Illustration of a circular microRNA sponge. The sponge has tiny microRNAs bound to it. This prevents the microRNAs from regulating the cell’s genes. (Illustration: Jørgen Kjems)

Genes are regulated by microRNA sponges

The discovery of an underlying level of gene regulation in the body’s cells presents new opportunities for treating serious diseases.

Kristian Sjøgren

Published 1 March 2013 - 06:01

Scientists have discovered a hitherto unknown way for the body’s cells to regulate their genes.

Danish researchers have identified tiny circular microRNA sponges (see factbox) that determine which proteins the body’s cells should produce.

This ground-breaking discovery is of great importance to our general understanding of gene regulation, but also to our understanding of a long series of genetic diseases.

“Our research shows that the body’s cells can contain very large amounts of these small, circular microRNA sponges. The one we have studied the most can regulate specific microRNAs that are heavily involved in the development of serious diseases such as cancer, Parkinson’s and diabetes,” says one of the authors, Professor Jørgen Kjems, of Aarhus University’s Department of Molecular Biology.

MicroRNAs are short, linear sequences of non-coding RNA that can bind to messenger RNA and prevent these from becoming translated into proteins. MicroRNAs also ensure that the inhibited messenger RNAs are broken down.

The circular microRNA sponges work by attracting the linear microRNA pieces and preventing them from interacting with the messenger RNA.

Since the microRNA sponges are circular, the linear microRNA pieces do not break down while they are bound to the microRNA sponges. This is because RNA degradation usually occurs at the tips of the RNA, but the circular microRNA sponges don’t have any such tips.

The findings, which are the result of a research partnership between Aarhus University and the University of Southern Denmark, are published in the journal Nature.

How are genes regulated?

For a long time, the prevalent view was that the regulation of gene expression occurs when the genes of a cell are copied into messenger RNA (the RNA sequence which is subsequently translated into proteins).

However, in February 2000, researchers found that small, non-coding RNA, known as microRNA, also play a key role in determining which genes are expressed. These tiny pieces of RNA are capable of binding to messenger RNA, thus preventing them from being translated into functional proteins.

This is achieved by the specific coding sequences in the microRNA pieces recognising and binding to similar coding sequences on the messenger RNA.

RNA is a single-stranded copy of the double-stranded DNA, which contains the cell’s genetic code.

When genes are translated into proteins, the cell produces a messenger RNA from the double-stranded DNA. The unique genetic code in the messenger RNA is then translated into a protein, whereby the gene is ‘expressed’.

The regulation of the messenger RNA occurs partly by means of microRNAs, which are tiny pieces of RNA that can bind to the messenger RNA and prevent it from being translated into a protein.

The new Danish study shows that microRNAs are controlled by circular pieces of RNA (microRNA sponges) that are capable of capturing and binding the microRNAs.

And now the Danish study shows that the tiny microRNA pieces are regulated by a hitherto unknown group of circular RNAs known as ‘microRNA sponges’.

“The circular RNA sponges are capable of binding to and inactivating the other regulating microRNAs. This means that the RNA sponges are fundamental in the regulation of the cells’ gene expression. We have thus uncovered a hitherto neglected regulatory element in the cell,” says Kjems.

Discovery made with unconventional techniques

The big question, then, is why these circular micro RNA sponges haven’t been discovered until now.

The answer lies in the technique that researchers normally use when they sequence or clone RNA pieces.

Most techniques consist of attaching the ends of the tiny pieces of RNA or DNA to other pieces of genetic code in order to amplify them.

But the circular microRNAs have no ends, and that’s why they have managed to evade scientists up to now.

“In our study we have used some analysis techniques that do not rely on linear pieces of RNA. This enabled us to find these circular micro RNA pieces and examine their function in the body,” says the researcher.

MicroRNA 7 plays a part in serious diseases

Specifically, the Danish researchers have found and studied a circular RNA, which regulates a microRNA known as microRNA 7.

Previous studies have revealed that microRNA 7 is involved in the regulation of processes such as:

A protein that causes Parkinson’s
A series of genes that cause brain tumours
A protein that’s involved in the development of diabetes

This makes the microRNA 7 a very interesting non-coding RNA that plays a crucial role in many serious diseases.

Important for the treatment of many diseases

The Danish group has found that the regulating circular microRNA sponges are among the most frequently expressed genes in the brain.

In other words, since they have been shown to have such a central role in the general well-being of an organism, regulating microRNA such as microRNA 7 need to be controlled.

But this also opens up for interesting new perspectives in relation to treatment.

“It’s obviously interesting that we have now discovered a circular microRNA that regulates microRNA 7, which is involved in lots of diseases. Further research into microRNA sponges can generate new targets for fighting these diseases,” says Kjems.

The Danish research group continues working on uncovering the microRNA sponge’s function in the body.

On 1 January 2013, they started working on a research project in which they aim to alleviate Parkinson’s disease in rats by manipulating the circular microRNA sponges.

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Read the Danish version of this article at videnskab.dk

Translated by: Dann Vinther