Age-Related Changes in Nuclear DNA Structure Make Transcription Mechanisms Faster and More Error-Prone

Some recent work on length-dependent issues in transcription of genes to RNA observed in aging have touched on the role of RNA polymerase II (Pol II), a protein that performs the initial work of moving along a DNA sequence in the genome, reading that sequence in order to assemble the precursor to a corresponding messenger RNA molecule. Do age-related changes in the maintenance of nuclear DNA structure and the activity of Pol II make it harder for longer genes to undergo accurate transcription? Today's open access paper is focused on fidelity of transcription in the context of Pol II behavior, but the work has relevance to those other discussions regarding a selective disadvantage applied to the transcription of longer gene sequences in later life.

The structural organization of nuclear DNA is exceedingly complex and dynamic, ever-changing as the result of a rapid interplay between histones, epigenetic structural additions, and other molecules to expose different regions to transcriptional machinery such as Pol II. At a high level, one might think of the genome as being wrapped around histones, with portions becoming unwrapped for transcription as needed. With age, a great deal changes in the epigenetic decorations placed upon DNA, and thus also in the arrangement of packaged DNA. It is not unreasonable to think that this has a range of effects on cell and tissue function.

A cell is state machine built upon a feedback loop: gene expression produces protein machinery that react to the environment to cause epigenetic changes that alter gene expression. Historically, we might have viewed epigenetic changes in aging as an issue that occurs far downstream of molecular damage and environmental change in tissues that causes aging, but recent discoveries have suggested that much of that epigenetic change characteristic of aging might result from depletion of specific resources following cycles of DNA repair, and thus be a direct consequence of stochastic damage to DNA. Much remains to be determined in certainty; the best approach to establishing the relevance of any specific mechanism involved in aging is to fix it in isolation of other mechanisms and observe the result.

Ageing studies in five animals suggests how to reverse decline

Researchers analysed genome-wide transcription changes in five organisms: nematode worms, fruit flies, mice, rats, and humans, at different adult ages. The researchers measured how ageing changed the speed at which the enzyme that drives transcription, RNA polymerase II (Pol II), moved along the DNA strand as it made the RNA copy. They found that, on average, Pol II became faster with age, but less precise and more error-prone across all five groups.

Previous research had shown that restricting diet and inhibiting insulin signalling can delay ageing and extend lifespan in many animals, so the researchers then investigated whether these measures had any effect on the speed of Pol II. In worms, mice and fruit flies that carried mutations in insulin signalling genes, Pol II moved at a slower pace. The enzyme also travelled more slowly in mice on a low-calorie diet. But the ultimate question was whether changes in Pol II speed affected lifespan. Researchers tracked the survival of fruit flies and worms that carried a mutation that slowed Pol II down. These animals lived 10% to 20% longer than their non-mutant counterparts. When the researchers used gene editing to reverse the mutations in worms, the animals' lifespans shortened.

The researchers wondered whether Pol II's acceleration could be explained by structural changes in how DNA is packed inside cells. To minimize the space that they take up, the vast threads of genetic information are tightly wound around proteins called histones into bundles called nucleosomes. By analysing human lung cells and umbilical vein cells, the researchers found that ageing cells contained fewer nucleosomes, smoothing the path for Pol II to travel faster. When the team boosted the expression of histones in the cells, Pol II moved at a slower pace. In fruit flies, the elevated histone levels seemed to increase their lifespans.

Ageing-associated changes in transcriptional elongation influence longevity

Physiological homeostasis becomes compromised during ageing, as a result of impairment of cellular processes, including transcription and RNA splicing. However, the molecular mechanisms leading to the loss of transcriptional fidelity are so far elusive, as are ways of preventing it. Here we profiled and analysed genome-wide, ageing-related changes in transcriptional processes across different organisms: nematodes, fruitflies, mice, rats and humans. The average transcriptional elongation speed (RNA polymerase II speed) increased with age in all five species. Along with these changes in elongation speed, we observed changes in splicing, including a reduction of unspliced transcripts and the formation of more circular RNAs.

Two lifespan-extending interventions, dietary restriction and lowered insulin-IGF signalling, both reversed most of these ageing-related changes. Genetic variants in RNA polymerase II that reduced its speed in worms and flies increased their lifespan. Similarly, reducing the speed of RNA polymerase II by overexpressing histone components, to counter age-associated changes in nucleosome positioning, also extended lifespan in flies and the division potential of human cells. Our findings uncover fundamental molecular mechanisms underlying animal ageing and lifespan-extending interventions, and point to possible preventive measures.