The effect of preconception paternal alcohol exposure on epigenetic remodeling of the h19 and rasgrf1 imprinting control regions in mouse offspring.
The effect of preconception paternal alcohol exposure on epigenetic remodeling of the h19 and rasgrf1 imprinting control regions in mouse offspring.
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DOI：
10.3389/fgene.2012.00010
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发表时间：
2012
影响因子：
3.7
通讯作者：
Ramsay M
中科院分区：
文献类型：
--
作者：
Knezovich JG;Ramsay M
印迹基因座在胎儿发育中起着关键作用。它们的表达通常受印迹控制区（ICRs）上ccctc结合因子（CTCF）蛋白结合的调控。产前酒精暴露已被证明可以降低发育中的小鼠胎儿的整体DNA甲基化。本研究探讨了孕前父亲酒精暴露对暴露的男性精子中两个父亲甲基化的ICRs （H19和Rasgrf1）的DNA甲基化的影响。经乙醇处理的小鼠后代的H19 CTCF 1和CTCF 2结合位点显著降低（p = 0.0027），与出生后35-42天体重下降显著相关（p < 0.05）。由于出生体重不受影响，生长只是在出生后断奶期间延迟，随后又重新收敛，我们假设这可能是智力缺陷导致断奶后独立喂养延迟的结果，并可以解释为什么这种影响是短暂的。在酒精暴露的雄性精子中没有观察到DNA甲基化的差异，这表明受孕时表观遗传信号的传递不是由于甲基化改变，而可能是rna介导的机制或染色质重塑改变的结果。
Imprinted loci play a critical role in fetal development. Their expression is often regulated by CCCTC-binding factor (CTCF) protein binding at imprinting control regions (ICRs). Prenatal alcohol exposure has been shown to reduce global DNA methylation in the developing mouse fetus. This study explored the effect of preconception paternal alcohol exposure on DNA methylation at two paternally methylated ICRs (H19 and Rasgrf1) in the sperm of exposed males and somatic DNA of sired offspring. Significant reductions at the H19 CTCF 1 (p = 0.0027) and CTCF 2 (p = 0.0009) binding sites were observed in the offspring of ethanol-treated sires, which was significantly correlated with reduced weight at postnatal days 35–42 (p < 0.05). As birth weight was unaffected and growth was only delayed during the postnatal weaning period, with subsequent re-convergence, we hypothesize that this may be the result of a mental deficit causing delayed establishment of independent feeding following weaning and would explain why this effect is transient. No difference in DNA methylation was observed in the sperm of alcohol-exposed males, indicating that the transmission of the epigenetic signal at conception is not due to altered methylation, but may be the result of an RNA-mediated mechanism or altered chromatin remodeling.