FEB 19, 2023 2:23 AM PST

A New Layer of Gene Regulation is Revealed in mRNA

WRITTEN BY: Carmen Leitch

Recent work reported in Nature highlighted the importance of methylation on messenger RNA (mRNA). Methyl tags that are added to mRNA can have a dramatic impact on the fate of mRNA transcripts. Now an unrelated study in Science has unraveled even more about the effect of methylation on mRNA. Active genes are transcribed into mRNA transcripts, which are often translated into proteins. But cells have to be very careful about which genes are expressed when, and there are many mechanisms involved in the regulation of genes, such as gene promotors, transcription factors, or epigenetic marks like methyl tags. Methyl tags are often seen on the genome, but they can be added to mRNA as well.

Image credit: Pixabay

University of Chicago researchers wanted to know how cells choose the sites where methyl tags should be added. Only a small portion of the genome is methylated.

"This is an incredibly important process that happens in everything from fish to cows to us. It's how some cells become skin and others become eyes and others become muscles, yet we lacked an understanding of the mechanism itself," noted study leader Chuan He, a Professor of Chemistry, Biochemistry and Molecular Biology at the University of Chicago.

The study authors discovered that cells don't choose methylation sites; instead, they decide where not to add methyl tags. The mechanism seems to involve certain parts of mRNA called the exon junction complex (EJC).

The genome carries a lot of information. In genes that code for protein, for example, there are exons, which are the coding parts, and introns, which sit in between exons. Those introns get spliced out of mRNA molecules before they are translated to protein. The EJC helps glue the remaining exons together once the introns are removed.

This work revealed that EJCs also appear to influence whether methylation occurs on a certain sequence of mRNA. EJCs are bulky molecules, so when they sit on short bits of mRNA, methylation is physically blocked from happening. On longer sequences of mRNA, the EJCs that sit at either end don't block the entire mRNA from being methylated, so the process can occur. Thus, EJCs are acting as methylation suppressors.

This research may have significant implications for a variety of fields. For example, when artificial genes are designed and engineered, they don't include EJCs. However, EJCs appear to have a common role in gene expression, so when they are left out, it may have other impacts.

"When people develop reporters for gene expression or even in gene therapy, there's this additional layer of regulation one needs to consider when designing," explained He. "It could be hypermethylated without this packaging, meaning it isn't an exact mimic of the natural process."

Since this process has been observed in organisms from zebrafish to humans (but not insects or shellfish), it may be related to how gene expression was fine-tuned during evolution, added He. There are very different levels of EJCs in brain and heart tissue as well, so it may be linked to how cells are differentiated during the growth of an embryo.

"This discovery suggests a new layer of gene expression regulation and a new pathway to regulate stability of mRNA in general. We will be working to understand the full implications for a long time," said He.

Sources: University of Chicago, Science

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