Imprinted Igf2r silencing depends on continuous Airn IncRNA expression and is not restricted to a developmental window
Imprinted Igf2r silencing depends on continuous Airn IncRNA expression and is not restricted to a developmental window
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DOI：
10.1242/dev.088849
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发表时间：
2013-03-01
期刊：
影响因子：
4.6
通讯作者：
Pauler, Florian M.
中科院分区：
文献类型：
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作者：
Santoro, Federica;Mayer, Daniela;Pauler, Florian M.
印迹Airn宏长非编码（Inc） RNA是一个已建立的顺式沉默IncRNA的例子。Airn的表达对于启动Igf2r基因的父本特异性沉默是必要的，随后在沉默的Igf2r启动子上获得体细胞DNA甲基化印记。然而，Igf2r沉默在发育过程中对Airn启动的要求以及Airn或DNA甲基化在维持Igf2r稳定抑制中的作用尚未得到研究。在这里，我们使用诱导系统来控制小鼠胚胎干细胞（ESC）分化过程中的Airn表达。通过在ESC分化过程中关闭Airn表达，我们发现需要持续的Airn表达来维持Igf2r沉默，但只有在父本Igf2r启动子甲基化之前。通过有条件地打开Airn表达，我们发现Airn启动Igf2r沉默并不局限于一个发育“机会之窗”，并且可以在没有DNA甲基化的情况下维持。总之，本研究表明，在ESC分化过程中，Airn表达是Igf2r沉默的必要和充分条件，而体细胞甲基化印记虽然不是启动或维持沉默所必需的，但却增加了第二层抑制性表观遗传信息。
The imprinted Airn macro long non-coding (Inc) RNA is an established example of a cis-silencing IncRNA. Airn expression is necessary to initiate paternal-specific silencing of the Igf2r gene, which is followed by gain of a somatic DNA methylation imprint on the silent Igf2r promoter. However, the developmental requirements for Airn initiation of Igf2r silencing and the role of Airn or DNA methylation in maintaining stable Igf2r repression have not been investigated. Here, we use inducible systems to control Airn expression during mouse embryonic stem cell (ESC) differentiation. By turning Airn expression off during ESC differentiation, we show that continuous Airn expression is needed to maintain Igf2r silencing, but only until the paternal Igf2r promoter is methylated. By conditionally turning Airn expression on, we show that Airn initiation of Igf2r silencing is not limited to one developmental 'window of opportunity' and can be maintained in the absence of DNA methylation. Together, this study shows that Airn expression is both necessary and sufficient to silence Igf2r throughout ESC differentiation and that the somatic methylation imprint, although not required to initiate or maintain silencing, adds a secondary layer of repressive epigenetic information.