The transmission of biological traits from one generation to the next is generally attributed to DNA. But could some changes be passed on without altering the DNA sequence? Scientists at the University of Geneva (UNIGE) have shown that, in nematodes – roundworms with long, thin bodies – a temporary change in gene regulation can persist for many generations, even though the descendants no longer carry the genetic element that initially triggered the change. These findings, published in EMBO Journal, provide new insights into the mechanisms underlying epigenetic inheritance.
Every cell in an organism contains the same DNA, which carries all the instructions needed for it to function. Yet cells do not all use the same genes: a nerve cell, for example, does not activate the same genes as a muscle cell. Epigenetics refers to the mechanisms that allow gene activity to be modulated without changing the DNA sequence.
These mechanisms involve, among other things, subtle and reversible modifications to the proteins that package and organise DNA. They can alter how DNA is organised – but not its content – and affect the accessibility of genes to cellular proteins. Some of these modifications can persist when cells divide and, in some cases, can be passed on to the next generation.
A temporary change with lasting effects
To determine how long an epigenetic change can persist across generations, the team led by Florian Steiner, Professor in the Department of Molecular and Cellular Biology at the UNIGE’s Faculty of Science, studied Caenorhabditis elegans. This tiny worm has become a major model organism in biology, thanks to the many discoveries of fundamental biological mechanisms it has enabled. Its rapid reproduction also makes it possible to follow several generations easily in the laboratory.
The scientists focused on a modification of histones – the proteins around which DNA is wrapped – known as H3K27me3. This epigenetic mark is associated with the repression of certain genes, meaning that it helps prevent them from being expressed. The researchers temporarily disrupted the distribution of H3K27me3 by causing the worms to express a mutated form of the H3.3 histone. This initial disruption led, among other effects, to reduced fertility, from around 300 offspring per parent to 100 or even 50. However, it was not genetically inherited: the descendants were genetically normal. The scientists then followed gene regulation and fertility from one generation to the next.
“Surprisingly, we found that the effects did not disappear when the initial trigger was gone. In the descendants, which were genetically normal, the changes in gene regulation and the fertility defects persisted for at least fifteen generations!” explain Isa Özdemir and François-Xavier Stubbe, respectively a PhD student and a postdoctoral researcher in Prof. Steiner’s group and co-first authors of the study.
The scientists then sought to understand how this information could be maintained for so long. The team identified two mechanisms that act successively. The first is required to establish the new epigenetic state following the initial disruption. The second then allows this state to be maintained across generations. “Our results show that maintaining an epigenetic state relies on a succession of specialised mechanisms, rather than on a single process,” explain Isa Özdemir and François-Xavier Stubbe.
A form of heredity independent of DNA
“A temporary disruption of gene regulation can leave a lasting and transmissible imprint, even though the genetic change that initially caused the disruption has disappeared in the descendants. This type of inheritance could represent an additional mechanism allowing organisms to respond and potentially adapt to changing environmental conditions,” concludes Florian Steiner.