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Transmission of epigenetic memory across multiple generations

Written by Lauren Robertson, Science Writer.

New research from UC Santa Cruz has shown that transgenerational epigenetic inheritance (the inheritance of epigenetic marks from one generation to the next) is possible in C. elegans worms. The study, published in PNAS, takes us one step closer to understanding how the experiences of our grandparents might, many years later, shape our own health and development.  

The epigenome

Epigenetic modifications (or “marks”) do not alter the DNA code, but they are able to change how a gene is expressed. Because they do not alter the DNA itself, scientists previously thought these epigenetic changes were not transmissible from one generation to the next – in other words, it was believed that these marks could not be inherited. Nowadays, a growing body of evidence suggests this might well be possible. However, the mechanisms of how this would work are still unclear.

To get a better understanding, Susan Strome (Professor Emerita, Department of Molecular, Cell and Developmental Biology) and a team of researchers at UC Santa Cruz decided to take a closer look at how sperm-inherited histone marking shapes offspring gene expression.

The modification they chose to look at was a widely studied epigenetic mark called H3K27me3. This mark is found in all multicellular animals and effects a histone protein that controls how DNA is packaged in chromosomes. The name refers to the specific amino acid in the H3 histone protein that, once methylated, causes DNA to be more densely packaged and leaves the genes less accessible for activation.

Worm’s Eye View

The nematode worm, C. elegans, was chosen as a model organism for the experiments. The researchers started by stripping the histone mark from chromosomes in C. elegans sperm, using them to fertilize eggs, and then studying the resulting offspring.

Figure 1: C. elegans embryos. Researchers created embryos of the worm C. elegans that inherited egg chromosomes properly packaged with the epigenetic mark H3K27me3 and sperm chromosomes lacking the mark. The one-cell embryo on the left inherited the pink chromosomes from the egg and the green chromosomes from the sperm. The colours show the presence or absence of H3K27me3.The two-cell embryo on the right shows the egg and sperm chromosomes united in each nucleus. Credit: Photo by Laura Gaydos.

They found that the offspring exhibited abnormal gene expression patterns. Genes on the paternal chromosomes were upregulated in the absence of the repressive H3K27me3 mark, causing tissues to turn on genes they wouldn’t normally express. For example, germline tissues started expressing neuronal genes.

“In all the tissues we analysed, 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.

Other studies in mammalian cells have shown similar findings, suggesting this is a conserved mechanism for chromatin-based regulation across both worms and mammals. “This looks like a conserved feature of gene expression and development in animals, not just a weird worm-specific phenomenon,” Strome said. “We can do amazing genetic experiments in C. elegans that can’t be done in humans, and the results of our experiments in worms could have broad implications in other organisms.”

Grappling with grandoffspring

Importantly, the team also observed several developmental defects in the next generation, or “grandoffspring,” of the worms – including some worms that were completely sterile. The mix of outcomes is down to how chromosomes are distributed among cells during cell division, which results in many different combinations of chromosomes being passed on to the next generation. This is the first time transgenerational inheritance (or transmission of epigenetic marks across multiple generations) has been demonstrated.

“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.”