A new study by Yale researchers has found that small, noncoding molecules of RNA called microRNA may play a large role in protecting organisms against stress by limiting genetic variability during early development.
The study looked at microRNA in zebrafish and found that specific microRNA work to limit excess variation that makes organisms more susceptible to environmental stressors and disease by silencing the expression of some genes. The finding provides key insight into how organisms achieve an optimal level of diversity on a cellular level, according to Dionna Kasper, a postdoctoral fellow at the School of Medicine and the first author of the research. The study, published in Developmental Cell on March 27, may also have broader implications for the study of cancer and heart disease in humans.
“A lot of times when we look at cardiovascular disease or cancer, we see a lot of heterogeneity in the population,” Kasper said. “One person can have one mutation which causes different types of diseases, depending on their gender or their age or environmental parameters, so we think that microRNA is one thing that could be working to limit variability.”
The researchers chose to study microRNA in zebrafish because the fish are vertebrates, like humans, and because they are transparent, which allows scientists to watch their development in real time. Zebrafish also have a cardiovascular system, which was of particular interest in this study, as researchers wanted to identify and study particular microRNA that may also play a role in the human cardiovascular system.
According to Kasper, the team deleted the gene that is responsible for forming microRNA in order to create a population of mutant zebrafish, and then looked at the effect of this deletion on different kinds of microRNA within the cardiovascular system. According to the study, the researchers found that two of the missing microRNAs had caused a greater range of variability of the corresponding trait.
“These microRNA mutants could live and survive to adulthood, but we thought that these mutants would be more sensitive to environmental stress, so we stressed them with chemicals, inhibitors of muscular signaling, as well as hypoxia,” she said. “What was interesting was that [the microRNAs] that had the extended range were sensitive to that.”
This finding allowed the scientists to conclude that vertebrate microRNA provide tissue robustness to changing environments in development and that the loss of certain microRNA increases the variance of developing vascular traits.
According to Yale Cancer Center professor of hematology Stephanie Halene, this finding could have important implications for the treatment of cancer and other diseases.
“Most likely if they perturb the system just enough, they cause just enough instability in maintaining the variance that the cell can still live and yet if there is more stress, it can turn into cancer,” she said.
Halene also said she thinks understanding the regulatory mechanism of microRNA could help researchers figure out how to stabilize it and prevent it from mutating.
She added that she believes scientists may even be able to use this knowledge to treat patients who already have cancer.
Kasper said that although she is excited about these implications, she believes there is a lot more work to be done on the microRNA-regulated pathway before scientists can make the comparison between zebrafish and humans. However, she added that she thinks her team’s research has made a great start.
According to the Centers for Disease Control and Prevention, heart disease and cancer are the two principal causes of death in the United States.