A study by researchers at UC Santa Cruz has demonstrated how a common type of epigenetic modification can be transmitted via sperm not only from parents to offspring, but to the next generation (“grandoffspring”). They suggest that this transgenerational epigenetic inheritance may explain how a person’s health and development could be influenced by the experiences of his or her parents and grandparents.

The study focused on a particular modification of a histone protein that changes the way DNA is packaged in the chromosomes. The widely studied epigenetic mark, H3K27me3, is known to turn off or “repress” the affected genes and is found in all multicellular animals—from humans to the nematode worm C. elegans used in the newly reported study.

“These results establish a cause-and-effect relationship between sperm-transmitted histone marks and gene expression and development in offspring and grandoffspring,” said corresponding author Susan Strome, PhD, professor emerita of molecular, cell and developmental biology at UC Santa Cruz. Strome and colleagues reported on their work in PNAS, in a paper titled “Sperm-inherited H3K27me3 epialleles are transmitted transgenerationally in cis,” in which the authors concluded, “we showed that the sperm-inherited pattern of gene marking and gene up-regulation were transmitted to grandoffspring, demonstrating that H3K27me3 marking can serve as a bona fide transgenerational epigenetic carrier in C. elegans.”

Without altering the genetic code in the DNA, epigenetic modifications can change how genes are expressed, affecting an organism’s health and development. The once radical idea that such changes in gene expression can be inherited now has a growing body of evidence behind it, but the mechanisms involved remain poorly understood.

“Studies of humans suggest that various lifestyle and dietary conditions can alter epigenetic information carried in sperm or oocytes, and epigenetic mechanisms underlie links between conditions experienced by parents and the health outcomes of their offspring,” the team wrote. “However, studies of humans are limited in their ability to identify the mechanisms that underlie these processes. Studies in model organisms are illuminating how epigenetic inheritance can shape the development and health of future generations.”

Histones are the main proteins involved in the packaging of DNA in the chromosomes. The epigenetic mark known as H3K27me3 refers to methylation of a particular amino acid in the histone H3. This leads to the DNA being more densely packaged, making the genes in that region less accessible for activation. For their newly reported study, the researchers selectively stripped this histone mark from the chromosomes of C. elegans sperm, which were then used to fertilize eggs with fully marked chromosomes.

The researchers observed that in the resulting offspring there were abnormal gene expression patterns, with genes on the paternal chromosomes (inherited from the sperm) upregulated in the absence of the repressive epigenetic mark. This led to tissues turning on genes that they would not normally express. For example, germline tissue—which produces eggs and sperm—turned on genes normally expressed in neurons.

“In all the tissues we analyzed, genes were aberrantly expressed, but different genes were turned up in different tissues, demonstrating that the tissue context determined which genes were upregulated,” Strome said. The authors further explained, “We found that absence of the conserved repressive mark H3K27me3 from the sperm genome caused upregulation from sperm alleles in offspring somatic and germline tissues, and that tissue context determined which genes were prone to up-regulation.”

Analysis of the chromosomes in the offspring’s germline tissue revealed that the upregulated genes still lacked the repressive histone mark, while the mark had been restored on the genes that were not upregulated. “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, and that pattern was passed on to the grandoffspring,” Strome explained. “We speculate that if this pattern of DNA packaging is maintained in the germline, it could potentially be passed on for numerous generations.”

In the grandoffspring, the researchers observed a range of developmental effects, including some worms that were completely sterile. This mix of outcomes is due to how chromosomes get distributed during the cell divisions that produce sperm and eggs, resulting in many different combinations of chromosomes that can be passed on to the next generation.

Researchers in Strome’s lab have been studying epigenetic inheritance in C. elegans for years, and she said the newly reported research represents the culmination of their work in this area. She noted that other researchers studying mammalian cells in culture have reported results very similar to her lab’s findings in worms, although those studies did not show transmission across multiple generations. The authors stated, “Our findings in worms mirror findings in mammalian cells and implicate a conserved mechanism for chromatin-based regulation between worms and mammals,” the team explained. “This model provides one way in which epigenetic changes to the parental genome can rapidly create epigenetic variation in an otherwise genetically identical population.”

Strome further commented, “This looks like a conserved feature of gene expression and development in animals, not just a weird worm-specific phenomenon. We can do amazing genetic experiments in C. elegans that can’t be done in humans, and the results of our experiments in worms can have broad implications in other organisms.”

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