Induction of altered epigenetic regulation of the hepatic glucocorticoid receptor in the offspring of rats fed a protein-restricted diet during pregnancy suggests that reduced DNA methyltransferase-1 expression is involved in impaired DNA methylation and changes in histone modifications.
Induction of altered epigenetic regulation of the hepatic glucocorticoid receptor in the offspring of rats fed a protein-restricted diet during pregnancy suggests that reduced DNA methyltransferase-1 expression is involved in impaired DNA methylation and changes in histone modifications.
复制标题
在怀孕期间喂养蛋白质限制饮食的大鼠后代中肝糖皮质激素受体的表观遗传调节改变的诱导表明，DNA甲基转移酶-1表达降低与DNA甲基化受损和组蛋白修饰的变化有关。
DOI：
10.1017/s000711450769196x
复制
发表时间：
2007-06
影响因子：
3.6
通讯作者：
Burdge, Graham C.
中科院分区：
文献类型：
--
作者：
Lillycrop, Karen A.;Slater-Jefferies, Jo L.;Hanson, Mark A.;Godfrey, Keith M.;Jackson, Alan A.;Burdge, Graham C.
产前营养限制会导致后代代谢表型改变，从而增加人类患非传染性疾病的风险。给怀孕大鼠喂食蛋白质限制（PR）饮食会导致后代特定基因启动子的低甲基化并改变表型。我们研究了如何改变肝糖皮质激素受体（GR）110启动子的表观遗传调控在后代中诱导。大鼠在整个妊娠期喂食对照（180 g酪蛋白/kg）或PR（90 g酪蛋白/kg）饮食，并在哺乳期喂食饲料。在出生后第34天处死后代（每个母体饮食组n 5）。甲基化敏感性PCR显示PR后代GR 110启动子甲基化水平降低33%（P<0.001），GR表达水平升高84%（P<0.05）。RT PCR结果显示，PR子代DNA甲基转移酶1（Dnmt 1）的表达降低17%（P<0.05），而Dnmt 3a/B和甲基结构域结合蛋白2的表达无明显变化。因此，GR 110启动子的低甲基化可能是由于有丝分裂期间甲基化半甲基化DNA的能力较低所致。在GR 110启动子处，促进转录的组蛋白修饰增加（147至921%，P<0.001），而抑制甲基化的组蛋白修饰减少（54%，P<0.01）或与对照组相似。在人脐带（n 15）中，GR 1-C总启动子甲基化的最高和最低水平之间存在2倍的差异。Dnmt 1而不是Dnmt 3a的表达预测了GR 1-CTotal启动子甲基化的49%（P = 0.003）。这些研究结果表明，诱导后代的肝脏GR 110启动子的表观遗传调节改变，因此代谢表型，可能是由于减少Dnmt 1的表达。
Prenatal nutritional constraint induces an altered metabolic phenotype in the offspring which in humans confers an increased risk of non-communicable disease. Feeding a protein-restricted (PR) diet to pregnant rats causes hypomethylation of specific gene promoters in the offspring and alters phenotype. We investigated how altered epigenetic regulation of the hepatic glucocorticoid receptor (GR) 110 promoter is induced in the offspring. Rats were fed a control (180g casein/kg) or a PR (90g casein/kg) diet throughout pregnancy, and chow during lactation. Offspring were killed at postnatal day 34 (n 5 per maternal dietary group). Methylation-sensitive PCR showed GR110 promoter methylation was 33% lower (P<0.001) and GR expression 84% higher (P<0.05) in the PR offspring. RT PCR showed DNA methyltransferase-1 (Dnmt1) expression was 17% lower (P<0.05) in PR offspring, while Dnmt3a/b and methyl domain binding protein-2 expression was not altered. Thus hypomethylation of the GR110 promoter may result from lower capacity to methylate hemimethylated DNA during mitosis. Histone modifications which facilitate transcription were increased at the GR110 promoter (147 to 921%, P<0.001), while those that suppress methylation were decreased (54%, P<0.01) or similar to controls. In human umbilical cord (n 15), there was a 2-fold difference between the highest and lowest level of GR1-CTotal promoter methylation. Dnmt1, but not Dnmt3a, expression predicted 49% (P = 0.003) of the variation in GR1-CTotal promoter methylation. These findings suggest that induction in the offspring of altered epigenetic regulation of the hepatic GR110 promoter, and hence metabolic phenotype, may be due to reduced Dnmt1 expression.