In the wake of the discovery of the DNA molecule, the nucleic acid code was usually considered the beginning and end of genetic inheritance.
It is now understood that chemical marks attached to key parts of a genetic sequence not only affect how genes are read, but can change in response to environmental exposures. In addition, they may actually be passed down from one generation to another.
Called transgenerational epigenetic inheritance, this could be a pathway through which the health, lifestyle, or even environment of parents affects the health and development of offspring down the family tree for generations.
Although the changes themselves seem clear, the exact mechanisms at work are not yet fully understood.
Now a new study in roundworms has shown how a common epigenetic modification can be transmitted through three generations via sperm, affecting gene activity and development in the “bastions”.
Although evidence from humans for such persistent 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 embellishments added to DNA that come in various forms and determine when and how genetic instructions are followed.
If the cell’s genome-reading machinery can’t access certain genes because bulky molecules stand in the way, then those genes won’t be decoded into proteins. Wrapping long strands of DNA around major protein complexes called histones in a fairly tight fashion can have a similar, silencing effect.
Most of these epigenetic modifications are believed to be erased and “reset” after fertilization, where sex cells are reprogrammed to ensure normal development. But as animal studies (including a number based on mammals) show, it appears that some epigenetic changes can escape reprogramming and be passed down through generations.
This latter study used C. elegans as a model organism to investigate whether epigenetic marks are maintained or rewritten in roundworm embryos and, if they persist, how these marks affect gene expression in the offspring.
An epigenetic mark on a histone protein that causes DNA to pack more densely, in turn turning off genes in that region, was the focus of the experiments.
The researchers selectively “stripped” this histone mark from its chromosomes C. elegans sperm, which were then used to fertilize eggs with fully marked chromosomes.
They then looked at the levels of gene activity in the resulting offspring and found that the genes on the chromosomes inherited from the sperm were no longer repressed.
“Some genes were aberrantly activated and remained in the state without the repressive mark, while the rest of the genome regained the mark, and this pattern was passed on to the large offspring,” explains Strome.
“We hypothesize that if this DNA packaging pattern is maintained in the germline, it could potentially be transmitted over many generations.”
Let’s not forget, these are roundworms we’re talking about. Previous research in these translucent creatures has shown that epigenetic changes can be passed down for 14 generations, which is wild, but that says little about humans.
Some rare and remarkable human studies have revealed evidence that a grandparent’s access to food affects the health outcomes of their children’s offspring two generations later.
Other research has looked at links between maternal health, including smoking habits, and childhood asthma, or shown how events in early childhood can imprint chemical changes in a person’s DNA that affect their health later in life.
But human studies that make a direct link 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 they yield only correlations, not causation.
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 conditions or environmental conditions that persist over generations?
That’s why animal studies like this one are useful 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 that sperm-inherited histone markers are also a feature of mice.
These parallels may mean that the mechanism can be extended to humans. But there’s still a lot we don’t know about how epigenetic inheritance works across multiple generations, or whether it actually works.
Given the ethical and logistical obstacles to investigating such questions in humans, it may be a long time before we do.
The research was published in PNAS.