m6A modification inhibits miRNAs’ intracellular function, favoring their extracellular export for intercellular communication

Gene expression, the process by which information from a gene is used to create proteins, is a highly regulated and complex system. One of the newest areas of study in this field is epitranscriptomics, which looks at chemical modifications to RNA that influence how genes are expressed. One such modification is N6-methyladenosine (m6A), which has significant effects on RNA.

What are MicroRNAs?

MicroRNAs (miRNAs) are small, non-coding RNA molecules that play crucial roles in regulating gene expression. They typically function by binding to messenger RNAs (mRNAs) and preventing them from being translated into proteins, effectively silencing the genes.

The Role of m6A in Gene Regulation

m6A is a chemical modification that can be added to RNA molecules. It’s known to regulate various aspects of RNA metabolism, including maturation, stability, degradation, and translation. While we know that m6A can influence the biogenesis (creation) of miRNAs, its effects on mature miRNAs—the ones that are actively working in the cell—have been less clear until now.

New Findings on m6A and miRNAs

Recent work by researchers at Istituto Pasteur has shed light on how m6A modifications affect mature miRNAs and their functions:

  1. Weakening Coupling to AGO2:
    • AGO2 is a protein that miRNAs typically bind to in order to function. The study found that when specific miRNAs have m6A modifications, their ability to bind to AGO2 is weakened. This means they are less effective at regulating their target mRNAs.
  2. Impeding miRNA Function:
    • Due to the weakened coupling to AGO2, these m6A-modified miRNAs are less able to silence their target mRNAs. This impairment suggests that the presence of m6A can reduce the regulatory power of miRNAs within the cell.
  3. Delivery into Extracellular Vesicles (EVs):
    • The study discovered that m6A modifications influence the loading of miRNAs into extracellular vesicles (EVs). EVs are small particles released by cells that can carry various molecules, including miRNAs, to other cells. This modification helps miRNAs get packaged into EVs and sent out to other cells.
  4. Function in Receiving Cells:
    • For the miRNAs to function in the recipient cells, they need to undergo demethylation (removal of the m6A modification). This process is facilitated by an enzyme called FTO, which ensures that the miRNAs can effectively regulate gene expression in the receiving cells.

Mechanistic Insights

  • Intracellular Impairment: The m6A modification inhibits the interaction between AGO2 and the miRNAs, thereby reducing their regulatory function within the cell.
  • EV Loading: The loading of miRNAs into EVs is promoted by the recognition of m6A-modified miRNAs by the RNA-binding protein hnRNPA2B1.
  • Function in Receiving Cells: Once these miRNAs are transferred to another cell via EVs, they require demethylation by FTO to regain their function.

Implications of the Findings

These findings highlight a new level of complexity in how miRNAs work. It shows that cells can express specific miRNAs that, due to m6A modifications, do not impact the cell’s own transcripts but can provide important regulatory information to other cells. This cell-to-cell communication via modified miRNAs could have significant implications for understanding cellular dynamics and the development of new therapeutic strategies.

Conclusion

The study of m6A modifications on miRNAs opens up exciting possibilities for understanding gene regulation and cell communication. These insights not only deepen our knowledge of molecular biology but also pave the way for novel approaches in treating diseases where gene expression goes awry, such as cancer and neurological disorders. As researchers continue to unravel these complex mechanisms, we move closer to harnessing these insights for advanced medical therapies and personalized medicine.

Garbo S, D’Andrea D, Colantoni A, Fiorentino F, Mai A, Ramos A, Tartaglia GG, Tancredi A, Tripodi M, Battistelli C. (2024) m6A modification inhibits miRNAs’ intracellular function, favoring their extracellular export for intercellular communication. Cell Rep 43(6):114369. [article]

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