Study on endo-siRNAs and the Suppression of Transposon Activity
The lack of DNA methylation and repressive chromatin marks in the mammalian germline leads to the risk of transcriptional activation of transposable elements (TEs).
Now, a new study, using mouse embryonic stem cells (ESCs) to identify an endosiRNA-based mechanism involved in suppression of TE transcription has elucidated the connection between endosiRNAs and the suppression of transposon activity.
Because mammalian germline cells are hard to study, the scientists at the Babraham Institute began their study by using mouse embryonic stem cells (ESCs) that had been genetically modified to lack DNA methylations. These cells mimicked the natural epigenetic reprogramming that occurs in primordial germ cells. Ultimately, the researchers used primordial germ cells to verify the key results from their study of stem cells.
Transposons, also called transposable elements, are ancient viruses that have become a permanent part of our genes. Around half of the human genome is made up of transposons, many are damaged, but some can become active. Active transposons can be harmful because they move about the genome. When transposons move they can damage genes, leading to genetic illnesses and playing a part in some cancers.
Chemical markers in DNA called
methylations can keep transposons inactive. Cells often use methylations to inactivate pieces of DNA, whether they are genes or transposons. Yet, in each new generation, most methylations are temporarily erased and renewed by a process called epigenetic reprogramming. This means that during sperm and egg production there is a short time when methylations do not control transposon activity, leaving them free to damage genes and shuffle DNA.The new findings show that transposons become active when cells erase DNA methylation and they are shut down by the endo-siRNA system. Just like active genes, active transposons produce messages in the form of RNA molecules, which have many similarities to DNA. The study reveals that cells can detect these transposon RNA messages and use them to create specific endogenous small interfering RNAs (endo-siRNAs). The endo-siRNAs then act like a trap allowing a protein called Argonaute2 (Ago2) to seek and destroy transposon messages before they cause any harm.
“Epigenetic reprogramming plays a vital role in wiping the genome clean at the start of development, but it leaves our genes vulnerable,” said the paper’s lead author, Rebecca Berrens. “Understanding the arms race between our genes and transposon activity has been a long-running question in molecular biology. This is the first evidence that endo-siRNAs moderate transposon activity during DNA demethylation. EndosiRNAs provide the first line of defense against transposons during epigenetic reprogramming.”
Senior scientist on the paper, Professor Wolf Reik, Head of the Epigenetics Laboratory at the Babraham Institute, said: “Transposons make up a large part of our genome and keeping them under control is vital for survival. If left unchecked their ability to move around the genome could cause extensive genetic damage. Understanding transposons help us to make sense of what happens when they become active and whether there is anything we can do to prevent it.”
The effects of active transposons vary; often they have no effect and only occasionally will they alter an important gene. Yet, transposons can affect almost any gene, potentially leading to different kinds of genetic disease. Studying the control of transposons, the Babraham Institute noted, adds to our understanding of the many ways that they can impact on human health.