In the wake of the discovery of the DNA molecule, the nucleic acid code was commonly considered the beginning and end of genetic inheritance.
Today it's understood that chemical markings bonded to key sections of a genetic sequence not only affect the way genes are read, but can change in response to environmental exposures. What's more, they may actually be transferred from one generation to the next.
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Called transgenerational epigenetic inheritance, this could be a route by which the health, lifestyle or even the environment of parents affects the health and development of offspring down the family tree for generations.
While the changes themselves seem clear, the exact mechanisms at work are yet to be fully understood.
Now a new study in roundworms has shown how a common epigenetic modification can be passed down through three generations via sperm, influencing gene activity and development in 'grand-offspring'.
Though evidence from humans of such an enduring epigenetic memory remains scant, the study of roundworms (Caenorhabditis elegans) is quite revealing.
"These results establish a cause-and-effect relationship between sperm-transmitted histone marks and gene expression and development in offspring and grand-offspring," says Susan Strome, a molecular and cell biologist at the University of California, Santa Cruz.
Epigenetic changes are molecular ornaments added to DNA that come in several forms and govern when and how genetic instructions are followed.
If the cell's machinery that reads its genome can't access certain genes because bulky molecules stand in their way, then those genes won't be deciphered into proteins. Winding long strands of DNA around major protein complexes called histones in a tight enough fashion can have a similar, silencing effect.
Most of these epigenetic modifications were thought to be erased and 'reset' following fertilization, whereby sex cells are reprogrammed to ensure normal development. But as animal studies show (including a number based on mammals), it seems that some epigenetic changes can escape reprogramming and be transferred across generations.
This latest study used C. elegans as a model organism to investigate whether epigenetic markings are preserved or rewritten in roundworm embryos and, if they do persist, how such markings influence gene expression in offspring.
An epigenetic marking on a histone protein that leads to DNA being more densely packaged, in turn switching off genes in that region, was the focus of experiments.
The researchers selectively 'stripped' that histone marking from the chromosomes of C. elegans sperm, which were then used to fertilize eggs with fully marked chromosomes.
Next, they looked at gene activity levels in the resulting offspring and found that genes on chromosomes inherited from sperm were no longer suppressed.
"Some genes were aberrantly turned on and stayed in the state lacking the repressive mark, while the rest of the genome regained the mark, and that pattern was passed on to the grand-offspring," explains Strome.
"We speculate that if this pattern of DNA packaging is maintained in the germline, it could potentially be passed on for numerous generations."
Let's not forget, these are roundworms we're talking about. Past research on these translucent creatures has shown that epigenetic changes can be passed down for a whopping 14 generations, which is wild, but that says little about humans.
A few rare and remarkable human studies have uncovered evidence that a grandparent's access to food affects the health outcomes of their children's offspring, two generations down the line.
Other research has looked at links between maternal health including smoking habits and childhood asthma, or shown how events in early childhood can etch chemical edits onto a person's DNA that influence their health in later life.
But human studies making a direct connection between parental health, epigenetic changes in sex cells, and offspring outcomes are "virtually non-existent" as one review of the field put it, in part because of the limitations of epidemiological studies that can only yield associations, not causal relationships.
Disentangling the influence of epigenetic markers from genetic, cultural, and behavioral influences is also a major challenge. How do you begin to separate genetics from social circumstances or environmental conditions that persist over generations?
That's why animal studies like this one are helpful in "illuminating how epigenetic inheritance can shape the development and health of future generations," Strome and colleagues write in their published paper.
The team says their findings mirror those from lab-grown mammalian cells, and that other recent studies have suggested sperm-inherited histone markers are a feature in mice, too.
Those parallels may mean the mechanism might also extend to humans. But there's a lot we still don't know about how epigenetic inheritance operates over multiple generations, or if indeed it does.
Given the ethical and logistical hurdles to investigating such questions in humans, it might be a long time until we do.
The research was published in PNAS.
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