,ZEE BM,WANG Y,et al.The RING finger protein MSL2 in the MOF complex is an E3 ubiquitin ligase for H2B K34 and is involved in crosstalk with H3K4 and K79 methylation[J].Mol Cell,2011,43(1):132-144.
[16]MCGINTY RK,KIM J,CHATTERJEE C,et al.Chemically ubiquitylated histone H2B stimulates hDot1Lmediated intranucleosomal methylation[J].Nature,2008,453(7196):812-816.
[17]NAKANISHI S,LEE JS,GARDNER KE,et al.Histone H2BK123 monoubiquitination is the critical determinant for H3K4 and H3K79 trimethylation by COMPASS and Dot1[J].J Cell Biol,2009,186(3):371-377.
[18]CHATTERJEE C,MCGINTY RK,FIERZ B,et al.Disulfide-directed histone ubiquitylation reveals plasticity in hDot1L activation[J].Nat Chem Biol,2010,6(4):267-269.
[19]CHENG X,COLLINS RE,ZHANG X.Structural and sequence motifs of protein(histone)methylation enzymes[J].Annu Rev Biophys Biomol Struct,2005,34:267-294.
[20]OH S,JEONG K,KIM H,et al.A lysine-rich region in Dot1p is crucial for direct interaction with H2B ubiquitylation and high level methylation of H3K79[J].Biochem Biophys Res Commun,2010,399(4):512-517.
[21]EZHKOVA E,TANSEY WP.Proteasomal ATPases link ubiquitylation of histone H2B to methylation of histone H3[J].Mol Cell,2004,13(3):435-442.
[22]LEE JS,SHUKLA A,SCHNEIDER J,et al.Histone crosstalk between H2B monoubiquitination and H3methylation mediated by COMPASS[J].Cell,2007,131(6):1084-1096.
[23]WOOD A,SCHNEIDER J,DOVER J,et al.The Paf1complex is essential for histone monoubiquitination by the Rad6-Bre1 complex,which signals for histone methylation by COMPASS and Dot1p[J].J Biol Chem,2003,278(37):34739-34742.
[24]KROGAN NJ,DOVER J,WOOD A,et al.The Paf1complex is required for histone H3 methylation by COMPASS and Dot1p:linking transcriptional elongation to histone methylation[J].Mol Cell,2003,11(3):721-729.
[25]KIM SK,JUNG I,LEE H,et al.Human histone H3K79methyltransferase DOT1L protein[corrected]binds actively transcribing RNA polymerase II to regulate gene expression[J].J Biol Chem,2012,287(47):39698-39709.
[26]FIERZ B,CHATTERJEE C,MCGINTY RK,et al.Histone H2B ubiquitylation disrupts local and higherorder chromatin compaction[J].Nat Chem Biol,2011,7(2):113-119.
[27]FINGERMAN IM,LI HC,BRIGGS SD.A charge-based interaction between histone H4 and Dot1 is required for H3K79 methylation and telomere silencing:identification of a new trans-histone pathway[J].Genes Dev,2007,21(16):2018-2029.
[28]ALTAF M,UTLEY RT,LACOSTE N,et al.Interplay of chromatin modifiers on a short basic patch of histone H4tail defines the boundary of telomeric heterochromatin[J].Mol Cell,2007,28(6):1002-1014.
[29]VAQUERO A,SCHER M,LEE D,et al.Human SirT1interacts with histone H1 and promotes formation of facultative heterochromatin[J].Mol Cell,2004,16(1):93-105.
[30]FREDERIKS F,VAN WELSEM T,OUDGENOEG G,et al.Heterologous expression reveals distinct enzymatic activities of two DOT1 histone methyltransferases of Trypanosoma brucei[J].J Cell Sci,2010,123(Pt 23):4019-4023.
[31]SCHULZE JM,JACKSON J,NAKANISHI S,et al.Linking cell cycle to histone modifications:SBF and H2B monoubiquitination machinery and cell-cycle regulation of H3K79 dimethylation[J].Mol Cell,2009,35(5):626-641.
[32]TAKAHASHI YH,SCHULZE JM,JACKSON J,et al.Dot1 and histone H3K79 methylation in natural telomeric and HM silencing[J].Mol Cell,2011,42(1):118-126.
[33]LIN YH,KAKADIA PM,CHEN Y,et al.Global reduction of the epigenetic H3K79 methylation mark and increased chromosomal instability in CALM-AF10-positive leukemias[J].Blood,2009,114(3):651-658.
[34]SWEET SM,LI M,THOMAS PM,et al.Kinetics of reestablishing H3K79 methylation marks in global human chromatin[J].J Biol Chem,2010,285(43):32778-32786.
[35]DE VOS D,FREDERIKS F,TERWEIJ M,et al.Progressive methylation of ageing histones by Dot1functions as a timer[J].EMBO Rep,2011,12(9):956-962.
[36]FOSTER ER,DOWNS JA.Methylation of H3 K4 and K79 is not strictly dependent on H2B K123 ubiquitylation[J].J Cell Biol,2009,184(5):631-638.
[37]STEGER DJ,LEFTEROVA MI,YING L,et al.DOT1L/KMT4 recruitment and H3K79 methylation are ubiquitously coupled with gene transcription in mammalian cells[J].Mol Cell Biol,2008,28(8):2825-2839.
[38]KATAN-KHAYKOVICH Y,STRUHL K.Heterochromatin formation involves changes in histone modifications over multiple cell generations[J].EMBO J,2005,24(12):2138-2149.
[39]SAWADO T,HALOW J,IM H,et al.H3 K79dimethylation marks developmental activation of the betaglobin gene but is reduced upon LCR-mediated high-level transcription[J].Blood,2008,112(2):406-414.
[40]ONTOSO D,KAUPPI L,KEENEY S,et al.Dynamics of DOT1L localization and H3K79 methylation during meiotic prophaseⅠin mouse spermatocytes[J].Chromosoma,2014,123(1-2):147-164.
[41]OOGA M,INOUE A,KAGEYAMA S,et al.Changes in H3K79 methylation during preimplantation development in mice[J].Biol Reprod,2008,78(3):413-424.
[42]TU S,BULLOCH EM,YANG L,et al.Identification of histone demethylases in Saccharomyces cerevisiae[J].J Biol Chem,2007,282(19):14262-14271.
[43]XU W,YANG H,LIU Y,et al.Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of alphaketoglutarate-dependent dioxygenases[J].Cancer Cell,2011,19(1):17-30.
[44]KIM W,KIM R,PARK G,et al.Deficiency of H3K79histone methyltransferase Dot1-like protein(DOT1L)inhibits cell proliferation[J].J Biol Chem,2012,287(8):5588-5599.
[45]WANG CM,TSAI SN,YEW TW,et al.Identification of histone methylation multiplicities patterns in the brain of senescence-accelerated prone mouse 8[J].Biogerontology,2010,11(1):87-102.
[46]BARRY ER,KRUEGER W,JAKUBA CM,et al.ES cell cycle progression and differentiation require the action of the histone methyltransferase Dot1L[J].Stem Cells,2009,27(7):1538-1547.
[47]FENG Y,YANG Y,ORTEGA MM,et al.Early mammalian erythropoiesis requires the Dot1L methyltransferase[J].Blood,2010,116(22):4483-4491.
[48]ILLI B,SCOPECE A,NANNI S,et al.Epigenetic histone modification and cardiovascular lineage programming in mouse embryonic stem cells exposed to laminar shear stress[J].Circ Res,2005,96(5):501-508.
[49]NGUYEN AT,XIAO B,NEPPL RL,et al.DOT1L regulates dystrophin expression and is critical for cardiac function[J].Genes Dev,2011,25(3):263-274.
[50]IM H,PARK C,FENG Q,et al.Dynamic regulation of histone H3 methylated at lysine 79 within a tissue-specific chromatin domain[J].J Biol Chem,2003,278(20):18346-18352.
[51]GONZALEZ A.Osteoarthritis year 2013 in review:genetics and genomics[J].Osteoarthritis Cartilage,2013,21(10):1443-1451.
[52]CASTANO BETANCOURT MC,CAILOTTO F,KERKHOF HJ,et al.Genome-wide association and functional studies identify the DOT1L gene to be involved in cartilage thickness and hip osteoarthritis[J].Proc Natl Acad Sci U S A,2012,109(21):8218-8223.
[53]EVANGELOU E,VALDES AM,CASTANOBETANCOURT MC,et al.The DOT1L rs12982744polymorphism is associated with osteoarthritis of the hip with genome-wide statistical significance in males[J].Ann Rheum Dis,2013,72(7):1264-1265.
[54]MOHAN M,HERZ HM,TAKAHASHI YH,et al.Linking H3K79 trimethylation to Wnt signaling through a novel Dot1-containing complex(DotCom)[J].Genes Dev,2010,24(6):574-589.
[55]HARTMANN C,TABIN CJ.Wnt-14 plays a pivotal role in inducing synovial joint formation in the developing appendicular skeleton[J].Cell,2001,104(3):341-351.
[56]MAHMOUDI T,BOJ SF,HATZIS P,et al.The leukemia-associated Mllt10/Af10-Dot1l are Tcf4/betacatenin coactivators essential for intestinal homeostasis[J].PLoS Biol,2010,8(11):e1000539.
[57]NGUYEN AT,TARANOVA O,HE J,et al.DOT1L,the H3K79 methyltransferase,is required for MLL-AF9-mediated leukemogenesis[J].Blood,2011,117(25):6912-6922.
[58]DAIGLE SR,OLHAVA EJ,THERKELSEN CA,et al.Selective killing of mixed lineage leukemia cells by a potent small-molecule DOT1L inhibitor[J].Cancer Cell,2011,20(1):53-65.