间充质干细胞特化心肌细胞的组蛋白乙酰化修饰调控机制
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摘要
目的:
筛选本课题组前期对Gcn5(组蛋白乙酰基转移酶辅激酶)基因设计的7条质粒片段中能高效抑制Gcn5表达的shRNA序列;探讨干扰Gcn5表达后是否能够引起体内组蛋白乙酰化修饰平衡的改变;观测下调组蛋白乙酰化修饰状态对体内、外MSCs(骨髓间充质干细胞)定向分化为心肌细胞的影响,从而探讨组蛋白低乙酰化状态对MSCs定向分化的调控机理;建立通过干预组蛋白乙酰化平衡状态来调节MSCs定向分化的“基因调节开关”的理论与实验技术平台。
方法:
采用不同组合质粒片段干扰体外培养的MSCs,通过观察细胞形态变化,ELISA技术检测MSCs细胞核蛋白HAT(组蛋白乙酰化酶)活性状态,Western-blotting分析MSCs细胞核Gcn5蛋白表达,荧光显微镜观察质粒转染细胞荧光表达量,流式细胞技术检测质粒转染效率,筛选有效质粒片段;利用筛选出的有效shRNA转染MSCs,通过ELISA技术检测MSCs细胞核HAT活性状态,验证通过沉默Gcn5基因是否能够下调组蛋白乙酰化修饰水平。利用shRNA-ZJ3转染单纯MSCs或经5-aza(5-氮杂胞苷)处理前后的MSCs,通过观察细胞形态变化, CHIP技术分析乙酰化的组蛋白H3肽链上的相关基因(Gcn5;GATA-4)表达,透射电镜观测细胞超微结构的变化,分析下调组蛋白乙酰化修饰状态是否能够干预MSCs体外特化心肌细胞的过程;移植经有效shRNA转染的MSCs至大鼠心肌组织,2W后检测移植区心肌组织中HAT活性状态,Gcn5、GATA-4基因及Gcn5、MHC、Cx43蛋白的表达状况,探讨心肌微环境中组蛋白乙酰化修饰对MSCs特化心肌细胞的调控机理。
结果:
1、观察各种质粒转染的MSCs形态变化显示经shRNA-ZJ3经各种预处理的MSCs较正常MSCs形态变化最大,生长比较缓慢;shRNA-ZJ3转染的MSCs细胞核HAT活性及Gcn5蛋白表达量均明显降低(P<0.05);荧光显微镜观察GFP表达量及流式细胞技术检测显示转染效率大于20%。
2、经shRNA-ZJ3转染的MSCs细胞核内HAT活性较正常MSCs及shRNA-HK(通用阴性质粒对照)转染的MSCs明显降低(P<0.05)。
3、5-aza诱导的MSCs细胞生长旺盛,单纯shRNA-ZJ3转染或5-aza诱导前后经shRNA-ZJ3转染的MSCs生长迟滞,形态瘦小;细胞核蛋白HAT测定显示:5-aza诱导组乙酰化水平最高,单纯转染组(TR组)、诱导后转染组(IN-TR组)以及转染后诱导组(TR-IN组)与正常组比较HAT活性均有显著性降低(P<0.05),TR组分别与Normal组、HK组及IN组比较HAT活性降低亦有显著性(P<0.05);经5-aza诱导后的MSCs(阳性对照组)与高乙酰化水平组蛋白H3相交联的Gcn5及GATA-4表达较正常组(正常培养MSCs组)、阴性对照组(HK转染组)及实验组(5-aza诱导后shRNA-ZJ3转染组)均有显著性增高(P<0.05);实验组中与高乙酰化水平组蛋白H3相交联的Gcn5表达较正常对照组、阴性对照组及阳性对照组均有显著性的降低(P<0.05);电镜检测细胞超微结构发现经5-aza诱导的MSCs增生活跃,外形长条化,胞浆出现肌丝结构,shRNA-ZJ3转染的MSCs细胞核中异染色质比例增大,部分细胞出现凋亡。
4、体内移植区心肌组织内HAT活性检测发现实验组(shRNA-ZJ3转染MSCs移植组)乙酰化酶活性较正常组(正常心肌组织)、阴性对照组1(shRNA-HK转染组)及阴性对照组2(DAPI标记MSCs移植组)均有显著性降低(P<0.05);实验组中可检测到Gcn5及GATA-4基因的低表达,较其它三个对照组表达量均有显著性降低(P<0.05)。
结论:
1、前期课题组构建的7条质粒片段中shRNA-ZJ3能够有效干预Gcn5基因的表达。
2、shRNA-ZJ3阻断Gcn5基因表达后能够下调细胞核组蛋白乙酰化修饰水平,导致组蛋白乙酰化失衡状态的出现。
3、组蛋白乙酰化修饰平衡参与调控MSCs体外特化心肌细胞的过程。
4、心肌微环境中MSCs的组蛋白乙酰化活性状态与分化活性及分化启动密切相关。
5、组蛋白乙酰化修饰参与调节MSCs在体内心肌微环境中特化为心肌细胞的过程。低组蛋白乙酰化修饰导致的静默状态的MSCs无法进入定向分化进程。
6、成功建立通过干预组蛋白乙酰化平衡调节MSCs定向分化的“基因调控开关”的理论与实验技术平台。
Objective:
The study is to screen valid plasmid targeted to Gcn5 among the constructed recombinant plasmids; and to detect weather it could silence Gcn5 gene expression. To confirm the effective plasmid which could cause low-grade acetylation. Then to explore the disbalance of histone acetylizad modification result in the effective plasmid could regulate MSCs differentiation in vivo and in vitro. Finally establish a technique platform for the switch which regulates the gene expression in the process of MSCs differentiation.
Methods and materials:
1. Screen an effective plasmid, transfect different plasmids into MSCs, and then investigate the cell morphologic change, HAT activity and the expression of Gcn5.
2. Confirm weather the plasmid ZJ3 could cut down the level of histone acetylation, transfect the MSCs with shRNA-ZJ3 and then detect the HAT activity of MSCs.
3. Analysis weather the low-grade acetylation of histone could regulate the MSCs differentiation, transfect the MSCs induced by 5-aza or not with shRNA-ZJ3 and then detect the cell morphologic change, HAT activity, the expression of Gcn5 and GATA-4 cross-linked to H3 peptide chain, and the ultra microstructure of MSCs.
4. Transfect the MSCs induced by 5-aza with shRNA-ZJ3, and transplant MSCs into myocardium which marked with GFP or DAPI. Two weeks later, collect the myocardium transplanted by MSCs, and detect the HAT activity, expression of gene Gcn5 and GATA-4 and the expression of protein Cx43, MHC, and Gcn5.
Results:
1. In MSCs transfected by different plasmids, some of MSCs which was transfected by shRNA-ZJ3 has a significant change in cell morphologic, low-grade activity of HAT and low-expression of protein Gcn5.
2. HAT activity of MSCs transfected by shRNA-ZJ3 is lower than normal MSCs.
3. MSCs induced by 5-aza grow vigorously, but the MSCs transfected by shRNA-ZJ3 grow flaggingly. HAT activity of MSCs induced by 5-aza shows at high-grade; however in the MSCs transfected by shRNA-ZJ3, HAT activity shows at a low-grade. The expression of Gcn5 and GATA-4 cross-linked to H3 peptide chain is obvious in the MSCs induced by 5-aza, and it is weak in the MSCs transfected by shRNA-ZJ3. Myofilament was detected in the cytoplasm of MSCs induced by 5-aza; and some apoptosis cells were found in the sample of MSCs transfected by shRNA-ZJ3; in the transfected MSCs, the percentage of heterochromatin is larger than in the normal MSCs and induced MSCs.
4. In the myocardium transplanted by MSCs which transfected by shRNA-ZJ3, HAT activity drop off obviously; the expression of gene Gcn5 and GATA-4 depressed significantly; and the expression of protein MHC, Cx43 and Gcn5 expressed also at a low level.
Conclusion:
1. shRNA-ZJ3 is the effective plasmid targeted to Gcn5.
2. Gcn5 blocked by shRNA-ZJ3 can obstruct the modification of histone, and break the balance of histone acetylation.
3. The balance of histone acetylation plays an important role to regulate the process of MSCs differention into cardiomyocytes.
4. In the myocardial microenvironment, the differentiation activity and priming of MSCs is closely related to the HAT activity.
5. In the myocardial microenvironment, silenced MSCs resulted from the disbalance of acetylation could not differentiate into cardiomyocytes.
6. The study established a technique platform for the research on histone acetylation mechanisams of regulating the gene expression in the process of MSCs differentiation successfully.
筛选本课题组前期对Gcn5(组蛋白乙酰基转移酶辅激酶)基因设计的7条质粒片段中能高效抑制Gcn5表达的shRNA序列;探讨干扰Gcn5表达后是否能够引起体内组蛋白乙酰化修饰平衡的改变;观测下调组蛋白乙酰化修饰状态对体内、外MSCs(骨髓间充质干细胞)定向分化为心肌细胞的影响,从而探讨组蛋白低乙酰化状态对MSCs定向分化的调控机理;建立通过干预组蛋白乙酰化平衡状态来调节MSCs定向分化的“基因调节开关”的理论与实验技术平台。
方法:
采用不同组合质粒片段干扰体外培养的MSCs,通过观察细胞形态变化,ELISA技术检测MSCs细胞核蛋白HAT(组蛋白乙酰化酶)活性状态,Western-blotting分析MSCs细胞核Gcn5蛋白表达,荧光显微镜观察质粒转染细胞荧光表达量,流式细胞技术检测质粒转染效率,筛选有效质粒片段;利用筛选出的有效shRNA转染MSCs,通过ELISA技术检测MSCs细胞核HAT活性状态,验证通过沉默Gcn5基因是否能够下调组蛋白乙酰化修饰水平。利用shRNA-ZJ3转染单纯MSCs或经5-aza(5-氮杂胞苷)处理前后的MSCs,通过观察细胞形态变化, CHIP技术分析乙酰化的组蛋白H3肽链上的相关基因(Gcn5;GATA-4)表达,透射电镜观测细胞超微结构的变化,分析下调组蛋白乙酰化修饰状态是否能够干预MSCs体外特化心肌细胞的过程;移植经有效shRNA转染的MSCs至大鼠心肌组织,2W后检测移植区心肌组织中HAT活性状态,Gcn5、GATA-4基因及Gcn5、MHC、Cx43蛋白的表达状况,探讨心肌微环境中组蛋白乙酰化修饰对MSCs特化心肌细胞的调控机理。
结果:
1、观察各种质粒转染的MSCs形态变化显示经shRNA-ZJ3经各种预处理的MSCs较正常MSCs形态变化最大,生长比较缓慢;shRNA-ZJ3转染的MSCs细胞核HAT活性及Gcn5蛋白表达量均明显降低(P<0.05);荧光显微镜观察GFP表达量及流式细胞技术检测显示转染效率大于20%。
2、经shRNA-ZJ3转染的MSCs细胞核内HAT活性较正常MSCs及shRNA-HK(通用阴性质粒对照)转染的MSCs明显降低(P<0.05)。
3、5-aza诱导的MSCs细胞生长旺盛,单纯shRNA-ZJ3转染或5-aza诱导前后经shRNA-ZJ3转染的MSCs生长迟滞,形态瘦小;细胞核蛋白HAT测定显示:5-aza诱导组乙酰化水平最高,单纯转染组(TR组)、诱导后转染组(IN-TR组)以及转染后诱导组(TR-IN组)与正常组比较HAT活性均有显著性降低(P<0.05),TR组分别与Normal组、HK组及IN组比较HAT活性降低亦有显著性(P<0.05);经5-aza诱导后的MSCs(阳性对照组)与高乙酰化水平组蛋白H3相交联的Gcn5及GATA-4表达较正常组(正常培养MSCs组)、阴性对照组(HK转染组)及实验组(5-aza诱导后shRNA-ZJ3转染组)均有显著性增高(P<0.05);实验组中与高乙酰化水平组蛋白H3相交联的Gcn5表达较正常对照组、阴性对照组及阳性对照组均有显著性的降低(P<0.05);电镜检测细胞超微结构发现经5-aza诱导的MSCs增生活跃,外形长条化,胞浆出现肌丝结构,shRNA-ZJ3转染的MSCs细胞核中异染色质比例增大,部分细胞出现凋亡。
4、体内移植区心肌组织内HAT活性检测发现实验组(shRNA-ZJ3转染MSCs移植组)乙酰化酶活性较正常组(正常心肌组织)、阴性对照组1(shRNA-HK转染组)及阴性对照组2(DAPI标记MSCs移植组)均有显著性降低(P<0.05);实验组中可检测到Gcn5及GATA-4基因的低表达,较其它三个对照组表达量均有显著性降低(P<0.05)。
结论:
1、前期课题组构建的7条质粒片段中shRNA-ZJ3能够有效干预Gcn5基因的表达。
2、shRNA-ZJ3阻断Gcn5基因表达后能够下调细胞核组蛋白乙酰化修饰水平,导致组蛋白乙酰化失衡状态的出现。
3、组蛋白乙酰化修饰平衡参与调控MSCs体外特化心肌细胞的过程。
4、心肌微环境中MSCs的组蛋白乙酰化活性状态与分化活性及分化启动密切相关。
5、组蛋白乙酰化修饰参与调节MSCs在体内心肌微环境中特化为心肌细胞的过程。低组蛋白乙酰化修饰导致的静默状态的MSCs无法进入定向分化进程。
6、成功建立通过干预组蛋白乙酰化平衡调节MSCs定向分化的“基因调控开关”的理论与实验技术平台。
Objective:
The study is to screen valid plasmid targeted to Gcn5 among the constructed recombinant plasmids; and to detect weather it could silence Gcn5 gene expression. To confirm the effective plasmid which could cause low-grade acetylation. Then to explore the disbalance of histone acetylizad modification result in the effective plasmid could regulate MSCs differentiation in vivo and in vitro. Finally establish a technique platform for the switch which regulates the gene expression in the process of MSCs differentiation.
Methods and materials:
1. Screen an effective plasmid, transfect different plasmids into MSCs, and then investigate the cell morphologic change, HAT activity and the expression of Gcn5.
2. Confirm weather the plasmid ZJ3 could cut down the level of histone acetylation, transfect the MSCs with shRNA-ZJ3 and then detect the HAT activity of MSCs.
3. Analysis weather the low-grade acetylation of histone could regulate the MSCs differentiation, transfect the MSCs induced by 5-aza or not with shRNA-ZJ3 and then detect the cell morphologic change, HAT activity, the expression of Gcn5 and GATA-4 cross-linked to H3 peptide chain, and the ultra microstructure of MSCs.
4. Transfect the MSCs induced by 5-aza with shRNA-ZJ3, and transplant MSCs into myocardium which marked with GFP or DAPI. Two weeks later, collect the myocardium transplanted by MSCs, and detect the HAT activity, expression of gene Gcn5 and GATA-4 and the expression of protein Cx43, MHC, and Gcn5.
Results:
1. In MSCs transfected by different plasmids, some of MSCs which was transfected by shRNA-ZJ3 has a significant change in cell morphologic, low-grade activity of HAT and low-expression of protein Gcn5.
2. HAT activity of MSCs transfected by shRNA-ZJ3 is lower than normal MSCs.
3. MSCs induced by 5-aza grow vigorously, but the MSCs transfected by shRNA-ZJ3 grow flaggingly. HAT activity of MSCs induced by 5-aza shows at high-grade; however in the MSCs transfected by shRNA-ZJ3, HAT activity shows at a low-grade. The expression of Gcn5 and GATA-4 cross-linked to H3 peptide chain is obvious in the MSCs induced by 5-aza, and it is weak in the MSCs transfected by shRNA-ZJ3. Myofilament was detected in the cytoplasm of MSCs induced by 5-aza; and some apoptosis cells were found in the sample of MSCs transfected by shRNA-ZJ3; in the transfected MSCs, the percentage of heterochromatin is larger than in the normal MSCs and induced MSCs.
4. In the myocardium transplanted by MSCs which transfected by shRNA-ZJ3, HAT activity drop off obviously; the expression of gene Gcn5 and GATA-4 depressed significantly; and the expression of protein MHC, Cx43 and Gcn5 expressed also at a low level.
Conclusion:
1. shRNA-ZJ3 is the effective plasmid targeted to Gcn5.
2. Gcn5 blocked by shRNA-ZJ3 can obstruct the modification of histone, and break the balance of histone acetylation.
3. The balance of histone acetylation plays an important role to regulate the process of MSCs differention into cardiomyocytes.
4. In the myocardial microenvironment, the differentiation activity and priming of MSCs is closely related to the HAT activity.
5. In the myocardial microenvironment, silenced MSCs resulted from the disbalance of acetylation could not differentiate into cardiomyocytes.
6. The study established a technique platform for the research on histone acetylation mechanisams of regulating the gene expression in the process of MSCs differentiation successfully.
引文
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[9] Berger S L, et a1. Gene activation by histone and actor acetyltrans-ferases [J].Curr Opin Cell Biol, 1999, 11(3):336-341.
[10] TADDEI A, ROCHE D,BICKMORE WA,et a1.The effect of histone deacetylase inhibitor on heterochromatin: implications for anticancer therapy[J]. EMBO Rep, 2006, 6(6):520-524.
[11] S Yamagoe,T Kanno,Yuka Kanno et al.Interaction of Histone Acetylases and Deacetylases in Vivo. Molecular and Celluar biology [J], 2003; 23(3):1025-1033.
[12] 2. Kikuchi H, Takami Y, Nakayama T, et al. GCN5: a supervisor in all-inclusive control of vertebrate cell cycle progression through transcription regulation of various cell cycle-related genes [J]. Gene, 2005, 347(1):83-97.
[13] Zhang W, Bone JR, Edmondson DG, Turner BM, Roth SY, et al. Essential and redundant functions of histone acetylation revealed by mutation of target lysines and loss of the Gcn5p acetyltransferase[J]. EMBO J, 1998, 17(11):3155-3167.
[14] Pazin M J,Kadonaga J T, et al. What up and down with histone acetyl deacetylation and transcription [J]? Cell, 1997, 89(3): (325-328).
[1] Jackson KA et al. Proc Natl Acad Sci USA, 1999, 96: 14482-14486.
[2] Rao Met al. Dev Biol, 2004, 275: 269- 286.
[3] Hattori N, Nishino K, Ko Y, et al. Epigenetic control of mouse Oct-4 gene expression in embryonic stem cells and trophoblast stem cells [J]. J Biol Chem, 2004, 279(17): (17063-17069).
[4] Rugg-Gunn P J, Ferguson-Smith A C, Pedersen R A, et al. Epigenetic status of human embryonic stem cells[J]. Nat Genet, 2005, 37: (585-587).
[5] Hattori N, Abe T, Suzuki M, et al. Preference of DNA methyltransferases for CpG islands in mouse embryonic stem cells [J]. Genome Res, 2004, 14: (1733-1740).
[6] Jackson M, Krassowska A, Gilbert N, et al. Severe global DNA hypomethylation blocks differentiation and induces histone hyperacetylation in embryonic stem cells[J]. Mol Cell Biol, 2004, 24: (8862-8871).
[7] Morris, K.V. siRNA-mediated transcriptional gene silencing: the potential mechanism and a possible role in the histone code [J]. Cell. Mol. Life Sci. 2005,62: (3057–3066).
[8] Jaenisch R, Hochedlinger K, Egan K. Nuclear cloning, epigenetic reprogramming and cellular differentiation [J]. Novartis Found Sump, 2005, 265: (107-128).
[9] 朱静,邓兵,王金菊,田杰,王应雄,等. 5-aza诱导干细胞经乙酰化特异RNAi后心肌细胞发育相关基因检测[J], 第三军医大学学报,2006,28(6):535-538.
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[15] Spivakov M, Fisher AG., et al. Epigenetic signatures of stem-cell identity [J]. Nat Rev Genet, 2007, 8(4):263-71.
[16] Jackson M, Krassowska A, Gilbert N, et al. Severe global DNA hypomethylation blocks differentiation and induces histone hyperacetylation in embryonic stemcells[J]. Mol Cell Biol, 2004, 24: (8862-8871).
[17] Park P H, Lim R W, Shukla S D. Involvement of histone acetyltransferase (HAT) in ethanol-induced acetylation of histone H3 in hepatocytes: potential mechanism for gene expression [J]. Am J Physiol Gastrointest Liver Physiol, 2005, 289: (G1124-G1136).
[18] Peterkin T, Gibson A, Patient R, et al. Redundancy and evolution of GATA factor requirements in development of the myocardium [J]. Dev Biol, 2007, 16.
[19] Mercier P, Li MX, Sykes BD, et a1.Role of the structural domain of troponin C in muscle regulation:NMR studies of Ca2+ bingding and subsequent interactions with regions 1-40 and 96-115 of troponin I[J]. Biochemistry,2000,39:(2902-29l1).
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[3] Wang js, Shum-Tim D, Chedrawy E, et a1. The coronary delivery of marrow stromal cells for myocardial regeneration : Pathophysiologic and therapeutic implications[J]. Thorac Cardiovasc Surg, 2001, 122: (699-705).
[4] Alison M R, Poulsom R, Forbes S, et al. An introduction to stem cells [J]. J Pathol, 2002, 197: (419-423)。
[5] Liu Y, Song J, Liu W, et a1. Growth and differentiation of rat bone marrow stromal cells : does 5-azacytidine trigger their cardiomyogenic differentiati0n? [J] Cardiovasc Res, 2003, 58:460-468.
[6] Fukuhara S, Tomita S, Yamashiro S, et a1. Direct cell-cell interaction of cardiomyocytes is a key for bone marrow stem cells to go into cardiac lineage in vitro [J]. J Throat Cardio vase Surg, 2003, 125(6):1470-1480.
[7] Toma C, Pittenger MF, Cahill KS, et a1. Human mesenchymal stem cells differentiate to a cardiomyocytes phenotype in the adult murine heart [J]. Circulation, 2002, 105(1):93-98.
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[1] Jackson KA et al. Proc Natl Acad Sci USA, 1999, 96: 14482-14486.
[2] Rao Met al. Dev Biol, 2004, 275: 269- 286.
[3] Hattori N, Nishino K, Ko Y, et al. Epigenetic control of mouse Oct-4 gene expression in embryonic stem cells and trophoblast stem cells [J]. J Biol Chem, 2004, 279(17): (17063-17069).
[4] Rugg-Gunn P J, Ferguson-Smith A C, Pedersen R A, et al. Epigenetic status of human embryonic stem cells[J]. Nat Genet, 2005, 37: (585-587).
[5] Hattori N, Abe T, Suzuki M, et al. Preference of DNA methyltransferases for CpG islands in mouse embryonic stem cells [J]. Genome Res, 2004, 14: (1733-1740).
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[7] Morris, K.V. siRNA-mediated transcriptional gene silencing: the potential mechanism and a possible role in the histone code [J]. Cell. Mol. Life Sci. 2005,62: (3057–3066).
[8] Jaenisch R, Hochedlinger K, Egan K. Nuclear cloning, epigenetic reprogramming and cellular differentiation [J]. Novartis Found Sump, 2005, 265: (107-128).
[9] 朱静,邓兵,王金菊,田杰,王应雄,等. 5-aza诱导干细胞经乙酰化特异RNAi后心肌细胞发育相关基因检测[J], 第三军医大学学报,2006,28(6):535-538.
[10] Lorch Y, LaPointe JW, Kornberg RD, et al. Nucleosomes inhibit the initiation of transcription but allow chain elongation with the displacement of histones [J]. Cell, 1987, 49(2):203-210.
[11] Park Y, Kuroda MI, et al. Epigenetic aspects of X-chromosome dosage compensation [J]. Science, 2001, 293(5532):1083-1085.
[12] Pennisi E. Behind the scenes of gene expression [J]. Science, 2001, 293(5532) :1064-1067.
[13] Berger S L, et a1. Gene activation by histone and actor acetyltrans-ferases [J].Curr Opin Cell Biol, 1999, 11(3):336-341.
[14] Santos-Rosa, H. et al. Active genes are trimethylated at K4 of histone H3 [J]. Nature, 2002, 419 (407-411).
[15] Spivakov M, Fisher AG., et al. Epigenetic signatures of stem-cell identity [J]. Nat Rev Genet, 2007, 8(4):263-71.
[16] Jackson M, Krassowska A, Gilbert N, et al. Severe global DNA hypomethylation blocks differentiation and induces histone hyperacetylation in embryonic stemcells[J]. Mol Cell Biol, 2004, 24: (8862-8871).
[17] Park P H, Lim R W, Shukla S D. Involvement of histone acetyltransferase (HAT) in ethanol-induced acetylation of histone H3 in hepatocytes: potential mechanism for gene expression [J]. Am J Physiol Gastrointest Liver Physiol, 2005, 289: (G1124-G1136).
[18] Peterkin T, Gibson A, Patient R, et al. Redundancy and evolution of GATA factor requirements in development of the myocardium [J]. Dev Biol, 2007, 16.
[19] Mercier P, Li MX, Sykes BD, et a1.Role of the structural domain of troponin C in muscle regulation:NMR studies of Ca2+ bingding and subsequent interactions with regions 1-40 and 96-115 of troponin I[J]. Biochemistry,2000,39:(2902-29l1).
[1] Reinlb L, Field L. Cell transplanntation as future therapy for cardiovascular disease [J].Circulation, 2000; 101:182-187.
[2] Mummery C, Ward-van Oostwaard D, Doevendans P, et a1. Differentiation of human embryonic stem cells to cardiomyocytes: role of coculture with visceral endoderm-Like cells [J]. Circulation, 2003, 107: (2733-2740).
[3] Wang js, Shum-Tim D, Chedrawy E, et a1. The coronary delivery of marrow stromal cells for myocardial regeneration : Pathophysiologic and therapeutic implications[J]. Thorac Cardiovasc Surg, 2001, 122: (699-705).
[4] Alison M R, Poulsom R, Forbes S, et al. An introduction to stem cells [J]. J Pathol, 2002, 197: (419-423)。
[5] Liu Y, Song J, Liu W, et a1. Growth and differentiation of rat bone marrow stromal cells : does 5-azacytidine trigger their cardiomyogenic differentiati0n? [J] Cardiovasc Res, 2003, 58:460-468.
[6] Fukuhara S, Tomita S, Yamashiro S, et a1. Direct cell-cell interaction of cardiomyocytes is a key for bone marrow stem cells to go into cardiac lineage in vitro [J]. J Throat Cardio vase Surg, 2003, 125(6):1470-1480.
[7] Toma C, Pittenger MF, Cahill KS, et a1. Human mesenchymal stem cells differentiate to a cardiomyocytes phenotype in the adult murine heart [J]. Circulation, 2002, 105(1):93-98.
[8] Orlie D, Kajstura J, Chimenti S, et a1. Bone marrow cells regenerate infracted myocardium[J]. Nature, 2001, 410(6825):701-705.
[9] Zhang W, Tian J, Jiang DQ, et a1. Temporal expression of regulative gene in theprocess of bone marrow mesenchymal stem cells differentiating into cardiomyocytes in vitro[J].Chin J Cardiol, 2004, 32 :1004-1008.
[10] 江德勤,田 杰,白永虹,张文,张蕾,朱静,陈沅,等. 骨髓间充质干细胞移植在心肌病大鼠体内存活、分化的实验研究[J],心脏杂志,2005,17(1):4-7.
[11] Watt FM, Hogan B. Out of eden:stem cells and their niches [J]. Science, 2000, 287:1427-1430.
[12] Fukuda K. Development of regenerative cardiomyocytes from mesenchymal stem cells for cardiovascular tissue engineering [J]. Artif Organs, 2001, 25:187-193.
[13] Toko H, Zhu W, Takimoto E, et a1. Csx/Nkx2.5 is required for homeostasis and survival of cardiac myocytes in the adult heart[J]. Biol Chem, 2002, 277: 24735-24743.
[14] Forbes SJ, Vig P, Poulsom R, et al. Adult stem cell plasticity: new pathway of tissue regeneration becomes visible [J]. Clin Sci (Lond), 2002, 103:355-369.
[15] Almeida-Porada G, Porada C, zanjani ED. 2001. Adult stem cell plasticity and methods of detection[J]. Rev Clin Exp Hematol, 2001, 5:26-41.
[16] Wolper L, Beddington R, Brockes J, Jessell T, Lawrence P, Meyerowitz E. Principles of Development [J]. Current Biology LTD, Oxford University Press. 1998.
[17] Jaenisch R, Hochedlinger K, Egan K. Nuclear cloning, epigenetic reprogramming and cellular differentiation [J]. Novartis Found Sump, 2005, 265: (107-128).
[18] Allrfey VG. Structural modifications if histones and their possible role in the regulation of ribonucleic acid synthesis [J]. Proc Can Cancer Conf, 1996; 6:313-335.
[19] Li E, et al. Chromatin modification and epigenetic reprogramming in mammalian development [J]. Nat Rev Genet, 2002, 3: (662-673).
[20] Wetlaufer D B. Ultraviolet Spectra of Protein and Amino Acids [J]. Protein Chemistry, 1962, 17:303-309.
[1] Zhang W, Bone JR, Edmondson DG, Turner BM, Roth SY, et al. Essential and redundant functions of histone acetylation revealed by mutation of target lysines and loss of the Gcn5p acetyltransferase. EMBO J, 1998, 17(11):3155-3167.
[2] Kikuchi H, Takami Y, Nakayama T, et al. GCN5: a supervisor in all-inclusive control of vertebrate cell cycle progression through transcription regulation of various cell cycle-related genes. Gene, 2005, 347(1):83-97.
[3] Baluchamy S, Sankar N, Navaraj A, Moran E, Thimmapaya B, et al. Relationship between E1A binding to cellular proteins, c-myc activation and S-phase induction. Oncogene, 2007, 26 (5):721-724.
[4] Early A, Drury LS, Diffley JF, et al. Mechanisms involved in regulating DNA replication origins during the cell cycle and in response to DNA damage. Philos Trans R Soc Lond B Biol Sci, 2004, 359(1441):31-38.
[5] Tang Y, Luo J, Zhang W, Gu W, et al. Tip60-dependent acetylation of p53 modulates the decision between cell-cycle arrest and apoptosis. Mol Cell, 2006, 24(6):827-839.
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