The right combination of parents can turn off a gene indefinitely

Evidence suggests that what happens over the course of a generation – diet, exposure to toxins, trauma, fear – can have lasting effects on future generations. Scientists believe that these effects result from epigenetic changes that occur in response to the environment and turn genes on or off without altering the genome or DNA sequence.

But how these changes are passed down from generation to generation has not been understood, in part because scientists have not had a simple way to study the phenomenon. A new study by researchers at the University of Maryland provides a potential tool to unravel the mystery of how experiments can cause hereditary changes in an animal’s biology. By mating nematode worms, they produced permanent epigenetic changes that lasted for over 300 generations. The research was published on July 9, 2021 in the journal Nature Communication.

“There is a lot of interest in inherited epigenetics,” said Antony Jose, associate professor of cell biology and molecular genetics at UMD and lead author of the study. “But getting clear answers is difficult. For example, if I am on a diet today, how does it affect my children and grandchildren and so on? No one knows, because there are so many different variables. involved. But we have found this to be a very simple, mating method of deactivating a single gene for multiple generations. And it gives us a huge opportunity to study how these stable epigenetic changes occur. “

In the new study, Jose and his team discovered while breeding nematode worms that certain matings resulted in epigenetic changes in the offspring that continued to be passed down through as many generations as scientists continued to breed. This discovery will allow scientists to explore how epigenetic changes are passed on to future generations and what characteristics make genes sensitive to permanent epigenetic changes.

Jose and his team began this work in 2013, while working with nematode worms, Caenorhabditis elegans (C. elegans), a species often used as a model for understanding animal biology. Scientists noticed that the worms reproduced to carry a gene they called T, which produces fluorescent proteins, sometimes bright and sometimes not. It was confusing because Glowers and non-Glowers had almost identical DNA.

“It all started when we came across a rare gene that has undergone permanent changes for hundreds of generations just by mating. We could easily have missed it,” said Sindhuja Devanapally (Ph.D. ’18, sciences biologicals), co-lead author of the study who is now a postdoctoral fellow at Columbia University.

To better understand the phenomenon, the researchers carried out breeding experiments in which only the mother or the father carried the fluorescent gene. The team expected that regardless of which parent carried the gene, the offspring would shine. Instead, they found that when the mother carried the fluorescent gene, the offspring always glowed, meaning the gene was always on. But when the father carried the gene, the offspring usually glowed weakly or did not glow at all.

“We found that there are these RNA-based signals controlling gene expression,” Jose said. “Some of these signals silence the gene and some of them are protective signals that prevent silence. These signals neutralize it as the offspring develop. When the gene comes from the mother, the protective signal always wins, but when the gene comes from the father, the signal for silence almost always wins. “

When the silence signal wins, the gene is silenced for good, or for at least 300 generations, which is how long Jose and his colleagues have been following their lab-reared worms. The previous examples of epigenetic changes were more complex or did not last more than two generations. Researchers don’t yet know why the silence signal wins only part of the time, but this new discovery puts them in a much better position to explore the details of epigenetic inheritance than ever before.

“Although we have found a set of genes that can be almost permanently silenced, most of the other genes are not affected in the same way,” the study’s other lead co-author said, Pravrutha Raman (Ph.D. ’19, Biological Sciences), who is now a postdoctoral fellow at the Fred Hutchinson Cancer Research Center. “After being silenced, they bounce back and express themselves in future generations.”

With their new findings, the researchers now believe that some genes may be more vulnerable to permanent epigenetic changes while other genes recover within a few generations. While studies in worms are not the same as in humans, the research provides a window into biological processes that are likely shared, at least in part, by all animals.

“The two big advantages we now have from this work are that this long lasting epigenetic change is easy to induce by mating and occurs at the single gene level,” said Jose. “Now we can manipulate this gene and control everything about it, which will allow us to determine what characteristics make a gene sensitive or resistant to hereditary epigenetic change.”

Jose and his colleagues expect that future studies may one day help scientists identify human genes that are vulnerable to long-lasting epigenetic changes.

The research paper, “Mating can initiate stable RNA silencing that overcomes epigenetic recovery”, Sindhuja Devanapally, Pravrutha Raman, Mary Chey, Samual Allgood, Farida Ettefa, Maïgane Diop, Yixin Lin, Yongyi E Cho and Antony M Jose, was published on July 9, 2021, in the newspaper Nature Communication.