Stem Cell Activity-Coupled Suppression of Endogenous Retrovirus Governs Adult Tissue Regeneration [ATAC-seq]

Mammalian retrotransposons constitute 40% of the genome. During tissue regeneration, adult stem cells coordinately repress retrotransposons and activate lineage genes, but how this coordination is controlled is poorly understood. Here, we observed that dynamic expression of histone methyltransferase SETDB1 (a retrotransposon repressor) closely mirrors stem cell activities in the murine skin. SETDB1 ablation leads to reactivation of endogenous retroviruses (ERVs, a type of retrotransposon) and assembly of viral-like particles, resulting in hair loss and stem cell exhaustion that is reversible by antiviral drugs. Mechanistically, at least two molecularly and spatially distinct pathways are responsible: antiviral defense mediated by hair follicle stem cells and progenitors, and antiviral independent response due to replication stress in transient amplifying cells. ERV reactivation is promoted by DNA demethylase TET-mediated hydroxymethylation and recapitulated by ablating cell fate transcription factors. Together, we demonstrated ERV silencing is coupled with stem cell activity and essential for adult hair regeneration. Overall design: The assay for transposase-accessible chromatin with sequencing (ATAC-Seq) for skin anagen hair follicle cells from P30 Setdb1 heterozygous (Het) and P30 conditional knock-out (cKO) mice. The assay for transposase-accessible chromatin with sequencing (ATAC-Seq) for hair follicle stem cells from second telogen skin of Setdb1 heterozygous (Het) and conditional knock-out (cKO) mice.