Epigenetic Inheritance in Nematodes

The memory of a temperature spike can persist for as many as 14 generations in C. elegans.

Jul 17, 2017
Catherine Offord

WARM MEMORIES: Researchers engineered C. elegans with multiple copies of a transgene called mCHERRY connected to a promoter for daf-21. When kept at 25 degrees, the worms began to fluoresce red and had progeny that showed similarly elevated expression of the transgenes, despite never having experienced the higher temperature—an effect that persisted for seven generations. When worms were kept at 25 degrees for five generations, the memory of the heatwave lasted longer, with expression levels taking as many as 14 generations to return to normal.THE SCIENTIST STAFF


The paper
A. Klosin et al., “Transgenerational transmission of environmental information in C. elegans,” Science, 356:320-23, 2017.

When genomicist Ben Lehner and his colleagues at the Centre for Genomic Regulation in Barcelona engineered nematode worms to express a fluorescent reporter, they were hoping to learn about the control of gene expression. Fluorescence indicated activation of the promoter for the gene daf-21, which encodes an essential C. elegans heat-shock protein. Glowing worms meant high expression levels; dull worms, low expression. But during the project, the team stumbled across something else.

“Working with this strain, we noticed that if you had individuals that were brighter, their progeny tended to be brighter,” says Lehner. With lab worms that are genetically identical, “this is something you don’t normally see. There seemed to be inheritance.”

Suspecting they had an epigenetic phenomenon on their hands, and knowing that daf-21 is temperature-sensitive, the researchers decided to grow worms at different temperatures to see if it would affect gene-expression levels through the generations. Sure enough, worms grown at 25 degrees Celsius had offspring that were brighter at normal temperature (20 degrees) than the offspring of worms that had always been kept at 20 degrees.
In worms engineered with multiple copies of the fluorescence transgene, this effect persisted for seven generations after the temperature spike, and even longer when the scientists raised multiple generations at 25 degrees. In one nematode line, the worms’ glow persisted for 14 generations after the temperature had been dialed back to normal.

“The number of generations the worms were kept in high temperatures somehow counted,” says Oded Rechavi, who studies inheritance in C. elegans at Tel Aviv University. “That’s very interesting to see.”

The basis of this inheritance remained unclear, however. DNA methylation is not extensive in C. elegans, but nematode studies by other labs, including Rechavi’s, have shown that small RNAs could mediate epigenetic effects for multiple generations. So the Barcelona team performed a cross between bright and dull worms, expecting the trait to blend in later generations as the RNA became diluted.

But that’s not what happened. In the second generation, some worms were very bright and others were very dull, just like their grandparents—a signature of Mendelian traits, not small RNAs. “Inheritance behaves like a gene,” says Lehner. “Without doing any molecular work, we can see that this is inheritance with a locus.”

Looking more closely, the team found that offspring of worms grown in warmer temperatures showed reduced modification of histone proteins around the transgenes from an early stage of embryonic development. Over generations kept at normal temperature, this histone modification gradually returned to normal, suggesting epigenetic readjustment. These findings, says Rechavi, are “the most surprising and interesting part.”

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