Study Title:

Stress Can Be Inhereted

Study Abstract

•Drosophila ATF-2 (dATF-2) is required for heterochromatin formation
•The stress-induced phosphorylation of dATF-2, via Mekk1-p38, disrupts heterochromatin
•Phosphorylation of dATF-2 results in its release from heterochromatin
•This heterochromatic disruption is transmitted to the next generation

Atf1, the fission yeast homolog of activation transcription factor-2 (ATF-2), contributes to heterochromatin formation. However, the role of ATF-2 in chromatin assembly in higher organisms remains unknown. This study reveals that Drosophila ATF-2 (dATF-2) is required for heterochromatin assembly, whereas the stress-induced phosphorylation of dATF-2, via Mekk1-p38, disrupts heterochromatin. The dATF-2 protein colocalized with HP1, not only on heterochromatin but also at specific loci in euchromatin. Heat shock or osmotic stress induced phosphorylation of dATF-2 and resulted in its release from heterochromatin. This heterochromatic disruption was an epigenetic event that was transmitted to the next generation in a non-Mendelian fashion. When embryos were exposed to heat stress over multiple generations, the defective chromatin state was maintained over multiple successive generations, though it gradually returned to the normal state. The results suggest a mechanism by which the effects of stress are inherited epigenetically via the regulation of a tight chromatin structure.

From press release:

None of us are strangers to stress of various kinds. It turns out the effects of all those stresses can change the fate of future generation, influencing our very DNA without any change to the underlying sequence of As, Gs, Ts and Cs. Now, researchers reporting in the June 24 issue of Cell, a Cell Press publication, have new evidence that helps to explain just how these epigenetic changes really happen.

"There has been a big discussion about whether the stress effect can be transmitted to the next generation without DNA sequence change," said Shunsuke Ishii of RIKEN Tsukuba Institute. "Many people were doubtful about such phenomena because the mechanism was unknown. Our finding has now demonstrated that such phenomena really can occur."

Our genes encode proteins, but whether and how those genetic instructions are ultimately read and expressed depends on how those genes are chemically modified and "packaged" into a more complex structure known as chromatin. Some portions of the genome are more tightly wound into what's known as heterochromatin. Heterochromatin is maintained from one generation to the next and typically doesn't contain active genes, Ishii explains.

Over 20 years ago, Ishii and his colleagues discovered a gene in yeast (called activation transcription factor-2 or ATF-2 for short)that is required for those tightly packed, heterochromatin structures to form. ATF-2 is altered by stress-activated protein kinases in response to environmental stress, inflammatory cytokines, and reactive oxygen species (ROS). But it wasn't entirely clear what this might mean for other organisms.

Ishii and his colleagues now confirm that ATF-2 is required for heterochromatin assembly in multicellular organisms. When fruitflies are exposed to stressful conditions, the ATF-2 is modified and disrupts heterochromatin, releasing genes from their usual silenced state. Importantly, these changes in genomic structure are passed on from one generation to the next.

The researchers expect that this finding in flies has relevance for humans, noting that we also carry the ATF-2 gene. Those epigenetic changes may influence basic cellular functions as well as metabolism, behavior and disease. In particular, Ishii suggests that epigenetic causes may play a role in "lifestyle diseases," including heart disease and diabetes, and in psychological diseases, such as schizophrenia.

If that's true, there may be some hope. Drugs targeting the enzymes that modify ATF-2 in response to stress have already been developed.

According to Ishii, the take-home message is this: "I hope that people understand that various stresses can change gene expression without DNA sequence change." He says the youngest among us -- developing embryos and infants -- may be especially sensitive to that kind of stress-induced epigenetic change and "we should be more careful about stresses on them."

Study Information

Ki-Hyeon Seong, Dong Li, Hideyuki Shimizu, Ryoichi Nakamura, Shunsuke Ishii.
Inheritance of Stress-Induced, ATF-2-Dependent Epigenetic Change
2011 June
RIKEN Tsukuba Institute

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