During early embryonic development, our genome lets down its DNA methylation defenses and becomes vulnerable to rebellious transposable elements (TEs). However, those rebel scum are quickly met with a barrage of endogenous short interfering RNAs (endosiRNAs), all before they realize even realize that “It’s A Trap!”
The mechanism of this cunning tactic employed by our imperial epigenomes was deciphered by the lab of Wolf Reik at the Babraham Institute (UK). Here’s what happened when the talented team probed mouse embryonic stem cells with a combination whole-genome bisulfite sequencing, total RNA-seq, small RNA-seq, and histone modification ChIP-seq:
- To recapitulate a global wave of DNA demethylation, the team employed a conditional Dnmt1 knockout, observing a surge in sense and anti-sense transcription from the now hypomethylated TEs
- Since there is an abundance of sense and antisense transcription, these transcripts can form double stranded RNA and induce an RNA interference (RNAi) response, where DICER will chop them up and generate endosiRNAs
- Immunoprecipitation of ARGONAUTE2 (AGO2), a key part of the RNA-induced silencing complex followed by small RNA-seq revealed that AGO2 binds the endosiRNAs
- Knockdown of either Dicer or Ago2 leads to an increase in TE expression over time, demonstrating that endosiRNAs bound by AGO2 are on a search and destroy mission for their host TE
- There’s also a second line of defense, as ChIP-seq of H3K9me2, H3K9me3, and H3K27me3, which are associated with repression, revealed that chronic repression of TEs depends on these modifications
Overall, these findings describe how a surge in TE expression driven by global demethylation is given away by its antisense transcription, which then sets up a trap to slice and dice TE transcripts before they can wreak havoc. This quick-acting endosiRNA trap is also complemented in the long-term by repressive histone modifications.
First author Rebecca Berrens shares, “Epigenetic reprogramming plays a vital role in wiping the genome clean at the start of development, but it leaves our genes vulnerable. 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 endosiRNAs moderate transposon activity during DNA demethylation. EndosiRNAs provide a first line of defence against transposons during epigenetic reprogramming.”
Senior Author Wolf Reik concludes, “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 helps us to make sense of what happens when they become active and whether there is anything we can do to prevent it.”
Go fall into this trap over at Cell Stem Cell, November 2017