Can Our Lifestyle Choices Biologically Impact Our Grandkids?

For years, it was understood that only traits or characteristics encoded in our DNA sequence could be transmitted to our offspring. Now, a growing field of research suggests that the mechanisms by which our genes are regulated can also be passed down.

Epigenetic changes are chemical processes that can alter gene expression, determining whether a gene is turned “on” or “off” in a specific cell. Such processes are critical for governing a cell’s unique function, as not all genes are required by all cells. Examples of epigenetic marks include DNA methylation, histone modification and non-coding RNA molecules.

Unlike DNA mutations, epigenetic changes can be reversible and often occur in response to stimuli. Examples might include environmental triggers such as chemical or UV light exposure, internal processes such as aging or cancer development and even stressful experiences like trauma.

Epigenetic inheritance – also referred to as transgenerational epigenetic inheritance – explores how epigenetic marks might be inherited by future generations. It has been observed in a variety of different organisms, with recent experiments suggesting that it can occur in humans. While its exact mechanisms are still being explored, it is becoming increasingly clear that epigenetic inheritance could have a significant impact on the way that traits – such as developmental processes, diseases and behaviors – are passed down from one generation to the next.

A recent study published in the Proceedings of the National Academy of Sciences (PNAS) found that epigenetic memories can be transmitted across multiple generations. The research was led by Dr. Susan Strome, professor of molecular, cell and developmental biology at the University of California, Santa Cruz. In Caenorhabditis elegans (C. elegans) models, a commonly used laboratory model, Strome and colleagues studied a histone modification that alters the way DNA is packaged into chromosomes, known as H3K27me3. This modification is well-studied and known to repress genes, turning them “off”, achieved by the methylation of an amino acid in the histone called H3.

The researchers removed this histone mark from sperm cells, which were then used to fertilize eggs that were marked. The offspring demonstrated irregular gene transcription – genes carried on the paternal chromosome were upregulated in the absence of H3K27me3. Gene expression across different tissue types was also found to be abnormal, with genes being expressed in tissues where they would typically be repressed.  

“In the germline of the offspring, some genes were aberrantly turned on and stayed in the state lacking the repressive mark, while the rest of the genome regained the mark,” Strome said. Interestingly, this pattern was also passed on to the grandoffspring – suggesting that epigenetic markers can be transmitted across multiple generations.

In this Ask the Researcher, we spoke with Dr. Strome to learn more about the field of epigenetic inheritance, why her research provides a significant stride forward for the field and what’s next for her lab.

Molly Campbell (MC): Can you talk about why studying the mechanisms involved in transgenerational epigenetic inheritance is challenging?

Susan Strome (SS): There are three possible mechanisms that get the most attention: histone modifications, small RNAs and DNA methylation. Our paper provided evidence for the involvement of a particular histone modification, H3K27me3. A big challenge is that any mechanism that affects gene expression and development across generations must survive the epigenome reprograming that occurs during embryogenesis and germline development.

MC: Your research used the model C. elegans. Can you discuss why you use this model in your lab for this application?

SS: The sophisticated genetics available in C. elegans allowed us to generate worms that inherited sperm chromosomes lacking H3K27me3, and egg chromosomes having their normal pattern of H3K27me3, which was the launchpad for our study.

MC: Why did you focus your studies on one specific epigenetic mark, H3K27me3?

SS: It is conserved across organisms and is one of the few histone modifications that causes (instead of just being correlated with) altered gene expression.

MC: What would you describe as the key finding of this study?

SS: I think the transgenerational (across three generations) influence of sperm marking is the most exciting and important finding in our study.

MC: You describe this publication as a “culmination” of your lab’s work in this area. Can you talk about some of the preceding research that has led to this paper being possible?

SS: We have been studying the roles of H3K27me3 in the germline for years. A 2014 landmark paper from Dr. Laura Gaydos in my lab showed that H3K27me3 marking is transmitted to the embryo from the sperm and the egg and then is maintained faithfully on sperm-derived and egg-derived chromosomes through embryonic cell divisions. Then, in 2019, Dr. Kiyomi Kaneshiro developed the system used in our PNAS paper to study the influence of sperm marking on offspring development.

MC: If gene expression patterns can be passed down multiple generations, what implications might this have across other organisms, such as humans?

SS: Several labs are studying if and how parental diet, stress and trauma influence those parents’ offspring, in mice and other systems as models for humans. There is growing evidence for such influences, although the mechanism(s) remain to be elucidated. My UC Santa Cruz colleague Dr. Upasna Sharma has discovered evidence in mice that the father’s diet influences offspring gene expression and development via small RNAs delivered to the offspring in sperm. This illustrates that histone marking is not the only possible mechanism for sending memories across generations.

MC: What are your next steps in this research space?

SS: I would love to test if sperm marking and gene upregulation can be sent beyond grandoffspring. For technical reasons, we probably will not tackle that.

Dr. Susan Strome was speaking to Molly Campbell, Senior Science Writer for Technology Networks.