“Flashing blue light” in the cell - the m6A modification regulates speed of RNA processing

Scientists from Berlin and Aarhus describe an RNA modification able to speed up or slow down processing of precursor-mRNAs, depending on its position

June 19, 2018

A controlled interaction of genes in the organism requires that every gene must be in the right place at the right time. In addition, the speed is important, in which the RNA is further processed after transcription. Now, scientists from the Max Planck Institute for Molecular Genetics and the University of Aarhus have described an RNA modification that influences the rate of mRNA processing by its position. They found that precursor mRNAs having the modification N-6-methyladenosine (m6A) deposited at the junction between coding- and non-coding regions are processed much faster than those without the m6A modification.

The DNA contains the blueprint for the development and function of each organism. However, for this information to become available, it needs to first be transcribed from DNA to RNA. Similar to DNA, RNA molecules also consist of four different modules (nucleotides), which sequence codes for the information contained. The information in the DNA remains the same from the genesis of the embryo until death of the organism. In contrast, RNA molecules are only stable in the organism for a limited time. They exert their function very specifically in certain places and at certain times, e.g. during development, before being depleted again.

In addition to the coding regions (exons), the genes of the DNA do also contain non-coding regions (introns). During formation of the mRNA, these, too, are transcribed at first, but then cut out of the precursor mRNA ("splicing") before they leave the nucleus and get active. In this context, scientists speak of “maturation” of the mRNA.

In contrast to double-stranded DNA, single-stranded RNA is well accessible to other molecules and can be altered by a variety of chemical modifications. One of the prevalent RNA modifications is N-6-methyladenosine (m6A), with a methyl group being put to a specific site of the nucleotide adenosine. Scientists from the research group "Long non-coding RNA" at the Max Planck Institute for Molecular Genetics (MPIMG) now have shown that the position, in which the methylation occurs, influences the speed of the RNA maturation process. In the current issue of the journal Cell Reports they describe that the speed of processing of immature RNA increases significantly, when m6A is deposited at the junction between introns and exons.

The scientists headed by Ulf Ørom (now at Aarhus University, Denmark) developed a method called TNT-sequencing. It allowed them to see m6A modifications put on the RNA within the first fifteen minutes of transcription. Thus, they were able to study the very early m6A modification patterns, before introns containing m6A had been removed during splicing.

"We were particularly interested in finding out, whether the position of m6A in the RNA molecule influences the speed of further processing," explains Annita Louloupi, first author of the study published now. For this purpose, the team analyzed two functional regions of the RNA, in which m6A mainly occurs.  "If m6A is deposited at the junction between exons and introns, the appropriate RNA transcripts are processed very quickly," says Louloupi. The scientist compares the function of m6A modifications at the exon-intron boundary with the flashing light on a police car. "In normal traffic, all cars drive with the same speed. Similarly, RNAs are processed with a standard pace. However, when a flashing police light is switched on, all other cars must make space and the police car can drive past them much faster."  However, there are also RNAs with m6A deposited not at the junction, but within an intron. In these cases, the processing of the RNA is significantly slowed down.

Modifications of RNA have been known for a long time. However, only since the development of recent high-throughput methods has it become possible to specifically analyze them. m6A modifications have been shown to be involved in RNA structure, protein interactions, brain development, aging and cancer. Based on their results, the scientists now propose another role for m6A in regulating gene expression.

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