Lillycrop Karen A, Slater-Jefferies Jo L, Hanson Mark A, Godfrey Keith M, Jackson Alan A, Burdge Graham C
Development and Cell Biology, Biomedical Sciences Building, University of Southampton, Bassett Crescent East, Southampton SO16 7PX, UK.
Br J Nutr. 2007 Jun;97(6):1064-73. doi: 10.1017/S000711450769196X. Epub 2007 Apr 12.
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 the phenotype. We investigated how altered epigenetic regulation of the hepatic glucocorticoid receptor (GR) 1(10) promoter is induced in the offspring. Rats were fed a control (180 g casein/kg) or a PR (90 g 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 that GR1(10) promoter methylation was 33 % lower (P < 0.001) and GR expression 84 % higher (P < 0.05) in the PR offspring. Reverse transcription-PCR showed that DNA methyltransferase-1 (Dnmt1) expression was 17 % lower (P < 0.05) in PR offspring, while Dnmt3a/b and methyl binding domain 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 GR1(10) promoter (147-921 %, 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 GR1(10) promoter, and hence metabolic phenotype, may be due to reduced Dnmt1 expression.
产前营养限制会使后代的代谢表型发生改变，在人类中，这会增加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。我们研究了后代肝脏糖皮质激素受体（GR）1(10)启动子的表观遗传调控是如何改变的。在整个怀孕期间，给大鼠喂食对照饮食（180克酪蛋白/千克）或PR饮食（90克酪蛋白/千克），并在哺乳期喂食普通食物。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PCR显示，PR后代中GR1(10)启动子甲基化降低了33%（P < 0.001），GR表达升高了84%（P < 0.05）。逆转录PCR显示，PR后代中DNA甲基转移酶-1（Dnmt1）表达降低了17%（P < 0.05），而Dnmt3a/b和甲基结合域蛋白-2表达未改变。因此，GR110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的能力降低所致。在GR1(10)启动子处，促进转录的组蛋白修饰增加（147 - 921%，P < 0.001），而抑制甲基化的组蛋白修饰减少（54%，P < 0.01）或与对照相似。在人脐带（n = 15）中，GR1 - C总启动子甲基化的最高水平与最低水平之间存在2倍差异。Dnmt1的表达而非Dnmt3a的表达预测了GR1 - C总启动子甲基化变化的49%（P = 0.003）。这些发现表明，后代肝脏GR1(10)启动子表观遗传调控的改变以及由此导致的代谢表型的诱导，可能是由于Dnmt1表达降低所致。
