Mutant fruit flies have helped solve one of the biggest puzzles in genetics: how the stress of starvation or drug addiction can pass on its ill effects to the sufferer’s children and grandchildren.

Stress is thought to cause “epigenetic” changes that do not alter the sequence of DNA but leave chemical marks on genes that dictate how active they are. Previous studies have shown that if mice are stressed for two weeks after birth, their offspring will show signs of depression and anxiety, despite enjoying the usual levels of maternal care. And there is mounting evidence that common health problems including diabetes, obesity, mental illness and even fear could be the result of stress on parents and grandparents.

However, until now attempts to identify changes in inherited DNA that might explain how these effects are passed on have failed.

Now, Shunsuke Ishii at the Riken Tsukuba Institute in Ibaraki, Japan, and colleagues have identified a molecular mechanism by which the effects of stress can be handed down without altering genes or DNA.


“We believe we can convince many sceptics by clarifying the mechanism,” says Ishii.

Open wide

His team have shown that chemical or environmental stress detaches a protein called activating transcription factor 2 (ATF-2) from chromatin, the densely packed DNA that makes up chromosomes.

ATF-2 serves as a kind of zipper, keeping the chromatin tightly bound. Once it is detached, the chromatin structure physically opens up, enabling otherwise hidden genes to become active.

Crucially, the unzipped chromatin is inherited in all descendants of the original “stressed” cell. If the stressed cell is an egg or sperm, the altered chromatin will pass to all cells in any offspring.

Seeing red

To identify this mechanism, Ishii first mutated fruit flies to give them a gene for red eyes. The gene was positioned so that it would lie dormant unless the chromatin was unzipped, making it easy to visually spot inheritance of the trait.

Ishii applied stress to one generation of mutated fruit flies by heating the eggs from which they hatched, or exposing the eggs to salty water. After they had matured to adulthood, he mated them with healthy flies and found that the unzipped chromatin passed to the second, but not third generation.

But when Ishii exposed both the first and the second generations to heat or salty water, the effects were more prolonged – affecting not just one but three subsequent generations. “So sustained stress over multiple generations resulted in the altered chromatin state being inherited by subsequent generations,” says Ishii.

He says that mammals have a counterpart to ATF-2 called ATF-7. Last year, his team showed that in mice it could be altered through psychological stress, leading to changes in chromatin, but experiments to see if the changes are heritable have not yet been done.

“What’s really exciting is that this study shows a clear molecular mechanism that responds to stress and results in a change in chromatin state in the germ line,” says Moshe Szyf at McGill University in Montreal, Canada. “This is a first, to my knowledge.”

Journal reference: Cell, DOI: 10.1016/j.cell.2011.05.029