Retrotransposons want to be the life of the party, but mammalian cells need peace and quiet to focus on recovering from an injury. New research shows that without careful coordination by the Setdb1 histone methyltransferase, stem cells become exhausted and the Tet DNA demethylase wakes up endogenous retroviruses (ERVs)—a type of retrotransposon. As a result of the ERV party, mouse skin cells experience inflammation, DNA damage, replication stress, and hair loss.
The talented team of Yejing Ge (University of Texas MD Anderson Cancer Center) wondered how cells keep unwelcome ERVs in check when stem cells help the body heal. It’s complicated—cells have to methylate the DNA of ERVs to make them behave, but demethylate the DNA of lineage genes. H3K9 methylation is also involved, but it’s unclear how. To make sense of it all, the meticulous team conditionally deleted Setdb1, an H3K9 lysine methyltransferase, in mouse skin. Here’s what they found:
- Stem cells in hair follicles become exhausted, with accelerated cell cycles and increased cell death; the mice also lose their hair
- ERVs are active, and cells even have virus-like particles in them
- Treating mice with antiviral drugs improves follicle regeneration and reduces cell death and hair loss
- Some of the effects of Setdb1 deletion are due to inflammation, which is a defense response against ENVs, because knocking out Aim2 partially restores hair cell function
- Other effects are due to an antiviral-independent effect of DNA damage and replication stress in a multipotent cell population derived from stem cells
- ERVs use DNA hydroxymethylation by the DNA demethylase Tet to hijack the host transcription machinery to selfishly get their mRNAs and proteins made
Overall, mouse skin cells put a damper on ERVs when injury occurs so they can regenerate tissue and heal. The researchers detected ERV proteins in other tissues, so they say that the mechanism could be more widespread.
Don’t be late to the party—read more at Cell, October 2024.