Highlight Publication February 2009

Redrup L, Branco MR, Perdeaux ER, Krueger C, Lewis A, Santos F, Nagano T, Cobb BS, Fraser P, Reik W (2009)
The long noncoding RNA Kcnq1ot1 organises a lineage-specific nuclear domain for epigenetic gene silencing.
Development 136 525-530
http://dx.doi.org/10.1242/dev.031328

Lay summary

The identity of each cell, and inherently the task it performs, is established by the activation of a particular repertoire of genes, whilst others remain silenced. Gene activation, or expression, is a result of a complex network of different regulatory mechanisms and starts at the point at which DNA is transcribed into RNA, the latter working as a ‘messenger’ that leads to the production a specific protein. The cell knows which genes to transcribe by having the DNA ‘flagged’ or marked in particular places by so-called epigenetic marks, which pre-determine gene activity or silencing. How these marks are first differently deposited between diverging cell types remains largely unclear.

Recently, RNAs have been emerging as much more than mere messengers. A large collection of non-coding RNAs (ncRNAs) has been shown to play major roles in the regulation of gene expression. Micro RNAs, for example, belong to this group and are known to act through a pathway named RNA interference (RNAi). The mechanism of action of other RNAs, namely long ncRNAs, has remained obscure. However, one well known long ncRNA has provided some clues: Xist is a ncRNA that becomes expressed early in development from one of the female X chromosomes; soon after, Xist is seen ‘coating’ the respective chromosome almost entirely and this eventually leads to its inactivation. This coating is thought to be the trigger for the establishment of progressively more stable silencing marks throughout the chromosome that ‘fix’ the silenced status of the genes.

In this work we provide evidence that the mechanism of action of Xist may not be exceptional, but potentially a paradigm for other regulatory long ncRNAs. We studied a long ncRNA called Kcnq1ot1, which is expressed solely from the paternally inherited copy of the gene and promotes silencing of surrounding genes on the respective chromosome. On the maternal copy of the same genes, however, the lack of Kcnq1ot1 expression allows their expression. This parent-of-origin specific expression is called imprinting and has important functions in the development of the embryo. We characterized the Kcnq1ot1 RNA in terms of its length, stability and localization and found striking similarities with Xist and another long ncRNA, Air. Furthermore, we showed that Kcnq1ot1 does not use the RNAi pathway to maintain silencing of the surrounding genes. Instead, we observed that Kcnq1ot1 coats the neighboring DNA much in the same way that Xist coats one of the X chromosomes. In fact, the extent of coating seems to dictate how many genes become inactivated.

We are now interested in finding out how this coating occurs at the molecular level, how its specificity is attained, and how it allows the recruitment of proteins that mediate silencing.

Lead author

Lisa Redrup obtained her first degree in Natural Sciences from Churchill College, Cambridge in 2003. She joined Wolf Reik’s laboratory in 2003 as a PhD student. Her PhD work characterised the long non-coding RNA Kcnq1ot1 and its role in establishing imprinting at the IC1 locus. Since finishing her PhD in 2007, Lisa continued her work on Kcnq1ot1 for a year as a post doc in the Reik lab before taking a job as a scientific communications writer for the NHS in autumn 2008.