Aberrant regulation of imprinted gene expression in Gtl2lacZ mice
Aberrant regulation of imprinted gene expression in Gtl2lacZ mice
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DOI：
10.1159/000090836
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发表时间：
2006-01-01
影响因子：
1.7
通讯作者：
Kaneko-Ishino, T.
中科院分区：
文献类型：
--
作者：
Sekita, Y.;Wagatsuma, H.;Kaneko-Ishino, T.
小鼠远端12号染色体上的印迹区约1 Mb，包含至少3个父系表达基因（peg: Pe9/Dlk1、Peg11/Rtl1和Dio3）和4个母系表达基因（meg: Meg3/Gtl2、antiPeg11/antiRlt1、Meg8/Rian和Meg9/Mirg）。Gtl2(lacZ)（基因诱捕位点2）小鼠在Meg3/Gtl2启动子上游2.3 kb处有一个转基因（TG）插入，当该TG插入的等位基因来自父本时，小鼠的生长迟缓约为40%。定量RT-PCR实验表明，该区域的peg表达量降低到50%以下。这些结果与在Gtl2(lac)z小鼠中观察到的表型一致，因为至少有两种peg （Peg9/Dlk1和Dio3）具有促进生长的作用。来自沉默父本等位基因的Megs的异常诱导也与位于Meg3/Gtl2外显子1附近的差异甲基化区域（DMR）的DNA甲基化水平变化有关。有趣的是，尽管幼崽没有表现出明显的生长或形态异常，但当母系衍生TG时，观察到所有meg减少了60%，类似于80%。因此，父系或母系遗传TG分别导致peg或Megs的cis下调，表明TG的插入影响了整个印迹区域的调节机制。
The imprinted region on mouse distal chromosome 12 covers about 1 Mb and contains at least three paternally expressed genes (Pegs: Pe9/Dlk1, Peg11/Rtl1, and Dio3) and four maternally expressed genes (Megs: Meg3/Gtl2, antiPeg11/antiRlt1, Meg8/Rian, and Meg9/Mirg). Gtl2(lacZ) (Gene trap locus 2) mice have a transgene (TG) insertion 2.3 kb upstream from the Meg3/Gtl2 promoter and show about 40% growth retardation when the TG-inserted allele is paternally derived. Quantitative RT-PCR experiments showed that the expression levels of Pegs in this region were reduced below 50%. These results are consistent with the observed phenotype in Gtl2(lac)z mice, because at least two Pegs (Peg9/Dlk1 and Dio3) have growth-promoting effects. The aberrant induction of Megs from silent paternal alleles was also observed in association with changes in the DNA methylation level of a differentially methylated region (DMR) located around Meg3/Gtl2 exon 1. Interestingly, a 60 similar to 80% reduction in all Megs was observed when the TG was maternally derived, although the pups showed no apparent growth or morphological abnormalities. Therefore, the paternal or maternal inheritance of the TG results in the down-regulation in cis of either Pegs or Megs, respectively, suggesting that the TG insertion influences the mechanism regulating the entire imprinted region.