Epigenetic Marks on Sperm Chromosomes Impact Gene Expression in Offspring

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Scientists at the University of California, Santa Cruz, say they have demonstrated that epigenetic information carried by parental sperm chromosomes can cause changes in gene expression and development in the offspring. Their study (“Sperm-inherited H3K27me3 impacts offspring transcription and development in C. elegans”), published March 20 in Nature Communications, involved a series of experiments using the nematode worm C. elegans.

In their experiments with C. elegans, researchers in the lab of Susan Strome, PhD, have focused on histone marks, modifications to specific amino acids in the tails of histone proteins. Strome, a professor of molecular, cell, and developmental biology, said the new study addressed a central question in the field of epigenetics.

“It’s a very direct question: Does inheriting sperm chromosomes with altered histone packaging of the DNA affect gene expression in the offspring? And the answer is yes,” she said.

“Paternal epigenetic inheritance is gaining attention for its growing medical relevance. However, the form in which paternal epigenetic information is transmitted to offspring and how it influences offspring development remain poorly understood. Here we show that in C. elegans, sperm-inherited chromatin states transmitted to the primordial germ cells in offspring influence germline transcription and development,” the investigators wrote.

“We show that sperm chromosomes inherited lacking the repressive histone modification H3K27me3 are maintained in that state by H3K36me3 antagonism. Inheritance of H3K27me3-lacking sperm chromosomes results in derepression in the germline of somatic genes, especially neuronal genes, predominantly from sperm-inherited alleles. This results in germ cells primed for losing their germ cell identity and adopting a neuronal fate. These data demonstrate that histone modifications are one mechanism through which epigenetic information from a father can shape offspring gene expression and development.”

First author Kiyomi Kaneshiro, a graduate student in Strome’s lab who led the study, said C. elegans is a good model for studying this question because histone packaging is fully retained in the worm’s sperm chromosomes. In humans and other mammals, histone packaging is only partially retained in sperm.

“There is debate over how much histone packaging is retained in humans, but we know it is retained in some developmentally important regions of the genome,” Kaneshiro said.

Researchers have focused on epigenetic inheritance in the paternal line because the sperm contributes little more than its chromosomes to the embryo. The egg contains many other components that may influence the development of the embryo, making it harder to tease out epigenetic effects in the maternal line.

In her experiments, Kaneshiro selectively removed a specific histone mark from sperm chromosomes, then fertilized eggs with the modified sperm and studied the resulting offspring. A crucial innovation was to use sperm and eggs from two different strains of C. elegans, which enabled Kaneshiro to distinguish between the chromosomes inherited from the sperm and those inherited from the egg. She chose worm strains from Britain and Hawaii that had evolved separately long enough to accumulate single nucleotide polymorphisms.

“The dads were British and the moms were Hawaiian, and there are enough differences between them that we could distinguish between the two parental genomes in the cells of their offspring,” Kaneshiro said. “Through this hybrid system, we were able to see differences in gene expression that were a direct result of the changes in histone marks on the sperm chromosomes.”

Furthermore, those changes in gene expression had developmental consequences. With removal of the histone marks, the sperm chromosomes lost a repressive signal that normally keeps certain genes from being active in the offspring’s germline. Kaneshiro observed that the offspring’s germline cells turned on neuronal genes and began developing into neurons.

The particular histone mark removed in these experiments is a widely studied epigenetic mark found in animals ranging from worms to fruit flies to humans. “This mark is found on the histones that are retained on sperm chromosomes in humans,” Kaneshiro said.

The new findings show that inherited epigenetic marks affect gene expression and development. But the study involved artificially changing the marks on the sperm chromosomes. What remains to be understood is how environmental effects on an adult organism could alter epigenetic marks in its germline cells, making it possible for those environmental effects to be transmitted to subsequent generations.

“Our findings raise the possibility that histone marks are carriers for transgenerational epigenetic inheritance,” Kaneshiro said. “We know that the environment an organism experiences can change gene expression patterns in somatic cells. If it changes gene expression patterns in the germline, we expect that those changes can be inherited, but we haven’t shown that yet.”

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