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Studies in roundworms by biologists at the University of Iowa suggest that a mother’s response to stress can influence her children and her grandchildren, through heritable epigenetic changes. Their research, reported in Molecular Cell, demonstrated that roundworm mothers subjected to heat stress passed—under certain conditions—the legacy of that stress exposure not only to their offspring but, if the period of stress to which the mother was exposed was long enough, even to their offspring’s children.

Research lead Veena Prahlad, PhD, associate professor in the department of biology and the Aging Mind and Brain Initiative, and colleagues, reported on their findings in a paper titled, “Gene bookmarking by the heat shock transcription factor programs the insulin-like signaling pathway.”

Maternal stress can have long-lasting epigenetic effects on offspring, the authors pointed out. “Many organisms display transgenerational plasticity, where the memory of parental exposure to stress alters later-life cellular responses and survival mechanisms of offspring.” But how epigenetic changes that occur during perinatal life are maintained to affect later-life physiology isn’t clear, they continued. “This question is underscored because, during normal development in all animals, chromatin modifications acquired during germline transcriptional activity are removed at fertilization to epigenetically reprogram the embryo.” And yet, in many organisms memory of early-life stress exposure can still persist, the researchers noted. “This early-life programming, or maternal effect, can be beneficial for progeny, altering their phenotypes to decrease predation risk; alternatively, it can be detrimental, as observed in humans, where maternal stress increases later-life susceptibility of offspring to metabolic and neuropsychiatric diseases.”

In the nematode Caenorhabditis elegans (as well as in other organisms), environmental stressors that affect the parent also affect the unfertilized gametes. Epigenetic mechanisms that affect chromatin in one generation have been found to alter the offspring lifespan and behavior in subsequent roundworm generations. “In the parent, stress activates the heat shock transcription factor HSF1 (HSF-1 in C. elegans), which increases expression of protective heat-shock protein (hsp) genes to counteract stress-induced damage,” the investigators explained. HSF1 is a protein that is present in all plants and animals, and is activated by changes in temperature, salinity, and other stressors.

For their newly reported study, Prahlad and colleagues wanted to find out how the memory of stress exposure was stored in the egg cell. The biologists looked at how a mother roundworm reacts when she senses danger, such as a change in temperature, which can be harmful or even fatal to the animal. In a study published last year, the biologists discovered that the mother roundworm releases serotonin when she senses danger. The serotonin travels from her central nervous system to warn her unfertilized eggs, where the warning is, effectively stored, and then passed to offspring after conception.

Examples of such genetic cascades abound, even in humans. Studies have shown that pregnant women affected by the Dutch Hunger Winter famine in the Netherlands from 1944 to 1945 gave birth to children who were influenced by that episode as adults—with higher rates than average of obesity, diabetes, and schizophrenia.

“Genes have ‘memories’ of past environmental conditions that, in turn, affect their expression even after these conditions have changed,” Prahlad said. “How this ‘memory’ is established and how it persists past fertilization, embryogenesis, and after the embryo develops into adults is not clear. “This is because during embryogenesis, most organisms typically reset any changes that have been made to genes because of the genes’ past activity.”

Turning to C. elegans for clues, the researchers exposed mother roundworms to unexpected stresses and found that the stress memory was ingrained in the mother’s eggs through the actions of HSF-1. The team’s experiments demonstrated that HSF-1 recruits another protein, an enzyme called a histone 3 lysine 9 (H3K9) methyltransferase.

H3K9 methyltransferase normally acts during embryogenesis to silence genes and erase the memory of their prior activity.  But Prahald’s team observed something else entirely. “We found that HSF1 collaborates with the mechanisms that normally act to ‘reset’ the memory of gene expression during embryogenesis to, instead, establish this stress memory,” Prahlad stated. The authors further explained in their paper, “… paradoxically, HSF-1 recruits the germline machinery normally responsible for erasing transcriptional memory but, instead, establishes a heritable epigenetic memory of prior stress exposure.”

One of these newly silenced genes encodes the insulin receptor, which is central to metabolic changes with diabetes in humans, and which, when silenced, alters an animal’s physiology, metabolism, and stress resilience. Because these silencing marks persisted in offspring, their stress-response strategy was switched from one that depended on the ability to be highly responsive to stress, to relying instead on mechanisms that decreased stress responsiveness but provided long-term protection from stressful environments. “These studies demonstrate a mechanism where, in response to maternal stress exposure, the conserved transcription factor HSF-1 recruits the putative histone H3K9 SET domain methyltransferase MET-2 to HSF-1 target genes in the germline, including to the insulin-like receptor gene daf-2, to increase heterochromatin, repress subsequent expression, establish a memory of prior stress exposure, and alter the animals’ later-life stress response strategy,” they wrote.

“What we found all the more remarkable was that if the mother was exposed to stress for a short period of time, only progeny that developed from her germ cells that were subjected to this stress in utero had this memory,” Prahlad said. “The progeny of these progeny (the mother’s grandchildren) had lost this memory. However, if the mother was subjected to a longer period of stress, the grandchildren generation retained this memory. Somehow the ‘dose’ of maternal stress exposure is recorded in the population.”

The researchers plan to investigate these changes further. HSF1 is not only required for stress resistance but also increased levels of both HSF1 and the silencing mark are associated with cancer and metastasis. Because HSF1 exists in many organisms, its newly discovered interaction with H3K9 methyltransferase to drive gene silencing is likely to have larger repercussions. “… it is also possible that HSF-1-dependent repressive H3K9me2 bookmarking upon heat shock serves other functions besides establishing increased stress tolerance. This remains to be explored,” the team concluded.

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