Scientists show the transmission of epigenetic memory over several generations

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A new research study reveals how a common type of epigenetic modification can be transmitted through sperm not only from parents to offspring, but also to the next generation (“little-offspring”).

Alteration of epigenetic marks on chromosomes leads to altered gene expression in offspring and grandchildren, demonstrating “transgenerational epigenetic inheritance”.

Without changing the genetic code of the DNA, epigenetic modifications can alter the way genes are expressed, affecting the health and development of an organism. It was once a radical idea that such changes in gene expression can be inherited. Today, there is a growing body of evidence behind this, but the mechanisms involved are still poorly understood.

Scientists from the University of California, Santa Cruz show in a new study how a common type of epigenetic modification can be transmitted through sperm not only from parents to offspring, but also to the next generation (“little offspring”). This is called “transgenerational epigenetic inheritance”. This may explain how a person’s health and development can be influenced by the experiences of their parents and grandparents.

Published the week of September 26 in the Proceedings of the National Academy of Sciences (PNAS), the study focused on a particular modification of a histone protein that alters the way DNA is packaged in chromosomes. This widely studied epigenetic mark (called H3K27me3) is known to turn off or “repress” affected genes. It is found in all multicellular animals, from humans to nematode worm C.elegans used in this research.

“These findings establish a causal relationship between sperm-borne histone marks and gene expression and development in offspring and offspring,” said corresponding author Susan Strome. She is Professor Emeritus of Molecular, Cellular, and Developmental Biology at UC Santa Cruz.

Histones are the main proteins involved in the packaging of DNA in chromosomes. The epigenetic mark known as H3K27me3 refers to the methylation of a certain amino acid in histone H3. This results in DNA being more densely packed, making genes in that region less accessible for activation.

C. elegans Embryos

In a study of epigenetic inheritance, researchers created embryos of the worm C. elegans that inherited correctly packaged egg chromosomes with the H3K27me3 epigenetic mark and sperm chromosomes lacking the mark. The single-cell embryo on the left has inherited the pink chromosomes from the egg and the green chromosomes from the sperm, the colors showing the presence or absence of H3K27me3. The two-cell embryo on the right shows the egg and sperm chromosomes joined together in each nucleus. Credit: Photo by Laura Gaydos

In recent work, this histone mark was selectively removed from the chromosomes of C.elegans sperm, which were then used to fertilize eggs with fully labeled chromosomes. In the resulting offspring, the scientists observed abnormal gene expression patterns, with genes on the paternal chromosomes (inherited from sperm) turned on or “upregulated” in the absence of the repressive epigenetic mark.

This resulted in the tissues activating genes that they would not normally express. For example, germline tissue (which produces eggs and sperm) activated genes normally expressed in neurons.

“In all tissues we analyzed, genes were aberrantly expressed, but different genes were detected in different tissues, demonstrating that tissue context determined which genes were upregulated,” Strome said.

Analysis of chromosomes in germline offspring showed that upregulated genes still lacked the repressive histone mark, while the mark was restored on genes that were not upregulated.

“In the germ line of the offspring, some genes were aberrantly activated and remained in the unmarked state, while the rest of the genome regained the mark, and this pattern was passed on to the small offspring” , explained Strome. “We speculate that if this DNA packaging pattern is maintained in the germline, it could potentially be passed on to many generations.”

In the small offspring, the researchers observed a range of developmental effects, including some worms that were completely sterile. This mix of results is due to the way chromosomes are distributed during 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 studied epigenetic inheritance in C.elegans for years, and she said that this document represents the culmination of their work in this area. She noted that other scientists researching cultured mammalian cells have reported results very similar to her lab’s findings on worms, although those studies have not shown multigenerational transmission.

“It looks like a conserved feature of gene expression and development in animals, not just some weird worm-specific phenomenon,” she said. “We can do amazing genetic experiments in C.elegans this cannot be done in humans, and the results of our worm experiments may have broad implications in other organisms.

Reference: “H3K27me3 epialleles inherited from sperm are transmitted transgenerationally in cis” Kiyomi Raye Kaneshiro, Thea A. Egelhofer, Andreas Rechtsteiner, Chad Cockrum and Susan Strome, September 26, 2022, Proceedings of the National Academy of Sciences.
DOI: 10.1073/pnas.2209471119

The paper’s co-first authors 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 research associate UCSC Thea Egelhofer. 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.

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