Division of Nutritional Sciences, College of Agriculture and Life Sciences, Cornell University, Ithaca, New York, United States of America.
PLoS One. 2010 Nov 2;5(11):e13784. doi: 10.1371/journal.pone.0013784.
Rasgrf1 is imprinted in mouse, displaying paternal allele specific expression in neonatal brain. Paternal expression is accompanied by paternal-specific DNA methylation at a differentially methylated domain (DMD) within the locus. The cis-acting elements necessary for Rasgrf1 imprinting are known. A series of tandem DNA repeats control methylation of the adjacent DMD, which is a methylation sensitive enhancer-blocking element. These two sequences constitute a binary switch that controls imprinting and represents the Imprinting Control Region (ICR). One paternally transmitted mutation, which helped define the ICR, induced paramutation, in trans, on the maternal allele. Like many imprinted genes, Rasgrf1 lies within an imprinted cluster. One of four noncoding transcripts in the cluster, AK015891, is known to be imprinted.
METHODOLOGY/PRINCIPAL FINDINGS: Here we demonstrate that an additional noncoding RNA, AK029869, is imprinted and paternally expressed in brain throughout development. Intriguingly, any of several maternally inherited ICR mutations affected expression of the paternal AK029869 transcript in trans. Furthermore, we found that the ICR mutations exert different trans effects on AK029869 at different developmental times.
CONCLUSIONS/SIGNIFICANCE: Few trans effects have been defined in mammals and, those that exist, do not show the great variation seen at the Rasgrf1 imprinted domain, either in terms of the large number of mutations that produce the effects or the range of phenotypes that emerge when they are seen. These results suggest that trans regulation of gene expression may be more common than originally appreciated and that where trans regulation occurs it can change dynamically during development.
Rasgrf1 在小鼠中呈印记状态，在新生脑中表现出父本等位基因特异性表达。父本表达伴随着在基因座内的差异甲基化域 (DMD) 上的父本特异性 DNA 甲基化。用于 Rasgrf1 印迹的顺式作用元件是已知的。一系列串联 DNA 重复序列控制着相邻 DMD 的甲基化，DMD 是一个甲基化敏感的增强子阻断元件。这两个序列构成了一个二进制开关，控制着印迹，并代表印迹控制区 (ICR)。一个父系传递的突变，帮助定义了 ICR，在顺式上诱导了母系等位基因的偏母现象。像许多印记基因一样，Rasgrf1 位于一个印记簇内。该簇中的四个非编码转录本之一，AK015891，已知是印记的。
方法/主要发现： 在这里，我们证明了簇中的另一个非编码 RNA，AK029869，在整个发育过程中是印记的，并在大脑中父本表达。有趣的是，几个母系遗传的 ICR 突变中的任何一个都以顺式影响父系 AK029869 转录本的表达。此外，我们发现 ICR 突变在不同的发育时间对 AK029869 产生不同的转导效应。
结论/意义： 在哺乳动物中，很少有转导效应被定义，而且那些存在的转导效应在数量上也没有看到 Rasgrf1 印记域中那么大的变化，无论是产生这些效应的突变数量，还是当它们出现时出现的表型范围。这些结果表明，基因表达的转导调控可能比最初想象的更为普遍，而且在转导调控发生的地方，它可以在发育过程中动态变化。
