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MicroRNAs can boost gene expression: study

MMicroRNAs – extracts of nucleic acids of about ten base pairs – are so small that they went unnoticed for decades despite their enormous influence on our cells. They are now known to suppress the expression of thousands of genes through a process called RNA interference, in which they bind to messenger RNAs (mRNAs) and prevent their translation. But a study published on November 9 in AEC Core Sciences finds that microRNAs (miRNAs) can also amplify gene expression.

“It changes the microRNA landscape,” says Lara Mahal, a chemist at the University of Alberta in Canada. The scientist. “There is not just one mode of microRNA regulation: there are two.”

See “Non-coding brain regulators”

This is not the first time that miRNAs have been discovered to improve gene expression. An article published in Science in 2007 reported cases of miRNA-mediated upregulation in cells that had stopped dividing. Yet since then, upregulation was considered rare and limited to inactive cells, Mahal says. So when she and her colleagues sought to better characterize the miRNAs involved in glycosylation (the process by which sugar molecules are stuck to proteins), they did not expect to find an acceleration in gene expression. .

They probed the miRNA profile of two glycosylation proteins: ST6GAL1, which is ubiquitously expressed, and ST6GAL2, which operates in only a few cell types. Work from their lab had previously revealed that ST6GAL1 is overactive in pancreatic cancer, peppering cancer cell membranes with a sugar called 2,6-sialic acid. An abundance of sugars on their surface allows tumor cells to evade the immune system, metastasize and invade other tissues.

To determine how miRNAs adjust enzyme expression, they developed a sensor consisting of a regulatory region of a gene (where miRNA binding occurs) and a sequence that codes for a fluorescent protein. They expressed the sensor, along with a library of human miRNAs, in dividing cells. If miRNAs inhibit the translation of a protein, cells fade in color, while if they increase gene expression, cells glow brighter.

They found that while miRNAs that interact with ST6GAL2 downregulate its expression, those that interact with ST6GAL1 boost its expression and therefore increase levels of 2,6-sialic acid binding. “We were floored. We thought it was a mistake,” says Mahal.

We were floored. We thought that was a mistake.

—Lara Mahal, University of Alberta

However, the team quickly replicated their findings in four cancer cell lines taken from the lungs, ovaries, pancreas and colon. Moreover, the mutation of potential binding sites of miRNAs resulted in the disappearance of upregulation, suggesting that miRNAs directly control gene expression.

Mahal thinks that miRNA-mediated upregulation may have gone largely unnoticed, as most groups tend to focus on much more abundant transcripts. When there are many copies of a protein being made, its effects can simply be tuned by measuring translation. But for genes already expressed at low levels, like those that regulate glycosylation, downregulation doesn’t make as much biological sense, she says.

“It’s an exciting study,” says Pinar Uysal Onganer, a cancer biologist at the University of Westminster in the UK who was not involved in the work. Similar high-throughput studies are essential for validating miRNA interactions, allowing researchers to better predict their effects, she says.

The accuracy of these predictions is especially crucial if miRNAs are to be used for therapeutic purposes, Mahal says, a possibility researchers have explored in recent years given their influence on protein production. Indeed, several miRNAs are currently in clinical trials for the treatment of several diseases, including Huntington’s disease and hepatitis C. what it can really do,” she says.

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