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首页> 外文期刊>Molecular and Cellular Biology >Timing and Sequence Requirements Defined for Embryonic Maintenance of Imprinted DNA Methylation at Rasgrf1
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Timing and Sequence Requirements Defined for Embryonic Maintenance of Imprinted DNA Methylation at Rasgrf1

机译：时间和序列要求定义为在Rasgrf1印迹DNA甲基化的胚胎维持。

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Epigenetic programming is critical for normal development of mammalian embryos. Errors cause misexpression of genes and aberrant development (E. Li, C. Beard, and R. Jaenisch, Nature 366:362-365, 1993). Imprinted genes are important targets of epigenetic regulation, but little is known about how the epigenetic patterns are established in the parental germ lines and maintained in the embryo. Paternal allele-specific expression at the imprinted Rasgrf1 locus in mice is controlled by paternal allele-specific methylation at a differentially methylated domain (DMD). DMD methylation is in turn controlled by a direct repeat sequence immediately downstream of the DMD which is required for establishing Rasgrf1 methylation in the male germ line (B. J. Yoon et al., Nat. Genet. 30:92-96, 2002). To determine if these repeats have a role in methylation maintenance, we developed a conditional deletion of the repeat sequence in mice and showed that the repeats are also required during a narrow interval to maintain paternal methylation of Rasgrf1 in developing embryos. Removing the repeats upon fertilization caused a total loss of methylation by the morula stage, but by the epiblast stage, the repeats were completely dispensable for methylation maintenance. This developmental interval coincides with genome-wide demethylation and remethylation in mice which most imprinted genes resist. Our data show that the Rasgrf1 repeats serve at least two functions: first, to establish Rasgrf1 DNA methylation in the male germ line, and second, to resist global demethylation in the preimplantation embryo.
机译：表观遗传编程对于哺乳动物胚胎的正常发育至关重要。错误导致基因的错误表达和异常发育（E.Li，C.Beard，和R.Jaenisch，Nature 366：362-365，1993）。印迹基因是表观遗传调控的重要靶标，但对表观遗传模式如何在亲本种系中建立并在胚胎中维持的了解甚少。小鼠等位基因在印记的 Rasgrf1 基因座上的父本等位基因特异性表达受甲基化域（DMD）上父本等位基因特异性甲基化的控制。 DMD甲基化又受直接在DMD下游的直接重复序列控制，这是在雄性种系中建立 Rasgrf1 甲基化所必需的（BJ Yoon等，Nat。Genet。30：92- 96，2002）。为了确定这些重复序列是否在甲基化维持中起作用，我们在小鼠中开发了条件性删除重复序列的序列，并表明在狭窄的间隔内也需要这些重复序列，以维持发育过程中 Rasgrf1 的父亲甲基化胚胎。受精后去除重复序列会在桑ula壳阶段导致甲基化的完全丧失，但是到表皮细胞阶段，重复序列对于维持甲基化作用是完全必要的。这个发育间隔与大多数印迹基因抵抗的小鼠的全基因组脱甲基和再甲基化相吻合。我们的数据表明， Rasgrf1 重复序列至少具有两个功能：首先，在雄性种系中建立 Rasgrf1 DNA甲基化;其次，在植入前抵抗整体脱甲基胚胎。

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