After it is transcribed from DNA, RNA can go on to many fates. While the most familiar path may lead directly to the production of protein, RNA molecules themselves can also become capable of altering the expression of genes.  The process of translating genetic information from DNA into the proteins that do most of the work in a cell is carried out by molecular machines made of a combination of RNA and protein. Surprisingly, it is the RNA, and not the protein, that does the critical work in this protein-making machine, which is called the ribosome.  The labels contained within the RNA sequence and their associate reader and writer proteins, which help make changes within the cell, are of great interest.

Now, a study from researchers at Rockefeller University and Columbia University has identified a protein that recognizes a chemical instruction tag affixed to an RNA sequence, an important step in the decision-making process.  The team state that their findings help to explain how the destiny of an RNA sequence is achieved.  The opensource study is published in the journal Cell.

Previous studies have implicated an abundant label, known as m6A, in several important processes that influence the production of proteins, as well as so-called microRNAs, which are small RNA molecules that do not code for proteins and instead turn down the activity of genes.  This tag was identified more than four decades ago on RNA sequences as a methyl group attached to a particular part of an adenosine, a component of RNA’s sequence. However, it was unclear what reads this chemical tag within the nucleus of cells. The current study has identified one such ‘reader’ protein. Due to the fundamental nature of the processes involved, this discovery has implications for cells’ normal function and for disease.

In earlier work from the team the m6A tag was identified as an important regulator of the production of microRNAs. The ‘writer’ protein that places this tag was already known to mark RNA molecules that need to be spliced before they are translated into proteins. The team explain that many genes contain sections that must be cut out, and the RNA splicing process is crucial to the function and identity of a cell.

The current study shows that the newly discovered reader, a protein known as HNRNPA2B1, recognizes m6A tags on RNA destined for two separate fates, trimming to become microRNAs or splicing for proper production into protein. Data findings show that after recognizing m6A tags on microRNA precursors, HNRNPA2B1 then recruits the cutting machinery responsible for further trimming and processing those RNA molecules.

To achieve this outcome the researchers first identified that the HNRNPA2B1 frequently binds to the same sites on the RNA molecule where the m6A tag attaches. To determine what the alleged reader was doing there, the team reduced its presence in cells.  Results show that in cells with reduced HNRNPA2B1 levels there is a shift in the expression of microRNAs overall, with many microRNAs reduced. The lab also looked at the effects on RNA destined for splicing. Here too, findings identified changes in the splicing of different RNA molecules that are dependent on m6A tags.

The team state that to their knowledge HNRNPA2B1 is the first m6A nuclear reader to be identified, and evidence from the experiments suggests the existence of additional readers within the nucleus that also recognize this tag.

The group surmise that the discovery of this new m6A reader has ramifications for a broad range of processes as RNA splicing establishes the repertoire of proteins available in cells and abnormalities in microRNAs have been associated with several diseases, including cancer.  For the future the team now plan to investigate how HNRNPA2B1 interacts with the proteins involved in the splicing of RNA.

Source: The Rockefeller University