Hepatic epigenetic phenotype predetermines individual susceptibility to hepatic steatosis in mice fed a lipogenic methyl-deficient diet.
Hepatic epigenetic phenotype predetermines individual susceptibility to hepatic steatosis in mice fed a lipogenic methyl-deficient diet.
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DOI：
10.1016/j.jhep.2009.03.021
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发表时间：
2009-07
影响因子：
25.7
通讯作者：
Beland FA
中科院分区：
文献类型：
--
作者：
Pogribny IP;Tryndyak VP;Bagnyukova TV;Melnyk S;Montgomery B;Ross SA;Latendresse JR;Rusyn I;Beland FA
表观遗传学改变在疾病的病因和发病机制中的重要性已日益被认识到。然而，表观遗传改变在肝脏脂肪变性发生中的作用以及个体对这种病理状态的易感性在很大程度上是未知的。给雄性近交系C57BL/6J和DBA/2J小鼠饲喂类似于人类非酒精性脂肪性肝炎(NASH)的致脂甲基缺乏饮食(MDD)6、12或18周，并测定肝脏中胞嘧啶甲基化、组蛋白修饰和负责这些表观遗传修饰的蛋白质的表达状态。近交系C57BL/6J和DBA/2J小鼠肝脏脂肪变性的发生伴随着显著的表观遗传学异常。基因组和重复序列胞嘧啶甲基化的显著丢失，特别是在主要和次要卫星上，伴随着重复相关转录水平的增加，组蛋白的异常修饰，以及维持DNA甲基转移酶1(DNMT1)和从头DNMT3A蛋白在两个品系小鼠肝脏中表达的变化。然而，与C57BL/6J小鼠相比，DBA/2J小鼠的特征是重复元件的甲基化程度较低，正常肝脏中组蛋白H3赖氨酸9(H3K9)和H3赖氨酸27(H3K27)的三甲基化程度较低，出现了更显著的NASH特异性病理形态变化。这些结果从机制上将表观遗传改变与肝脏脂肪变性的发病机制联系起来，并强烈表明细胞表观遗传状态的差异可能是个体对肝脏脂肪变性易感性的一个先决因素。
The importance of epigenetic changes in etiology and pathogenesis of disease has been increasingly recognized. However, the role of epigenetic alterations in the genesis of hepatic steatosis and cause of individual susceptibilities to this pathological state are largely unknown. Male inbred C57BL/6J and DBA/2J mice were fed a lipogenic methyl-deficient diet (MDD) that causes liver injury similar to human nonalcoholic steatohepatitis (NASH) for 6, 12, or 18 weeks, and the status of global and repetitive elements cytosine methylation, histone modifications, and expression of proteins responsible for those epigenetic modifications in livers was determined. The development of hepatic steatosis in inbred C57BL/6J and DBA/2J mice was accompanied by prominent epigenetic abnormalities. This was evidenced by pronounced loss of genomic and repetitive sequences cytosine methylation, especially at major and minor satellites, accompanied by the increased levels of repeat-associated transcripts, aberrant histone modifications, and alterations in expression of the maintenance DNA methyltransferase 1 (DNMT1) and de novo DNMT3A proteins in the livers of both mouse strains. However, the DBA/2J mice, which were characterized by initially lower degree of methylation of repetitive elements and lower extent of histone H3 lysine 9 (H3K9) and H3 lysine 27 (H3K27) trimethylation in the normal livers, as compared to those in the C57BL/6J mice, developed more prominent NASH-specific pathomorphological changes. These results mechanistically link epigenetic alterations to the pathogenesis of hepatic steatosis and strongly suggest that differences in the cellular epigenetic status may be a predetermining factor to individual susceptibilities to hepatic steatosis.
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通过DNA低甲基化的口袋在丝粒处的允许转录活性。
影响因子：
4.5
作者：
Wong, Nicholas C.;Wong, Lee H.;Quach, Julie M.;Canham, Paul;Craig, Jeffrey M.;Song, Jenny Z.;Clark, Susan J.;Choo, K. H. Andy
通讯作者：
Choo, K. H. Andy
DOI：
10.1006/bbrc.1999.1187
发表时间：
1999-09-07
影响因子：
3.1
作者：
Pogribny, I;Yi, P;James, SJ
通讯作者：
James, SJ
影响因子：
5.3
作者：
Liang, GG;Chan, MF;Jones, PA
通讯作者：
Jones, PA
影响因子：
11.4
作者：
Martens, JHA;O'Sullivan, RJ;Jenuwein, T
通讯作者：
Jenuwein, T
影响因子：
4.7
作者：
Bagnyukovay, Tetyana V.;Tryndyaky, Volodymyr P.;Pogribny, Igor P.
通讯作者：
Pogribny, Igor P.