LSD1对斑马鱼发育的影响及其机制的初步研究
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摘要
赖氨酸特异的脱甲基酶1(也称为LSD1,BHC110或者AOF2)是第一个发现的组蛋白脱甲基酶。在CoREST(corepressor for REST)、BHC80和HADC等辅助因子帮助下,LSD1能够使组蛋白H3-K4位脱去一个或二个甲基。组蛋白脱甲基后引起染色质重塑或改变靶基因的转录活性。通常H3-K4脱甲基化抑制靶基因转录活性,而H3-K9脱甲基化则导致靶基因转录被激活。
LSD1与很多疾病有密切的关系。例如,在人肿瘤细胞中LSD1表现为沉默,而一些LSD1作用的靶基因却大量表达。这些基因在癌症的发展中有重要的作用。又如,lsd1敲除的小鼠在围产早期死亡,这也导致难以深入研究lsd1在发育过程中的作用及其机制。模式生物斑马鱼胚胎透明、体外发育、个体小、繁殖率高以及其心血管、血液、消化道、肝脏、肾脏以及视觉系统与人类相应系统有许多共同点,基因组序列与人的同源性更是达到75%以上。此外,斑马鱼所需部分的氧可以通过体表渗透,因此特别适用于心血管和血液系统早期发育的研究。本课题就是利用斑马鱼作为模型来研究LSD1对于发育的影响并对其机制进行了初步的探索。
第一部分LSD1在脊椎动物中的同源性及其在斑马鱼胚胎发育早期的表达
LSD1的cDNA共编码689个氨基酸残基,蛋白质分子量约为110KD。生物信息学的方法聚类比较显示LSD1在脊椎动物的进化过程中,蛋白质结构非常保守(同源性＞65%)。不同物种的LSD1蛋白质分子上有两个很保守的结构域:SWIRM和FAD结构域;在斑马鱼发育中,lsd1在胚胎上表达从受精后一直持续到整个发育早期,而且lsd1的表达量始终处于高水平,特别是在神经系统中。
第二部分斑马鱼中lsd1基因表达下调方法的建立
本研究通过吗啡啉修饰的反义寡核苷酸技术(morpholino)干扰目标mRNA翻译的方法下调lsd1表达,并观察斑马鱼发育受到的影响。我们设计了两个具有剪接功能的吗啡啉修饰反义寡核苷酸,下调了lsd1基因在斑马鱼中的表达。外显子11和17是LSD1功能蛋白必需的编码序列,失去其中任何一段,LSD1即丧失脱甲基酶活性。RT—PCR结果显示外显子11和17在两种MO注射后分别被剪切掉,这也验证了吗啡啉修饰的反义寡核苷酸的有效性,说明LSD1 MO能够有效下调内源性的lsd1。此外,当斑马鱼暴露在一定浓度的PCPA(＞20μM,反环苯丙胺)中,LSD1具有的组蛋白脱甲基酶活性H3-K4(2m)也被强烈抑制。
第三部分lsd1基因表达下调对斑马鱼血液系统发育的影响
斑马鱼是研究血管和造血的良好模型,常被应用于血管异常和造血障碍的研究。体外实验提示LSD1对于血细胞的分化起着重要作用。因为在小鼠模型中致死性,所以原始造血系统功能与LSD1的关系了解不多。我们利用斑马鱼第一次发现PCPA可以诱导斑马鱼的贫血现象,进一步研究显示贫血是由于原始造血系统被抑制造成的。这种贫血现象是由于与LSD1相关的表观遗传学变化引起的;吗啡啉下调lsd1后,斑马鱼中出现了相似的贫血表型。表明原始造血系统的发育需要LSD1的H3K4脱甲基酶参与。制备sc1、lmo2、gata2、gata1、globin、pu.1、mpx、L-plastin和flk1探针进行了胚胎整体原位杂交。结果显示,血管发育基本不受影响,但是原始红系细胞数量减少。红系发育受阻的同时髓系发育则基本无影响。此外,血细胞流动速度也受到影响。
第四部分lsd1基因表达下调对斑马鱼神经系统发育的影响
lsd1在斑马鱼的CNS部位持续高表达表明LSD1在神经系统发育上有一定的作用。PCPA曾作为临床上使用的抑郁药,因对患者有副作用导致使用范围减小。可是副作用分子机制不详。据报道,PCPA可以共价结合LSD1蛋白的FAD结构域从而对其酶活性产生不可逆的抑制,从而调控与神经发育相关的基因。我们观察到浓度大于或等于75μM的PCPA处理的斑马鱼较对照组活跃程度下降。原位杂交显示soxla和huc的表达水平下调,TUNEL检测结果说明上述现象是由于神经元细胞过度凋亡。注射LSD1吗啡啉后胚胎神经细胞也表现为过渡凋亡。RT-PCR结果显示,P53依赖的信号通路参与了LSD1介导的凋亡过程。
Lysine-specific demethylase 1(LSD1 also known as BHC110 or AOF2) is the first discovered histone lysine demethylase(110×10~3 Daltons).With the help of its cofactors CoREST,BHC80 and HADC,it specifically demethylates mono-and dimethylated histone H3 lysine 4(H3-K4) or H3-H9,thus exhibiting diverse transcriptional activities by chromatin reconfiguration.Methylation of H3-K4 is predominantly associated with transcriptionally active genes,whereas methylation of H3-K9 marks silent genes or heterochromatin.
A loss-of-function LSD1 in the human colon carcinoma cells causes a phenotype with a reexpression of multiple and aberrantly silenced genes which are important in the development of colon cancer.Using standard gene targeting technology in mouse embryonic stem cells,lsd1 knockout mice die in prenatal-perinatal.Despite of the sudden cardiac death phenotype,lsd1 knockout strategy resulted in big impact to development of pituitary and neural system at very early stage.More detailed phenotypic analysis of animals with lsd1 mutations will be required to uncover its biological function.
The zebrafish,Danio rerio,offers several distinct advantages as a genetic and embryological model system,including the external fertilization,rapid development and optical clarity of its embryos.Being a vertebrate,the zebrafish has a notochord, blood,heart and vasculature,kidney and optical systems that share many features with corresponding human systems.The zebrafish system bridges the gap between fruit fly/worm and mouse/human genetics(genomic sequences similar identity＞75%), making it feasible to address issues of early development,organ formation,integrative physiology,pharmacology and complex disease.Even in the total absence of blood circulation,they receive part of oxygen by passive diffusion to survive and continue to develop in a relatively normal fashion for several days,thereby allowing a detailed analysis of animals with severe cardiovascular defects.So far,we used zebrafish as a modle to study the functions of LSD1 and related mechanisms.
Section 1 Evolutionarily Conserved Structure and Spatiotemporal Expression of lsd1 in Zebrafish
The complete open reading frame of the LSD1 cDNA encodes a 689 amino acid protein with a calculated molecular weight of 110 kDa.The zebrafish LSD1 protein sequence shares high similar identity with other species'sequences.Further analysis of the zebrafish LSD1 sequence predicts the presence of several motifs(SWIRM and FAD domain) important to function of histone demethylation,lsd1 is expressed throughout the developing stages from one cell embryo.As embryonic development progresses,the expression pattern becomes restricted to the anterior of the embryo and in particular of the neural structures.
Section 2 Loss-of-function LSD1 Zebrafish Can Be Obtained by LSD1 MO and PCPA Treatment
To study the effects of LSD1 down regulation on the development of the embryonic zebrafish,two types of well designed morpholino oligonucleotide antisenses were injected into zebrafish embryos which can splice the exon11 and exon17 of lsd1 at one or two cells stage.Exon11 and exon17 play a crucial role in function of histone demethylation.After injection,the validity of morpholinos were tested by RT-PCR and sequencing.Furthermore,LSD1 histone demethylase is be inhibited when embryos were exposure to Trans-2-phenylcyclopropylamine(referred to as PCPA hereafter;also known as tranylcypromine and Parnate,＞20μM).Western blot showed that the H3K4 methylation level of PCPA treatment group was upregulted compared to the control.
Section 3 Requirements of LSD1 in Zebrafish Hematopoietic System
Development
In recent years,zebrafish has emerged as an exciting animal model system for studying vertebrate organ development,in particular,the development of hematopoietic system.In vitro studies suggested that lsd1 expression was of particular importance during establishment or regeneration of the mammalian definitive hematopoiesis.But little is known about its in vivo functions during primitive hematopoiesis because of embryonic lethality of mammalian knockout models.In the present study,we turn to the zebrafish embryos to pursue the role of LSD1 during hematopoiesis.
In the present study,we noticed for the first time that antidepressant PCPA treatment induces short time anemia in zebrafish.The phynotype was caused by inhibition of pirimitive hematopoiesis in zebrafish embryos.We predict that it is an epigenetic events associated with LSD1.Furthermore,we also found that lsd1 knockdown by morpholino-modified antisense oligonucleotides resulted in similar phenotype(anemia).It is suggested that LSD1 H3-K4 histone demethylase is required for primitive erythropoiesis in zebrafish.Whole-mount in situ hybridization with scl, lmo2,gata2,gata1,globin,pu.1,mpx,L-plastin and flk1 RNA probes showed that the number primitive erythropoiesis cell was decrease,but it did not nearly affect vascular development.Based on these findings we put forward an assumption that down regulation of lsd1 expression leads to inhibition of primitive erythropoiesis but not myelopoiesis.Besides,we found that gatal+of blood cells flow slowly in LSD1 MO embryos which drops a hint that LSD1 are involved in appropriate circulation of blood cells.
Section 4 LSD1 Is Essential for Zebrafish Neural System Development
We previously showed that lsd1 is highly expressed in zebrafish CNS during zebrafish embryogenesis.PCPA is used clinically as an antidepressant.The study of its adverse reaction has shown its side effect to patients.However,little is known about the molecule mechanism of the adverse reaction.Recent study showed that PCPA is an irreversible inhibitor of LSD1 which regulates neuronal specific genes by covalently modifying the FAD cofactor.We provide the first evidence that zebrafish embryos showed sluggish action at PCPA treatment(75μM) compared to the controls. Down-regulation of some neuron marker genes expression(soxla and huc) is evaluated by whole mount in situ hybridization,which indicates the decrease in the number of nerve cells.Then,nerve cells apoptosis is determined by TUNEL assay in PCPA-treated embryos as well as LSD1 MO embryos.We demonstrate that the PCPA induces apoptosis mediated by LSD1 demethylase activity,and our data also suggest that p53-depended signaling pathway may be required for the maintenance nerve cell apoptosis in LSD1-deficient zebrafish embryo.
LSD1与很多疾病有密切的关系。例如,在人肿瘤细胞中LSD1表现为沉默,而一些LSD1作用的靶基因却大量表达。这些基因在癌症的发展中有重要的作用。又如,lsd1敲除的小鼠在围产早期死亡,这也导致难以深入研究lsd1在发育过程中的作用及其机制。模式生物斑马鱼胚胎透明、体外发育、个体小、繁殖率高以及其心血管、血液、消化道、肝脏、肾脏以及视觉系统与人类相应系统有许多共同点,基因组序列与人的同源性更是达到75%以上。此外,斑马鱼所需部分的氧可以通过体表渗透,因此特别适用于心血管和血液系统早期发育的研究。本课题就是利用斑马鱼作为模型来研究LSD1对于发育的影响并对其机制进行了初步的探索。
第一部分LSD1在脊椎动物中的同源性及其在斑马鱼胚胎发育早期的表达
LSD1的cDNA共编码689个氨基酸残基,蛋白质分子量约为110KD。生物信息学的方法聚类比较显示LSD1在脊椎动物的进化过程中,蛋白质结构非常保守(同源性＞65%)。不同物种的LSD1蛋白质分子上有两个很保守的结构域:SWIRM和FAD结构域;在斑马鱼发育中,lsd1在胚胎上表达从受精后一直持续到整个发育早期,而且lsd1的表达量始终处于高水平,特别是在神经系统中。
第二部分斑马鱼中lsd1基因表达下调方法的建立
本研究通过吗啡啉修饰的反义寡核苷酸技术(morpholino)干扰目标mRNA翻译的方法下调lsd1表达,并观察斑马鱼发育受到的影响。我们设计了两个具有剪接功能的吗啡啉修饰反义寡核苷酸,下调了lsd1基因在斑马鱼中的表达。外显子11和17是LSD1功能蛋白必需的编码序列,失去其中任何一段,LSD1即丧失脱甲基酶活性。RT—PCR结果显示外显子11和17在两种MO注射后分别被剪切掉,这也验证了吗啡啉修饰的反义寡核苷酸的有效性,说明LSD1 MO能够有效下调内源性的lsd1。此外,当斑马鱼暴露在一定浓度的PCPA(＞20μM,反环苯丙胺)中,LSD1具有的组蛋白脱甲基酶活性H3-K4(2m)也被强烈抑制。
第三部分lsd1基因表达下调对斑马鱼血液系统发育的影响
斑马鱼是研究血管和造血的良好模型,常被应用于血管异常和造血障碍的研究。体外实验提示LSD1对于血细胞的分化起着重要作用。因为在小鼠模型中致死性,所以原始造血系统功能与LSD1的关系了解不多。我们利用斑马鱼第一次发现PCPA可以诱导斑马鱼的贫血现象,进一步研究显示贫血是由于原始造血系统被抑制造成的。这种贫血现象是由于与LSD1相关的表观遗传学变化引起的;吗啡啉下调lsd1后,斑马鱼中出现了相似的贫血表型。表明原始造血系统的发育需要LSD1的H3K4脱甲基酶参与。制备sc1、lmo2、gata2、gata1、globin、pu.1、mpx、L-plastin和flk1探针进行了胚胎整体原位杂交。结果显示,血管发育基本不受影响,但是原始红系细胞数量减少。红系发育受阻的同时髓系发育则基本无影响。此外,血细胞流动速度也受到影响。
第四部分lsd1基因表达下调对斑马鱼神经系统发育的影响
lsd1在斑马鱼的CNS部位持续高表达表明LSD1在神经系统发育上有一定的作用。PCPA曾作为临床上使用的抑郁药,因对患者有副作用导致使用范围减小。可是副作用分子机制不详。据报道,PCPA可以共价结合LSD1蛋白的FAD结构域从而对其酶活性产生不可逆的抑制,从而调控与神经发育相关的基因。我们观察到浓度大于或等于75μM的PCPA处理的斑马鱼较对照组活跃程度下降。原位杂交显示soxla和huc的表达水平下调,TUNEL检测结果说明上述现象是由于神经元细胞过度凋亡。注射LSD1吗啡啉后胚胎神经细胞也表现为过渡凋亡。RT-PCR结果显示,P53依赖的信号通路参与了LSD1介导的凋亡过程。
Lysine-specific demethylase 1(LSD1 also known as BHC110 or AOF2) is the first discovered histone lysine demethylase(110×10~3 Daltons).With the help of its cofactors CoREST,BHC80 and HADC,it specifically demethylates mono-and dimethylated histone H3 lysine 4(H3-K4) or H3-H9,thus exhibiting diverse transcriptional activities by chromatin reconfiguration.Methylation of H3-K4 is predominantly associated with transcriptionally active genes,whereas methylation of H3-K9 marks silent genes or heterochromatin.
A loss-of-function LSD1 in the human colon carcinoma cells causes a phenotype with a reexpression of multiple and aberrantly silenced genes which are important in the development of colon cancer.Using standard gene targeting technology in mouse embryonic stem cells,lsd1 knockout mice die in prenatal-perinatal.Despite of the sudden cardiac death phenotype,lsd1 knockout strategy resulted in big impact to development of pituitary and neural system at very early stage.More detailed phenotypic analysis of animals with lsd1 mutations will be required to uncover its biological function.
The zebrafish,Danio rerio,offers several distinct advantages as a genetic and embryological model system,including the external fertilization,rapid development and optical clarity of its embryos.Being a vertebrate,the zebrafish has a notochord, blood,heart and vasculature,kidney and optical systems that share many features with corresponding human systems.The zebrafish system bridges the gap between fruit fly/worm and mouse/human genetics(genomic sequences similar identity＞75%), making it feasible to address issues of early development,organ formation,integrative physiology,pharmacology and complex disease.Even in the total absence of blood circulation,they receive part of oxygen by passive diffusion to survive and continue to develop in a relatively normal fashion for several days,thereby allowing a detailed analysis of animals with severe cardiovascular defects.So far,we used zebrafish as a modle to study the functions of LSD1 and related mechanisms.
Section 1 Evolutionarily Conserved Structure and Spatiotemporal Expression of lsd1 in Zebrafish
The complete open reading frame of the LSD1 cDNA encodes a 689 amino acid protein with a calculated molecular weight of 110 kDa.The zebrafish LSD1 protein sequence shares high similar identity with other species'sequences.Further analysis of the zebrafish LSD1 sequence predicts the presence of several motifs(SWIRM and FAD domain) important to function of histone demethylation,lsd1 is expressed throughout the developing stages from one cell embryo.As embryonic development progresses,the expression pattern becomes restricted to the anterior of the embryo and in particular of the neural structures.
Section 2 Loss-of-function LSD1 Zebrafish Can Be Obtained by LSD1 MO and PCPA Treatment
To study the effects of LSD1 down regulation on the development of the embryonic zebrafish,two types of well designed morpholino oligonucleotide antisenses were injected into zebrafish embryos which can splice the exon11 and exon17 of lsd1 at one or two cells stage.Exon11 and exon17 play a crucial role in function of histone demethylation.After injection,the validity of morpholinos were tested by RT-PCR and sequencing.Furthermore,LSD1 histone demethylase is be inhibited when embryos were exposure to Trans-2-phenylcyclopropylamine(referred to as PCPA hereafter;also known as tranylcypromine and Parnate,＞20μM).Western blot showed that the H3K4 methylation level of PCPA treatment group was upregulted compared to the control.
Section 3 Requirements of LSD1 in Zebrafish Hematopoietic System
Development
In recent years,zebrafish has emerged as an exciting animal model system for studying vertebrate organ development,in particular,the development of hematopoietic system.In vitro studies suggested that lsd1 expression was of particular importance during establishment or regeneration of the mammalian definitive hematopoiesis.But little is known about its in vivo functions during primitive hematopoiesis because of embryonic lethality of mammalian knockout models.In the present study,we turn to the zebrafish embryos to pursue the role of LSD1 during hematopoiesis.
In the present study,we noticed for the first time that antidepressant PCPA treatment induces short time anemia in zebrafish.The phynotype was caused by inhibition of pirimitive hematopoiesis in zebrafish embryos.We predict that it is an epigenetic events associated with LSD1.Furthermore,we also found that lsd1 knockdown by morpholino-modified antisense oligonucleotides resulted in similar phenotype(anemia).It is suggested that LSD1 H3-K4 histone demethylase is required for primitive erythropoiesis in zebrafish.Whole-mount in situ hybridization with scl, lmo2,gata2,gata1,globin,pu.1,mpx,L-plastin and flk1 RNA probes showed that the number primitive erythropoiesis cell was decrease,but it did not nearly affect vascular development.Based on these findings we put forward an assumption that down regulation of lsd1 expression leads to inhibition of primitive erythropoiesis but not myelopoiesis.Besides,we found that gatal+of blood cells flow slowly in LSD1 MO embryos which drops a hint that LSD1 are involved in appropriate circulation of blood cells.
Section 4 LSD1 Is Essential for Zebrafish Neural System Development
We previously showed that lsd1 is highly expressed in zebrafish CNS during zebrafish embryogenesis.PCPA is used clinically as an antidepressant.The study of its adverse reaction has shown its side effect to patients.However,little is known about the molecule mechanism of the adverse reaction.Recent study showed that PCPA is an irreversible inhibitor of LSD1 which regulates neuronal specific genes by covalently modifying the FAD cofactor.We provide the first evidence that zebrafish embryos showed sluggish action at PCPA treatment(75μM) compared to the controls. Down-regulation of some neuron marker genes expression(soxla and huc) is evaluated by whole mount in situ hybridization,which indicates the decrease in the number of nerve cells.Then,nerve cells apoptosis is determined by TUNEL assay in PCPA-treated embryos as well as LSD1 MO embryos.We demonstrate that the PCPA induces apoptosis mediated by LSD1 demethylase activity,and our data also suggest that p53-depended signaling pathway may be required for the maintenance nerve cell apoptosis in LSD1-deficient zebrafish embryo.
引文
[1] Martin C, Zhang Y. The diverse functions of histone lysine methylation. Nat Rev Mol Cell Biol, 2005, 6(11): 838-849
[2] Marmorstein R. Structure of SET domain proteins - a new twist on histone methylation.Trends Biochem Sci, 2003, 28(2): 59-62
[3] Lee DY C. Teyssier, B. D. Strahl, and M. R. Stallcup. Role of protein methylation in regulation of transcription. Endocr Rev, 2005, 26(2): 147-170
[4] Shi Y J, Sawada J I, Sui G, et al. Coordinated histone modifications mediated by a CtBP co-repressor complex. Nature, 2003,422: 735-738
[5] Lee M J, Wynder C, Cooch N, et al. An essential role for CoREST in nucleosomal histone 3 lysine 4 demethylation. Nature, 2005,437: 432-435
[6] Metzger E, Wissmann M, Yin N, Muller JM, Schneider R, Peters AH, Gunther T, Buettner R, Schule R. LSD1 demethylates repressive histone marks to promote androgen-receptor-dependent transcription. Nature, 2005,437(7057): 436-439
[7] Tsukada Y I, Fang J, Erdjument-Bromage H, et al. Histone demethylation by a family of JmjC domain-containing proteins. Nature,2006,439: 811-816.
[8] Takeuchi T, Watanabe Y, Takano-Shimizu T, Roles of jumonji and jumonji family genes in chromatin regulation and development,Dev Dyn,2006,235(9):2449-59
[9] Paik W K, Kim S. Enzymatic demethylation of calf thymus histones. Biochem. Biophys. Res. Commun, 1973,51: 781-788.
[10] Shi Y, Lan F, Matson C, et al. Histone demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell, 2004,119: 941-953
[11] Hakimi M, Bochar D A, Chenoweth J, et al. A core-BRAF35 complex containing histone deacetylase mediates repression of neuronal-specific genes. Proc. Natl Acad. Sci, 2002, 99: 7420-7425.
[12] Hakimi M, Dong Y, Lane W S, et al. A candidate X-linked mental retardation gene is a component of a new family of histone deacetylase-containing complexes. J. Biol. Chem, 2003, 278: 7234-7239.
[13] Beumer K, Bhattacharyya G., Bibikova M., Trautman, J.K., Carroll D., Efficient gene targeting in Drosophila with zinc-finger nucleases. Genetics, 2006 172, 2391-2403
[14] Bibikova, M, Beumer, K., Trautman, J.K. & Carroll, D. enhancing gene targeting with designed zinc finger nucleases. Science, 2003 300, 764-779.
[15] Bibikova, M, Golic, M., Golic, K.G., Carroll, D. Targeted chromosomal cleavage and mutagenesis in Drosophila using zinc-finger nucleases. Genetics, 2002 161,1169-1175
[16]Mani, M., Smith, J., Kandavelou, K., Berg, J.M. & Chandrasegaran, S. Binding of two zinc finger nuclease monomers to two specific sites is required for effective double-strand DNA cleavage. Biochem. Biophys. Res. Commun, 2005 334, 1191-1197
[17]David Awright,Standardized reagents and protocols for engineering zinc finger nucleases by modular assembly, 2006 Nature Protoclos, vol.1 no.3
[18]Nasevicius A, Ekker S C. Effective targeted gene 'knockdown' in zebrafish. Nat Genet, 2000,26(2): 216-220
[18]Ando H, Furuta T, Tsien R Y, et al. Photo-mediated gene activation using caged RNA/DNA in zebrafish embryos. Nat Genet, 2001,28 (4): 317-325
[19]Halloran M C, Sato-Maeda M, Warren J T, et al. Laser-induced gene expression inspecific cells of transgenic zebrafish. Development, 2000,127 (9):1953-1960
[20]M. G. Lee, C. Wynder,, D. M.Schmidt, D. G. McCafferty, R. Shiekhattar, Histone H3 lysine 4 demethylation is a target of nonselective antidepressive medications, Chem. Biol. 2006 13, 563-567.
[21]D.M. Schmidt, D.G. McCafferty, trans-2-Phenylcyclopropylamine is a mechanism-based inactivator of the histone demethylase LSD1, Biochemistry 2007, 46 4408-4416.
[22]Huber, T.L.,and Zon,L.I. Transcriptional regulation of blood formation during Xenopus development. Semin Immunol. 1998,10, 103-109.
[23]Hsu K, Kanki JP, Look AT. Zebrafish myelopoiesis and blood cell development. Curr Opin Hematol. 2001 8(4):245-51.
[24]Paw BH, Zon LI. Zebrafish: a genetic approach in studying hematopoiesis. Curr Opin Hematol. 2000 7(2):79-84.
[25]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, 2007,19;446(7138):882-7.
[26]Thompson, M. A., Ransom, D. G., Pratt, et al. The cloche and spadetail genes differentially affect hematopoiesis and vasculogenesis. Dev. Biol. 1998, 197, 248-269.
[27]Nelson Hsia and Leonard I. ZonTranscriptional regulation of hematopoietic stem celldevelopment in zebrafish Experimental Hematology 33 (2005) 1007-1014
[28] Lee MG, Wynder C, Schmidt DM, McCafferty DG, Shiekhattar R. Histone H3 lysine 4 demethylation is a target of nonselective antidepressive medications.Chem Biol. 2006 13(6):563-7.
[29] Metzger E, Wissmann M, Yin N, Mttller JM, Schneider R, Peters AH, Gunther T, Buettner R, Sch(?)le R.LSD1 demethylates repressive histone marks to promote androgen-receptor-dependent transcription. Nature. 2005 15;437(7057):436-9
[30] Nasevicius, A., Ekker, S.C., 2000. Effective targeted gene knockdown in zebrafish. Nat. Genet. 26,216-220.
[31]Crowhurst MO, Layton JE, Lieschke GJ. Developmental biology of zebrafish myeloid cells. Int J Dev Biol. 2002;46(4):483-92
[32]Kalev-Zylinska ML, Horsfield JA, Flores MV, et al. Runxl is requiredfor zebrafish blood and vessel development and expression of a humanRUNXl-CBF2Tl transgene advances a model for studies of leukemogenesis. Development. 2002;129:2015-2030.
[33]Vandenbunder B, Pardanaud L, Jaffredo T, Mirabel MA, Stehelin D. Complementary patterns of expression of c-ets 1, c-myb and c-myc in the blood-forming system of the chick embryo. Development. 1989; 107: 265-274.
[34] Mukouyama Y, Chiba N, Mucenski ML, et al. Hematopoietic cells in cultures of the murine embryonic aorta-gonad-mesonephros region are induced by c-Myb. Curr Biol. 1999;9:833-836.
[35] Mukouyama Y, Chiba N, Hara T, et al. The AML1 transcription factor functions to develop and maintain hematogenic precursor cells in the embryonic aorta-gonad-mesonephros region. Dev Biol. 2000;220: 27-36.
[36]Ward AC.lieschke GJ.The zebrafish as a model system for human disease.Front Biosci,2002, 7: d 827-d833
[37]Thisse C,Zon I.Organogenesis-heart and blood formation from the zebrafish point of view. Science. 2002,295(5554):457-462
[38]Ackermann GE,Paw BH. Zebrafish:a genetic model for vertebrate organogenesis and human disorders.Front Biosci,2003.8:d1227-d1253
[39] Shireen Saleque,l,5 Jonghwan Kim,1,2,5 Heather M. Rooke,1,2,6 and Stuart H. Orkin Epigenetic Regulation of Hematopoietic Differentiation by Gfi-1 and Gfi-1b Is Mediated by the Cofactors CoREST and LSD1, Molecular Cell, 2007, 27, 562-572.
[40]Detrich WH, Kieran MW, Chan FY et al. Intraembryonic hematopoietic cell migration during vertebrate development. Proc Natl Acad Sci USA 1995 92:10713-10717.
[41]Amatruda JF, Zon LI. Dissecting hematopoiesis and disease using the zebrafish. DevBiol,1999,216(1):1-15.
[42]Whatley SD, Ducamp S, Gouya L, Grandchamp B, Beaumont C, Badminton MN, Elder GH, Holme SA, Anstey AV, Parker M, Corrigall AV, Meissner PN, Hift RJ, Marsden JT, Ma Y, Mieli-Vergani G, Deybach JC, Puy H.C-terminal deletions in the ALAS2 gene lead to gain of function and cause X-linked dominant protoporphyria without anemia or iron overload.Am J Hum Genet. 2008 ;83(3):408-14
[43]Camaschella C, Campanella A, De Falco L, Boschetto L, Merlini R, Silvestri L, Levi S, Iolascon A.The human counterpart of zebrafish shiraz shows sideroblastic-like microcytic anemia and iron overload.Blood. 2007 Aug 15;110(4):1353-8
[44]Lee PL, Barton JC, Rao SV, Acton RT, Adler BK, Beutler E. Three kinships with ALAS2 P520L (c. 1559 C→ T) mutation, two in association with severe iron overload, and one with sideroblastic anemia and severe iron overload.Blood Cells Mol Dis. 2006; 36(2):292-7
[45]LK Cole, LS Ross. Apoptosis in the developing zebrafish embryo. Developmental Biology, 2001 ,240 (1) :123-142
[46]Sanders E J, Wride M A. Programmed cell death in development. Int Rev Cytol, 1995,163 :105-173
[47]Jacobson MD, Weil M, Raff M C. Programmed cell death in animal development. Cell, 1997 , 88 (3) :347-354
[48]Vaux D L, Korsmeyer S J. Cell death in development. Cell, 1999, 96 (2) :245-254
[49]Wood H., Episkopou V. Comparative Expression of the Mouse SOX1 ,SOX2 and SOX3 Genes from Pregast rulation to Early Somite Stages. Mechanisms of Development , 1999 , 86(1-2): 197-201
[50]Kan L., Israsen N., Zhan G Z ,et al. SOX1 Acts through Multiple Independent Pathways to Promote Neurogenesis. Developmental Biology, 2004 ,269 (23):580 -594
[51]Kullmann M, Gopfert U, Siewe B, et al. ELAV /Hu proteins inhibit p27 translation via an IRES element in the p27 5'UTR. Genes Dev. 2002, 16(23): 3087-3099
[52]Sun Y, Nadal,Vicens M, Misono S , et al. Neurogenin promotes neurogenesis and inhibits glial differentiation by independent mechanisms. Cell, 2001, 104(3): 365-376
[53]Romero Alema'n M M,Monzo'n Mayor M, Yanes C , et al .Radial glial cells, proliferating periventricular cells , and microglia might contribute to successful structural repair in the cerebral cortex of the lizard Gallotia galloti. Experimental Neurology ,2004 ,188(l):74-85
[54]Bizon J.,Lee H.,Gallagher M. Neurogenesis in a rat model of age related cognitive decline. Aging Cell, 2004 ,3(4):227-2341
[55]Maojun Yang, Jeffrey C. Culhane, Lawrence M. et al.Structural Basis for the Inhibition of the LSD1 Histone Demethylase by the Antidepressant trans-2-Phenylcyclopropylamine. Biochemistry 2007,46(27) :8058-8065
[56]Cross L, Cookma, Lin S, et al. Rapid Analysis of Angiogenesis Drugs in a Live Fluorescent Zebrafish Assay. Arterioscler Thromb Vasc Biol , 2003 , 23(5): 911-912
[57]Brady H. , Gil-Gomez G. The pro-apoptotic Bcl-2 family member, Bax. Int J Biochem Cell Biol ,1998, 30(6):647-650
[58]Langheinrich U , Hennen E , Stott G, Vacun G. Zebrafish as a model organism for the identification and characterization of drugs and genes affecting p53 signaling. Curr Biol, 2002 , 12(23) :2023-2028
[59]Cheng R , Ford B L , O'Neal P E , Mathews C Z , Bradford C S ,Thongtan T , Barnes D W, Hendricks J D , Bailey G S. Zebrafish (Danio rerio) p53 tumor suppressor gene: cDNA sequence and expression during embryogenesis. Mol Mar Bio Biotechnol ,1997 , 6 (2):88-97
[60]Thisse C , Neel H, Thisse B , Daujat S , Piette J . The Mdm2 gene of zebrafish (Danio rerio): preferential expression during development of neural and muscular tissues , and absence of tumor formation after overexpression of its cDNA during early embryogenesis. Differentiation , 2000 , 66 (223) :61-70
[61]Chen M C , Gong H Y, Cheng C Y, Wang J P , Hong J R , Wu J L. Cloning and characterization of zfBLP1 , a Bcl2XL homologue from the zebrafish , Danio rerio . Biochim Biophys Acta , 2001 ,1519 (122) :127-133
[62] Chen M C , Gong H Y, Cheng C Y, Wang J P , Hong J R , Wu J L. Cloning and characterization of a novel nuclear Bcl22 family protein , zfMcl21a, in zebrafish embryo. Biochem Biophys Res Commun , 2000 , 279 (2): 725-731
[63] Hong J R , Hsu YL , Wu J L. Infectious pancreatic necrosis virus induces apoptosis due to down2regulation of survival factor MCL21 protein expression in a fish cell line . Virus Res, 1999 , 63 (122) :75-83
[64] Jing Huang, Roopsha Sengupta, Alexsandra B. et al. p53 is regulated by the lysine demethylase LSD1. nature, 2007, 449(6): 105-109
[65] Gartel A. L., Tyner A. L. The role of the cyclin-dependent kinase inhibitor p21 in apoptosisl.Mol Cancer Ther, 2002 ,1(8):639-647
[66] Huang J, Sengupta R, Alexsandra B. p53 is regulated by the lysine demethylase LSD1, Nature 2007; 449: 105-09.
[1]Strahl BD,Allis CD.The language of covalent histone modifications,Nature,2000,403:41-45
[2]Martin C,Y Zhang et al.The diverse functions of histone lysine methylation Nat Rev Mol Cell Biol,2005,6(11):838-849
[3]Rea S,F Eisenhaber,DO'Carroll,et al.Regulation of chromatin structure by site-specific histone H3 methyltransferases,Nature,2000,406(6796):593-599
[4]Marmorstein R.Structure of SET domain proteins:a new twist on histone methylation,Trends Biochem Sci,2003,28(2):59-62
[5]Mulligan,JR Whetstine,Shi Y et al.Historic Demethylation Mediated by the Nuclear Amine Oxidase Homolog LSD1,Cell,2004,119(7):941-953
[6]CUTHBERT G L,DAUJAT S,SNOWDEN A W,et all Histone deimination antagonizes arginine methylation[J]Cell,2004,118(5):545-553
[7]TSUKADA Y,FANG J,ERDJUMENT2BROMAGE H,et al.Histone demethylation by a family of JmjC domain containing proteins[J]Nature,2006,439(7078):811-816
[8]WHETSTINE J R,NOTTKE A,LAN F,et all Reversal of histone lysine trimethylation by the JMJD-family of histone demethylases[J]Cell,2006,125(3):467-481
[9]HUANG Y,FANG J,BEDFORD M T,et all Recognition of histone H3 lysine-4methylation by the double tudor domain of JMJD2A[J]Science,2006,312 (5774): 748-751
[10] Briggs S D, Xiao T, Sun Z W, et al. Gene silencing: trans-histone regulatory pathway in chromatin. Nature, 2002,418 (6897): 498
[11] Henry K W, Wyce A, Lo W S, et al. Transcriptional activation via sequential histone H2B ubiquitylation and deubiquitylation, mediated by SAGA-associated Ubp8. Genes Dev, 2003,17 (21): 2648-2663
[12] Lachner M, O!Carroll D, Rea S, et al. Methylation of histone H3 lysine 9 creates a binding site for HP1 proteins. Nature, 2001,410(6824): 116-120
[13] Czermin B, Schotta G, H(?)lsmann B B, et al. Physical and functional association of SU (VAR)3-9 and HDAC1 in Drosophila. EMBO Reports, 2001, 2 (10): 915- 919
[14] Jones D O, Cowell I G, Singh P B. Mammalian chromodomain proteins: their role in genome organisation and expression. Bioessays, 2000,22 (2): 124-137
[15] enuwein T, Allis C D. Translating the histone code. Science, 2001, 293 (5532): 1074-1080
[16] Ryan R F, Schultz D C, Ayyanathan K, et al. KAP-1 corepressor protein interacts and co-localises with heterochromatic and eurochromatic HP1 proteins: a potential role for Kr u ppel-associated box-zinc finger proteins in heterochromatin-mediated genesilencing. Mol Cell Biol, 1999,19(6): 4366-4378
[17] Brown K E, Guest S S, Smale S T, et al. Association of transcriptionally silent genes with Ikaros complexes at centromeric heterochromatin. Cell, 1997, 91 (6): 845-854
[18] C. Cristofre Martin,Lynda Laforest, Marie-Andre'e Akimenko,and Marc Ekker, A Role for DNA Methylation in Gastrulationand Somite Patterning, Developmental Biology 1999, 206,189-205
[19] Benjamine, J. Cooper, Brian Key, Suppression and Overexpression of Adenosylhomocysteine Hydrolase-like Protein 1 (AHCYL1) Influences ZebrafishEmbryo Development , THE JOURNAL OF BIOLOGICAL CHEMISTRY, 2006, 281 (32) 22471-22484
[20] Cirillo,L,Zaret K. A linker histone restricts muscle development Science , 2004, 304,1607-1609.
[21] Xungang Tan, Josep Rotllant, Huiqing Li,et al SmyD1, a histone methyltransferase, is required for myofibril organization and muscle contractionin zebrafish embryos Proc.Natl.Acad.Sci.2006, 103 (8 ) 2713-2718
[22]Suzanne R. L. Young, Christen Mumaw,et al.Antisense Targeting of CXXC Finger Protein 1 InhibitsGenomic Cytosine Methylation and Primitive Hematopoiesis in ZebrafishTHE,JOURNAL OF BIOLOGICAL CHEMISTRY, 2006,281,37034-37044,
[23]Rai K, Nadauld LD, Chidester S et al,Zebra fish Dnmtl and Suv39hl regulate organ-specific terminal differentiation during development Mol Cell Biol.2006 Oct;26(19):7077-85
[24]Yamaguchi M, Tonou-Fujimori N, Komori A,et al. Histone deacetylase 1 regulates retinal neurogenesis in zebrafish by suppressing Wnt and Notch signaling pathways. Development.2005 132(13):3027-43
[25]Cunliffe VT, Casaccia-Bonnefil P. Histone deacetylase 1 is essential for oligodendrocyte specification in the zebrafish CNS , Development.2006, 123(1):24-30
[26]Takeuchi T, Watanabe Y, Takano-Shimizu T, Roles of jumonji and jumonji family genes in chromatin regulation and development,Dev Dyn,2006,235(9):2449-59
[27]Barbara Illi, Alessandro Scopece, Simona Nanni,Epigenetic Histone Modification and Cardiovascular Lineage Programming in Mouse Embryonic Stem Cells Exposed to Laminar Shear Stress, Circ. Res. 2005, 96, 501-508
[2] Marmorstein R. Structure of SET domain proteins - a new twist on histone methylation.Trends Biochem Sci, 2003, 28(2): 59-62
[3] Lee DY C. Teyssier, B. D. Strahl, and M. R. Stallcup. Role of protein methylation in regulation of transcription. Endocr Rev, 2005, 26(2): 147-170
[4] Shi Y J, Sawada J I, Sui G, et al. Coordinated histone modifications mediated by a CtBP co-repressor complex. Nature, 2003,422: 735-738
[5] Lee M J, Wynder C, Cooch N, et al. An essential role for CoREST in nucleosomal histone 3 lysine 4 demethylation. Nature, 2005,437: 432-435
[6] Metzger E, Wissmann M, Yin N, Muller JM, Schneider R, Peters AH, Gunther T, Buettner R, Schule R. LSD1 demethylates repressive histone marks to promote androgen-receptor-dependent transcription. Nature, 2005,437(7057): 436-439
[7] Tsukada Y I, Fang J, Erdjument-Bromage H, et al. Histone demethylation by a family of JmjC domain-containing proteins. Nature,2006,439: 811-816.
[8] Takeuchi T, Watanabe Y, Takano-Shimizu T, Roles of jumonji and jumonji family genes in chromatin regulation and development,Dev Dyn,2006,235(9):2449-59
[9] Paik W K, Kim S. Enzymatic demethylation of calf thymus histones. Biochem. Biophys. Res. Commun, 1973,51: 781-788.
[10] Shi Y, Lan F, Matson C, et al. Histone demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell, 2004,119: 941-953
[11] Hakimi M, Bochar D A, Chenoweth J, et al. A core-BRAF35 complex containing histone deacetylase mediates repression of neuronal-specific genes. Proc. Natl Acad. Sci, 2002, 99: 7420-7425.
[12] Hakimi M, Dong Y, Lane W S, et al. A candidate X-linked mental retardation gene is a component of a new family of histone deacetylase-containing complexes. J. Biol. Chem, 2003, 278: 7234-7239.
[13] Beumer K, Bhattacharyya G., Bibikova M., Trautman, J.K., Carroll D., Efficient gene targeting in Drosophila with zinc-finger nucleases. Genetics, 2006 172, 2391-2403
[14] Bibikova, M, Beumer, K., Trautman, J.K. & Carroll, D. enhancing gene targeting with designed zinc finger nucleases. Science, 2003 300, 764-779.
[15] Bibikova, M, Golic, M., Golic, K.G., Carroll, D. Targeted chromosomal cleavage and mutagenesis in Drosophila using zinc-finger nucleases. Genetics, 2002 161,1169-1175
[16]Mani, M., Smith, J., Kandavelou, K., Berg, J.M. & Chandrasegaran, S. Binding of two zinc finger nuclease monomers to two specific sites is required for effective double-strand DNA cleavage. Biochem. Biophys. Res. Commun, 2005 334, 1191-1197
[17]David Awright,Standardized reagents and protocols for engineering zinc finger nucleases by modular assembly, 2006 Nature Protoclos, vol.1 no.3
[18]Nasevicius A, Ekker S C. Effective targeted gene 'knockdown' in zebrafish. Nat Genet, 2000,26(2): 216-220
[18]Ando H, Furuta T, Tsien R Y, et al. Photo-mediated gene activation using caged RNA/DNA in zebrafish embryos. Nat Genet, 2001,28 (4): 317-325
[19]Halloran M C, Sato-Maeda M, Warren J T, et al. Laser-induced gene expression inspecific cells of transgenic zebrafish. Development, 2000,127 (9):1953-1960
[20]M. G. Lee, C. Wynder,, D. M.Schmidt, D. G. McCafferty, R. Shiekhattar, Histone H3 lysine 4 demethylation is a target of nonselective antidepressive medications, Chem. Biol. 2006 13, 563-567.
[21]D.M. Schmidt, D.G. McCafferty, trans-2-Phenylcyclopropylamine is a mechanism-based inactivator of the histone demethylase LSD1, Biochemistry 2007, 46 4408-4416.
[22]Huber, T.L.,and Zon,L.I. Transcriptional regulation of blood formation during Xenopus development. Semin Immunol. 1998,10, 103-109.
[23]Hsu K, Kanki JP, Look AT. Zebrafish myelopoiesis and blood cell development. Curr Opin Hematol. 2001 8(4):245-51.
[24]Paw BH, Zon LI. Zebrafish: a genetic approach in studying hematopoiesis. Curr Opin Hematol. 2000 7(2):79-84.
[25]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, 2007,19;446(7138):882-7.
[26]Thompson, M. A., Ransom, D. G., Pratt, et al. The cloche and spadetail genes differentially affect hematopoiesis and vasculogenesis. Dev. Biol. 1998, 197, 248-269.
[27]Nelson Hsia and Leonard I. ZonTranscriptional regulation of hematopoietic stem celldevelopment in zebrafish Experimental Hematology 33 (2005) 1007-1014
[28] Lee MG, Wynder C, Schmidt DM, McCafferty DG, Shiekhattar R. Histone H3 lysine 4 demethylation is a target of nonselective antidepressive medications.Chem Biol. 2006 13(6):563-7.
[29] Metzger E, Wissmann M, Yin N, Mttller JM, Schneider R, Peters AH, Gunther T, Buettner R, Sch(?)le R.LSD1 demethylates repressive histone marks to promote androgen-receptor-dependent transcription. Nature. 2005 15;437(7057):436-9
[30] Nasevicius, A., Ekker, S.C., 2000. Effective targeted gene knockdown in zebrafish. Nat. Genet. 26,216-220.
[31]Crowhurst MO, Layton JE, Lieschke GJ. Developmental biology of zebrafish myeloid cells. Int J Dev Biol. 2002;46(4):483-92
[32]Kalev-Zylinska ML, Horsfield JA, Flores MV, et al. Runxl is requiredfor zebrafish blood and vessel development and expression of a humanRUNXl-CBF2Tl transgene advances a model for studies of leukemogenesis. Development. 2002;129:2015-2030.
[33]Vandenbunder B, Pardanaud L, Jaffredo T, Mirabel MA, Stehelin D. Complementary patterns of expression of c-ets 1, c-myb and c-myc in the blood-forming system of the chick embryo. Development. 1989; 107: 265-274.
[34] Mukouyama Y, Chiba N, Mucenski ML, et al. Hematopoietic cells in cultures of the murine embryonic aorta-gonad-mesonephros region are induced by c-Myb. Curr Biol. 1999;9:833-836.
[35] Mukouyama Y, Chiba N, Hara T, et al. The AML1 transcription factor functions to develop and maintain hematogenic precursor cells in the embryonic aorta-gonad-mesonephros region. Dev Biol. 2000;220: 27-36.
[36]Ward AC.lieschke GJ.The zebrafish as a model system for human disease.Front Biosci,2002, 7: d 827-d833
[37]Thisse C,Zon I.Organogenesis-heart and blood formation from the zebrafish point of view. Science. 2002,295(5554):457-462
[38]Ackermann GE,Paw BH. Zebrafish:a genetic model for vertebrate organogenesis and human disorders.Front Biosci,2003.8:d1227-d1253
[39] Shireen Saleque,l,5 Jonghwan Kim,1,2,5 Heather M. Rooke,1,2,6 and Stuart H. Orkin Epigenetic Regulation of Hematopoietic Differentiation by Gfi-1 and Gfi-1b Is Mediated by the Cofactors CoREST and LSD1, Molecular Cell, 2007, 27, 562-572.
[40]Detrich WH, Kieran MW, Chan FY et al. Intraembryonic hematopoietic cell migration during vertebrate development. Proc Natl Acad Sci USA 1995 92:10713-10717.
[41]Amatruda JF, Zon LI. Dissecting hematopoiesis and disease using the zebrafish. DevBiol,1999,216(1):1-15.
[42]Whatley SD, Ducamp S, Gouya L, Grandchamp B, Beaumont C, Badminton MN, Elder GH, Holme SA, Anstey AV, Parker M, Corrigall AV, Meissner PN, Hift RJ, Marsden JT, Ma Y, Mieli-Vergani G, Deybach JC, Puy H.C-terminal deletions in the ALAS2 gene lead to gain of function and cause X-linked dominant protoporphyria without anemia or iron overload.Am J Hum Genet. 2008 ;83(3):408-14
[43]Camaschella C, Campanella A, De Falco L, Boschetto L, Merlini R, Silvestri L, Levi S, Iolascon A.The human counterpart of zebrafish shiraz shows sideroblastic-like microcytic anemia and iron overload.Blood. 2007 Aug 15;110(4):1353-8
[44]Lee PL, Barton JC, Rao SV, Acton RT, Adler BK, Beutler E. Three kinships with ALAS2 P520L (c. 1559 C→ T) mutation, two in association with severe iron overload, and one with sideroblastic anemia and severe iron overload.Blood Cells Mol Dis. 2006; 36(2):292-7
[45]LK Cole, LS Ross. Apoptosis in the developing zebrafish embryo. Developmental Biology, 2001 ,240 (1) :123-142
[46]Sanders E J, Wride M A. Programmed cell death in development. Int Rev Cytol, 1995,163 :105-173
[47]Jacobson MD, Weil M, Raff M C. Programmed cell death in animal development. Cell, 1997 , 88 (3) :347-354
[48]Vaux D L, Korsmeyer S J. Cell death in development. Cell, 1999, 96 (2) :245-254
[49]Wood H., Episkopou V. Comparative Expression of the Mouse SOX1 ,SOX2 and SOX3 Genes from Pregast rulation to Early Somite Stages. Mechanisms of Development , 1999 , 86(1-2): 197-201
[50]Kan L., Israsen N., Zhan G Z ,et al. SOX1 Acts through Multiple Independent Pathways to Promote Neurogenesis. Developmental Biology, 2004 ,269 (23):580 -594
[51]Kullmann M, Gopfert U, Siewe B, et al. ELAV /Hu proteins inhibit p27 translation via an IRES element in the p27 5'UTR. Genes Dev. 2002, 16(23): 3087-3099
[52]Sun Y, Nadal,Vicens M, Misono S , et al. Neurogenin promotes neurogenesis and inhibits glial differentiation by independent mechanisms. Cell, 2001, 104(3): 365-376
[53]Romero Alema'n M M,Monzo'n Mayor M, Yanes C , et al .Radial glial cells, proliferating periventricular cells , and microglia might contribute to successful structural repair in the cerebral cortex of the lizard Gallotia galloti. Experimental Neurology ,2004 ,188(l):74-85
[54]Bizon J.,Lee H.,Gallagher M. Neurogenesis in a rat model of age related cognitive decline. Aging Cell, 2004 ,3(4):227-2341
[55]Maojun Yang, Jeffrey C. Culhane, Lawrence M. et al.Structural Basis for the Inhibition of the LSD1 Histone Demethylase by the Antidepressant trans-2-Phenylcyclopropylamine. Biochemistry 2007,46(27) :8058-8065
[56]Cross L, Cookma, Lin S, et al. Rapid Analysis of Angiogenesis Drugs in a Live Fluorescent Zebrafish Assay. Arterioscler Thromb Vasc Biol , 2003 , 23(5): 911-912
[57]Brady H. , Gil-Gomez G. The pro-apoptotic Bcl-2 family member, Bax. Int J Biochem Cell Biol ,1998, 30(6):647-650
[58]Langheinrich U , Hennen E , Stott G, Vacun G. Zebrafish as a model organism for the identification and characterization of drugs and genes affecting p53 signaling. Curr Biol, 2002 , 12(23) :2023-2028
[59]Cheng R , Ford B L , O'Neal P E , Mathews C Z , Bradford C S ,Thongtan T , Barnes D W, Hendricks J D , Bailey G S. Zebrafish (Danio rerio) p53 tumor suppressor gene: cDNA sequence and expression during embryogenesis. Mol Mar Bio Biotechnol ,1997 , 6 (2):88-97
[60]Thisse C , Neel H, Thisse B , Daujat S , Piette J . The Mdm2 gene of zebrafish (Danio rerio): preferential expression during development of neural and muscular tissues , and absence of tumor formation after overexpression of its cDNA during early embryogenesis. Differentiation , 2000 , 66 (223) :61-70
[61]Chen M C , Gong H Y, Cheng C Y, Wang J P , Hong J R , Wu J L. Cloning and characterization of zfBLP1 , a Bcl2XL homologue from the zebrafish , Danio rerio . Biochim Biophys Acta , 2001 ,1519 (122) :127-133
[62] Chen M C , Gong H Y, Cheng C Y, Wang J P , Hong J R , Wu J L. Cloning and characterization of a novel nuclear Bcl22 family protein , zfMcl21a, in zebrafish embryo. Biochem Biophys Res Commun , 2000 , 279 (2): 725-731
[63] Hong J R , Hsu YL , Wu J L. Infectious pancreatic necrosis virus induces apoptosis due to down2regulation of survival factor MCL21 protein expression in a fish cell line . Virus Res, 1999 , 63 (122) :75-83
[64] Jing Huang, Roopsha Sengupta, Alexsandra B. et al. p53 is regulated by the lysine demethylase LSD1. nature, 2007, 449(6): 105-109
[65] Gartel A. L., Tyner A. L. The role of the cyclin-dependent kinase inhibitor p21 in apoptosisl.Mol Cancer Ther, 2002 ,1(8):639-647
[66] Huang J, Sengupta R, Alexsandra B. p53 is regulated by the lysine demethylase LSD1, Nature 2007; 449: 105-09.
[1]Strahl BD,Allis CD.The language of covalent histone modifications,Nature,2000,403:41-45
[2]Martin C,Y Zhang et al.The diverse functions of histone lysine methylation Nat Rev Mol Cell Biol,2005,6(11):838-849
[3]Rea S,F Eisenhaber,DO'Carroll,et al.Regulation of chromatin structure by site-specific histone H3 methyltransferases,Nature,2000,406(6796):593-599
[4]Marmorstein R.Structure of SET domain proteins:a new twist on histone methylation,Trends Biochem Sci,2003,28(2):59-62
[5]Mulligan,JR Whetstine,Shi Y et al.Historic Demethylation Mediated by the Nuclear Amine Oxidase Homolog LSD1,Cell,2004,119(7):941-953
[6]CUTHBERT G L,DAUJAT S,SNOWDEN A W,et all Histone deimination antagonizes arginine methylation[J]Cell,2004,118(5):545-553
[7]TSUKADA Y,FANG J,ERDJUMENT2BROMAGE H,et al.Histone demethylation by a family of JmjC domain containing proteins[J]Nature,2006,439(7078):811-816
[8]WHETSTINE J R,NOTTKE A,LAN F,et all Reversal of histone lysine trimethylation by the JMJD-family of histone demethylases[J]Cell,2006,125(3):467-481
[9]HUANG Y,FANG J,BEDFORD M T,et all Recognition of histone H3 lysine-4methylation by the double tudor domain of JMJD2A[J]Science,2006,312 (5774): 748-751
[10] Briggs S D, Xiao T, Sun Z W, et al. Gene silencing: trans-histone regulatory pathway in chromatin. Nature, 2002,418 (6897): 498
[11] Henry K W, Wyce A, Lo W S, et al. Transcriptional activation via sequential histone H2B ubiquitylation and deubiquitylation, mediated by SAGA-associated Ubp8. Genes Dev, 2003,17 (21): 2648-2663
[12] Lachner M, O!Carroll D, Rea S, et al. Methylation of histone H3 lysine 9 creates a binding site for HP1 proteins. Nature, 2001,410(6824): 116-120
[13] Czermin B, Schotta G, H(?)lsmann B B, et al. Physical and functional association of SU (VAR)3-9 and HDAC1 in Drosophila. EMBO Reports, 2001, 2 (10): 915- 919
[14] Jones D O, Cowell I G, Singh P B. Mammalian chromodomain proteins: their role in genome organisation and expression. Bioessays, 2000,22 (2): 124-137
[15] enuwein T, Allis C D. Translating the histone code. Science, 2001, 293 (5532): 1074-1080
[16] Ryan R F, Schultz D C, Ayyanathan K, et al. KAP-1 corepressor protein interacts and co-localises with heterochromatic and eurochromatic HP1 proteins: a potential role for Kr u ppel-associated box-zinc finger proteins in heterochromatin-mediated genesilencing. Mol Cell Biol, 1999,19(6): 4366-4378
[17] Brown K E, Guest S S, Smale S T, et al. Association of transcriptionally silent genes with Ikaros complexes at centromeric heterochromatin. Cell, 1997, 91 (6): 845-854
[18] C. Cristofre Martin,Lynda Laforest, Marie-Andre'e Akimenko,and Marc Ekker, A Role for DNA Methylation in Gastrulationand Somite Patterning, Developmental Biology 1999, 206,189-205
[19] Benjamine, J. Cooper, Brian Key, Suppression and Overexpression of Adenosylhomocysteine Hydrolase-like Protein 1 (AHCYL1) Influences ZebrafishEmbryo Development , THE JOURNAL OF BIOLOGICAL CHEMISTRY, 2006, 281 (32) 22471-22484
[20] Cirillo,L,Zaret K. A linker histone restricts muscle development Science , 2004, 304,1607-1609.
[21] Xungang Tan, Josep Rotllant, Huiqing Li,et al SmyD1, a histone methyltransferase, is required for myofibril organization and muscle contractionin zebrafish embryos Proc.Natl.Acad.Sci.2006, 103 (8 ) 2713-2718
[22]Suzanne R. L. Young, Christen Mumaw,et al.Antisense Targeting of CXXC Finger Protein 1 InhibitsGenomic Cytosine Methylation and Primitive Hematopoiesis in ZebrafishTHE,JOURNAL OF BIOLOGICAL CHEMISTRY, 2006,281,37034-37044,
[23]Rai K, Nadauld LD, Chidester S et al,Zebra fish Dnmtl and Suv39hl regulate organ-specific terminal differentiation during development Mol Cell Biol.2006 Oct;26(19):7077-85
[24]Yamaguchi M, Tonou-Fujimori N, Komori A,et al. Histone deacetylase 1 regulates retinal neurogenesis in zebrafish by suppressing Wnt and Notch signaling pathways. Development.2005 132(13):3027-43
[25]Cunliffe VT, Casaccia-Bonnefil P. Histone deacetylase 1 is essential for oligodendrocyte specification in the zebrafish CNS , Development.2006, 123(1):24-30
[26]Takeuchi T, Watanabe Y, Takano-Shimizu T, Roles of jumonji and jumonji family genes in chromatin regulation and development,Dev Dyn,2006,235(9):2449-59
[27]Barbara Illi, Alessandro Scopece, Simona Nanni,Epigenetic Histone Modification and Cardiovascular Lineage Programming in Mouse Embryonic Stem Cells Exposed to Laminar Shear Stress, Circ. Res. 2005, 96, 501-508
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