A non-coding RNA within the Rasgrf1 locus in mouse is imprinted and regulated by its homologous chromosome in trans.
A non-coding RNA within the Rasgrf1 locus in mouse is imprinted and regulated by its homologous chromosome in trans.
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DOI：
10.1371/journal.pone.0013784
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发表时间：
2010-11-02
期刊：
影响因子：
3.7
通讯作者：
Soloway PD
中科院分区：
文献类型：
--
作者：
Brideau CM;Kauppinen KP;Holmes R;Soloway PD
Rasgrf1 被印记在小鼠体内，在新生儿大脑中显示出父系等位基因的特异性表达。父本表达伴随着基因座内差异甲基化结构域 (DMD) 的父本特异性 DNA 甲基化。 Rasgrf1 印记所需的顺式作用元件是已知的。一系列串联 DNA 重复序列控制相邻 DMD 的甲基化，DMD 是甲基化敏感的增强子阻断元件。这两个序列构成了控制压印的二进制开关并代表压印控制区域（ICR）。一种父系遗传的突变有助于定义 ICR，它在母体等位基因上诱导了反式副突变。与许多印记基因一样，Rasgrf1 位于印记簇内。已知该簇中的四个非编码转录本之一 AK015891 带有印记。在这里，我们证明了另一个非编码 RNA，AK029869，在整个发育过程中在大脑中被印记和父系表达。有趣的是，几种母系遗传的 ICR 突变中的任何一个都会影响父系 AK029869 转录物的反式表达。此外，我们发现ICR突变在不同的发育时期对AK029869产生不同的反式效应。在哺乳动物中很少有反式效应被定义，并且即使存在，也没有表现出在 Rasgrf1 印记结构域中看到的巨大变异，无论是产生这种效应的大量突变还是在看到它们时出现的表型范围。这些结果表明，基因表达的反式调节可能比最初理解的更常见，并且发生反式调节的地方可以在发育过程中动态变化。
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. 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. 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.