New study shows transmission of epigenetic memory across generations

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

A new study by researchers at UC Santa Cruz shows how a common type of epigenetic modification can be passed through sperm not only from parents to offspring, but also to the next generation (“little offspring”). This is called “transgenerational epigenetic inheritance,” and it may explain how a person’s health and development might be influenced 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 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 and is found in all multicellular animals, from humans to nematode worms. C.elegans used in this study.

“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, Professor Emeritus of Molecular, Cellular, and Developmental Biology at UC Santa Cruz.

Histones are the main proteins involved in the packaging of DNA into chromosomes. The epigenetic mark known as H3K27me3 refers to the methylation of a particular amino acid in histone H3. This leads to denser packaging of DNA, which makes genes in this region less accessible for activation.

The new study was to selectively remove this histone mark from the chromosomes of C.elegans sperm, which were then used to fertilize eggs with fully labeled chromosomes. In the resulting offspring, the researchers 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 caused the tissues to activate 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 revealed that upregulated genes still lacked the repressive histone mark, while the mark was restored to 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 researchers studying 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.

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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