Faculty, Staff and Student Publications

Language

English

Publication Date

12-26-2024

Journal

Cell

DOI

10.1016/j.cell.2024.10.007

PMID

39476839

PMCID

PMC11682924

PubMedCentral® Posted Date

12-26-2025

PubMedCentral® Full Text Version

Author MSS

Abstract

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 murine skin. SETDB1 ablation leads to the reactivation of endogenous retroviruses (ERVs, a type of retrotransposon) and the 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 ten-eleven translocation (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.

Keywords

Animals, Endogenous Retroviruses, Mice, Regeneration, Histone-Lysine N-Methyltransferase, Hair Follicle, Stem Cells, Mice, Inbred C57BL, Adult Stem Cells, Virus Activation, DNA Methylation

Published Open-Access

yes

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