英语文献信度与评价分析

1、文献阅读+信度与权威分析生命学院d201577459林生彦large conserved domains of low dna methylation maintained by dnmt3asummary :gains and losses in dna methylation are prominent features of mammalian cell types. to gain insight into the mechanisms that promote shifts in dna methylation and contribute to changes in cell fa

2、te, including malignant transformation, we performed genome-wide mapping of 5-methylcytosine and 5hydroxymethylcytosine in purified mouse hematopoietic stem cells we discovered extended regions of low methylation (canyons) that span conserved domains frequently containing transcription factors and a

3、re distinct from cpg islands and shores about half of the genes in these methylation canyons are coated with repressive histone marks, whereas the remainder are covered by activating histone marks and are highly expressed in hematopoietic stem cells (hscs). canyon borders are demarked by 5-hydroxyrn

4、ethylcytosine and become eroded in the absence of dna methyltransferase 3a (dnmt3a). genes dysregulated in human leukemias are enriched for canyon-associated genes the new epigenetic landscape we describe may provide a mechanism for the regulation of hematopoiesis and may contribute to leukemia deve

5、lopment.摘要：(屮文)dna甲基化的积累和丢失是哺乳动物细胞中显著存在的特征。为了深刻解析促进dna甲 基化的发生以及导致细胞命运变化的机制(包括恶性转化)，我们在纯净的小鼠造血细胞中 进行了 5甲基胞吨唏以及5疑甲基胞喘噪全基因组比对。我们发现，低甲基化部分的延伸 区跨越了转录因子频率较高的保守结构域，而这个区域与cpg岛是截然不同的。在这个甲 基化延伸区，将近一半的基因表面含有具有抑制作用的组蛋白标记，而剩余部位则被具有活 性的组蛋白标记覆盖，并且在造血细胞(hscs)中高表达。(低甲基化部分)延伸区边缘被 5瓮甲基胞喘噪分隔开，并且在dna甲基转移酶3a (dnmt3a)缺乏的情

6、况下被侵蚀掉。在 人类白血病中，基因的调节异常丰富了(低甲基化部分)延伸区边缘的基因。我们描述的这 个新表观遗传现象也许能为造血作用的调节作用提供一种机制，并可能对白血病的发展有贡 献。the r882h dnmt3a mutation associated with aml dominantly inhibits wild-type dnmt3a by blocking its ability to form active tetramerssummary： somatic mutations in dnmt3a, which encodes a de novo dna methyltran

7、sferase, are found in 30% of normal karyotype acute myeloid leukemia (aml) cases most mutations are heterozygous and alter r882 within the catalytic domain (most commonly r882h), suggesting the possibility of dominant-negative consequences the methyltransferase activity of r882h dnmt3a is reduced by

8、 80% compared with the wt enzyme. in vitro mixing of wt and r882h dnmt3a does not affect the wt activity, but coexpression of the two proteins in cells profoundly inhibits the wt enzyme by disrupting its ability to homotetramerize. aml cells with the r882h mutation have severely reduced de novo meth

9、yltransferase activity and focal hypomethylation at specific cpgs throughout aml cell genomes.摘要：（中文）dnmt3a编码了一个从头合成型dna甲基转移酶，在30%正常核型的急性髓系白血病(aml)中发现含有该突变。大部分的突变是杂合的，并且r882在催化域屮会发生突变(大 多数是r882h),表明了显性负结果的可能性。和野生型酶进行对比，r882h dnmt3a的 甲基化转移酶活性下降了 80%o在体内，野生型和r882h dnmt3a的混合酶并没影响野生 型酶的活性，但在细胞中，两种蛋白的共同表

10、达将通过扰乱野生型酶形成同源四聚体的活性 明显抑制野生型酶的活性。含有r882h突变的aml细胞能显著降低整个aml基因组上从 头合成型甲基化转移酶的活性以及在特定cpg岛病灶区的低甲基化现象。the comparison of creditability and authority between two paperstwo papers are both articles. so why the two worth reading?lett first look atr882h dnmt3a mutation associated with aml dominantly inhibits

11、wild-type dnmt3a by blocking its ability to form active tetramers.there were several research work about r882h dnmt3a mutation. previous studies of r882 mutations in recombinant dnmt3a produced in several systems have demonstrated that r882 mutations reduced de novo methyltransfeiase activity in vit

12、ro. complexes of full-length dnmt3a and dnmt3l copurified from e. coli demonstrated the hypomorphic activity of r882h dnmt3a relative to wt dnmt3a (yan et al., 2011). more detailed analysis of the properties of the catalytic domain of dnmt3a (also purified from e. coli) revealed that the r882h mutat

13、ion disrupted its ability to form tetramers (holz-schietinger et alm 2012). this mutation reduced the processive methylation of consecutive cpg dinucleotides in vitro, but this effect was significantly rescued by the addition of dnmt3l importan什y, the dominant-negative potential of the r882 mutation

14、s was highlighted by a recent study where murine dnmt3a r878h (equivalent to r882h in human dnmt3a) was shown to inhibit de novo dna methylation by wt dnmt3a in murine es cells (kim et al., 2013). in this paper, researchers explored potential mechanisms that could explain how a heterozygous, hypomor

15、phic r882h allele could affect de novo methylation beyond causing simple haploinsufficiency and these genetic and molecular data suggest that there are two distinct classes of dnmt3a mutations that contribute to leukemogenesis in different ways.while in thelarge conserved domains of low dna methylat

16、ion maintained by dnmt3a， this article not exactly told the story about a mutation like r882h which belongs to dnm3a in last paper as referred but the dnm3a. although regions with low levels of cpg methylation are considered generally permissive for gene expression when present in promoter regions,

17、it is still only poorly understood how dna methylation patterns vary among normal cell types, how they are added and erased, and how they influence gene expression. identification of recurrent leukemia-associated mutations in genes encoding regulators of dna methylation such as dnmt3a and tet2 has u

18、nderscored the importance of dna methylation in the maintenance of normal physiology. so, to gain insight into how dna methylation exerts this central role, determining the genome-wide pattern of dna methylation in the normal precursors of leukemia cells, hscs, and to investigate the factors that af

19、fect alterations in dna methylation and gene expression is very important. this paper reported poor correlation between changes in methylation and gene expression in both mouse models28 and human samples3 may reflect complex regulation at these loci, indicating the need to take multiple epigenetic f

20、actors into account as one seeks to understand the pathogenesis of these malignancies.the examination criteria for the papersacademic value are as followed :1 ) authors credential.the author ofr882h dnmt3a mutation associated with aml dominantlyinhibits wild-type dnmt3a by blocking its ability to fo

21、rm active tetramersdavid russler-germain ,who is a md/phd student in washington university school of medicine and has published six papers since 2004. what calls for special attention is that this paper has been cited for 37 times since 2014 and he had also published several papers in the molecular

22、biology field. and the author oflarge conserved domains of low dna methylation maintained by dnmt3ais a very famous instructor of baylor college of medicine and her research work has been cited for 1269 times since 2010.2 ) appropriate focous.r882h dnmt3a mutation associated with aml dominantly inhi

23、bitswild-type dnmt3a by blocking its ability to form active tetramers, researchers explored the consequences of the r882h mutation on dnmt3a function and identified the mechanism of its dominant-negative effect on wtdnmt3a in mammalian cells further, we identified a focal hypomethylation phenotype i

24、n nk-aml cases possessing heterozygous dnmt3a mutations at r882, which demonstrates the profound loss of de novo methyltransferase activity resulting from the domina njnegative con sequences of these heterozygous alterations. and in large conserved domains of low dna methylation maintained by dnmt3a

25、， researchers have demonstrated the existence of very large methylation lacunae associated with highly conserved, developmentally important genes.3 ) sufficient coverage.r882h dnmt3a mutation associated with aml dominantly inhibitswild-type dnmt3a by blocking its ability to form active tetramersmain

26、ly consists of several sections : introduction, results, discussion, experimental procedure, supplemental information, acknowledgement, reference while the structure oflarge conserved domains of low dna methylation maintained bydnmt3aare more simple : results, discussion, methods.4 ) reputable publi

27、sher or journal :r882h dnmt3a mutation associated with amldominantly inhibits wild-type dnmt3a by blocking its ability to form active tetramersandlarge conserved domains of low dna methylation maintained bydnmt3aare extracted from the journals named cancer cell(impact factor :23.523 ) and nature gen

28、etics(impact factor : 29.648 ) respectively.5 ) affiliation and sponsorship : the affiliations ofr882h dnmt3a mutationassociated with aml dominantly inhibits wild-type dnmt3a by blocking its ability to form active tetramersare mainly come from washington university.this work was funded by the national institutes of health (grants t32-hl007088 to d.a.r.-g. and ca162086 and ca101937 to t.j.l.) and the barnes jewish hospital foundation (to t.j.l.). the washington university proteomics core is supported by grants fr