Without altering the genetic code in DNA, epigenetic modifications can alter the way 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 are still poorly understood.
A new study by researchers at UC Santa Cruz shows how a common type of epigenetic modification can be transmitted via sperm not only from parents to offspring, but also to the next generation (“grandchildren”). This is called “transgenerational epigenetic inheritance” and may explain how a person’s health and development can be affected by the experiences of their parents and grandparents.
The study, published the week of September 26 in the Proceedings of the National Academy of Sciences (PNAS), focused on a specific modification of a histone protein that changes the way DNA is packaged in the chromosomes. This widely studied epigenetic mark (dubbed H3K27me3) is known to turn off or “suppress” the affected genes and is found in all multicellular animals – from humans to the nematode worm C. elegans used in this study.
“These findings establish a cause-and-effect relationship between sperm-transmitted histone marks and gene expression and development in offspring and grandchildren,” said corresponding author Susan Strome, professor emeritus of molecular, cellular, and developmental biology at UC Santa Cruz .
Histones are the main proteins involved in packaging DNA in the chromosomes. The epigenetic mark known as H3K27me3 refers to the methylation of a specific amino acid in histone H3. This causes the DNA to pack more tightly, making the genes in that region less accessible for activation.
The new study involved selectively stripping this histone mark from the chromosomes of C. elegans Sperm, which were then used to fertilize eggs with fully marked chromosomes. In the resulting offspring, the researchers observed abnormal patterns of gene expression, in which genes on the paternal chromosomes (inherited from sperm) were turned on, or ‘up-regulated’, when the repressive epigenetic mark was absent.
This caused tissues to activate genes that they would not normally express. For example, germline tissue (which produces eggs and sperm) activated genes that are normally expressed in neurons.
“All of the tissues we analyzed had genes expressed abnormally, but different genes were found in different tissues, showing that tissue context determines which genes were upregulated,” Strome said.
Analysis of the chromosomes in the germline tissue of the offspring revealed that the upregulated genes still lacked the repressive histone tag, while the tagging on the non-upregulated genes had been restored.
“In the germline of the offspring, some genes were turned on incorrectly 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 grandchildren,” Strome explained. “We speculate that if this pattern of DNA packaging persists in the germline, it could potentially be passed through numerous generations.”
In the grandchildren, the researchers observed a range of developmental effects, including some worms that were completely sterile. This mix of results is due to how chromosomes are 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 studied epigenetic inheritance in C. elegans for years, and she said this paper represents the culmination of her work in the field. She noted that other researchers studying mammalian cells in culture reported results very similar to her laboratory’s results in worms, although these studies did not showed transmission over several generations.
“This looks like a conserved trait of gene expression and development in animals, not just a weird worm-specific phenomenon,” she said. “We can do amazing genetic experiments C. elegans This is not possible in humans, and the results of our experiments with worms may have far-reaching implications for other organisms.”
The co-first authors of the paper are Kiyomi Kaneshiro, who worked on the study as a graduate student in Strome’s lab and is currently a postdoctoral fellow at the Buck Institute for Research on Aging, and Thea Egelhofer, a research associate at UCSC. Co-authors also include bioinformatician Andreas Rechtsteiner and graduate student Chad Cockrum (now at IDEXX Laboratories). This work was supported by the National Institutes of Health.
