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首页> 外文期刊>The Journal of Nutritional Biochemistry >Prenatal caloric restriction enhances DNA methylation and MeCP2 recruitment with reduced murine placental glucose transporter isoform 3 expression
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Prenatal caloric restriction enhances DNA methylation and MeCP2 recruitment with reduced murine placental glucose transporter isoform 3 expression

机译：产前热量限制通过减少鼠胎盘葡萄糖转运蛋白亚型3的表达增强DNA甲基化和MeCP2募集。

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Diminished transplacental glucose transport plays an important role in prenatal calorie restriction (CR) induced reduction in fetal growth. Fetal growth restriction (FGR) has an impact in shaping the adult phenotype with transgenerational implications. To understand the mechanisms underlying prenatal CR-induced transplacental glucose transport, we examined the epigenetic regulation of placental glucose transporter (Glut1 and Glut3) expression. We restricted calories by 50% in C57BL6 pregnant mice from gestational days 10 to 19 (CR; n=8) vs. controls (CON; n=8) and observed a 50% diminution in placental Glut3 expression (P.05) with no effect on Glut1 expression by reverse transcription and quantitative real-time polymerase chain reaction (PCR). CR enhanced DNA methylation of a CpG island situated similar to 1000 bp upstream from the transcriptional start site of the glut3 gene, with no such effect on the glut1 gene as assessed by methylation-sensitive PCR and bisulfite sequencing. Chromatin immunoprecipitation (ChIP) assays demonstrated enhanced MeCP2 binding to the CpG island of the glut3 gene in response to CR vs. CON (P.05). Sequential ChIP demonstrated that enhanced MeCP2 binding of the glut3-(m)CpG island enhanced histone deacetylase 2 recruitment (P.05) but interfered with Sp1 binding (P.001), although it did not affect Sp3 or Creb/pCreb interaction. We conclude that late-gestation CR enhanced DNA methylation of the placental glut3 gene. This epigenetic change augmented specific nuclear protein DNA complex formation that was associated with prenatal CR-induced reduction of placental glut3 expression and thereby transplacental glucose transport. This molecular complex provides novel targets for developing therapeutic interventions aimed at reversing FGR. (C) 2014 Elsevier Inc. All rights reserved.
机译：经胎盘葡萄糖转运减少在产前卡路里限制（CR）诱导的胎儿生长减少中起重要作用。胎儿生长受限（FGR）对塑造具有跨代影响的成人表型有影响。为了了解产前CR诱导的胎盘葡萄糖转运的潜在机制，我们检查了胎盘葡萄糖转运蛋白（Glut1和Glut3）表达的表观遗传调控。从妊娠第10到19天（CR; n = 8）与对照组（CON; n = 8），我们将C57BL6妊娠小鼠的卡路里限制为50％，观察到胎盘Glut3表达降低了50％（P <.05），逆转录和定量实时聚合酶链反应（PCR）对Glut1表达无影响。 CR增强了CpG岛的DNA甲基化，该岛位于glut3基因的转录起始位点上游1000 bp上游，而对甲基化敏感的PCR和亚硫酸氢盐测序所评估的glut1基因没有这种作用。染色质免疫沉淀（ChIP）分析表明，响应于CR与CON相比，MeCP2与glut3基因CpG岛的结合增强了（P <.05）。顺序ChIP表明，增强的MeCP2与glut3-（m）CpG岛的结合增强了组蛋白脱乙酰基酶2的募集（P <.05），但干扰了Sp1的结合（P <.001），尽管它不影响Sp3或Creb /​​ pCreb的相互作用。 。我们得出结论，妊娠晚期CR增强了胎盘glut3基因的DNA甲基化。这种表观遗传学变化增加了特定的核蛋白DNA复合物的形成，这与产前CR诱导的胎盘glut3表达减少以及由此的胎盘葡萄糖转运有关。这种分子复合物为开发旨在逆转FGR的治疗干预措施提供了新的靶标。 （C）2014 Elsevier Inc.保留所有权利。

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