Contrary to historic understanding of RNA’s longevity in cells, some RNAs can persist in cells throughout the life of an organism. Lead authors, Martin Hetzer, PhD, president of the Institute of Science and Technology (ISTA) and Tomohisa Toda, PhD, professor at Friedrich-Alexander University (FAU), along with their research team found that long-lived RNA in the brain of mice remained active and functional throughout the two-year lifespan of the animals. Their study, “Life-long persistence of nuclear RNAs in the mouse brain,” is published in the latest issue of Science.

While nuclear DNA is protected and maintained throughout the life of the cell, and in the case of neurons, the life of the individual, RNAs are often more transient and short-lived. mRNA is notably very short lived, however, the life span of nuclear RNAs, which help maintain DNA in the nucleus, has not been well studied. Using a mouse model, researchers delved into clarifying this exact concern. “These long-lived RNAs were stably retained in nuclei in a neural cell type–specific manner and were required for the maintenance of heterochromatin,” the authors wrote.

RNA labels show RNA longevity

Hetzer and his team used mice to track labeled RNAs from birth through death. “For this labeling, we used RNA analogs—structurally similar molecules—with little chemical hooks that click fluorescent molecules on the actual RNAs,” Hetzer said. This labeling allowed for the RNAs to be visualized at various timepoints throughout the life of the mice.

“Surprisingly, our initial images revealed the presence of long-lived RNAs, in various cell types within the brain. We had to further dissect the data to identify the ones in the nerve cells,” added Hetzer. The research team used the data collected to identify and map the long-lived RNAs throughout the mouse life cycle. Further, they quantified concentrations and locations of the RNAs in the brain tissues.

RNA and DNA are indicated with grey (EU; 5- ethynyluridine) and blue (DAPI) staining, respectively. Visible brain regions include the olfactory bulb (OB), rostral migratory stream (RMS), subventricular zone (SVZ), and the dentate gyrus (DG).
RNA and DNA are indicated with grey (EU; 5- ethynyluridine) and blue (DAPI) staining, respectively. Visible brain regions include the olfactory bulb (OB), rostral migratory stream (RMS), subventricular zone (SVZ), and the dentate gyrus (DG).

They found that during the approximate two-and-a-half-year lifespan of mice, there was a slight reduction in concentration of long-lived RNAs, but they were still detectable after two years, toward the end of the mouse’s life. These data indicate that labeled RNAs persisted throughout the life of these mice. “As their name and our previous experiments suggest, these long-lived RNAs are extremely stable,” said Hetzer.

Long-lived RNA function

Once the team established the retention of these long-lived RNAs in the neural tissue, they set out to determine their function in the cell. These RNAs were a mix of mRNA and noncoding RNA colocalizing near the heterochromatin and likely have a function in DNA maintenance.

Using an in vitro method to more easily manipulate the long-lived RNAs, researchers modeled the brain using neural stem cells and reduced the amount of long-lived RNAs. They found that DNA in the modified cells was unstable and there were problems with the heterochromatin architecture, suggesting an important role of DNA maintenance by long-lived RNAs. Hetzer added, “Lifelong cellular maintenance during aging involves an extended life span of key molecules like the long-lived RNAs, we just identified.”

While a significant step in understanding how neural tissue survives and is maintained throughout the lifespan of an individual has been elucidated, the researchers acknowledged that more work is needed to fill in the gaps. “Together with unidentified proteins, long-lived RNAs likely form a stable structure that somehow interacts with the heterochromatin.” Researchers plan to continue their work to determine how these RNAs conduct their important maintenance work in long-lived cells, like neurons. Hertzer concluded, “The life span of neural cells may depend on both the molecular longevity of DNA for the storage of genetic information and also the extreme stability of RNA for the functional organization of chromatin.”

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