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. 2024 Dec 26;187(26):7414-7432.e26.
doi: 10.1016/j.cell.2024.10.007. Epub 2024 Oct 29.

Stem cell activity-coupled suppression of endogenous retrovirus governs adult tissue regeneration

Ying Lyu  1 , Soo Jin Kim  2 , Ericka S Humphrey  3 , Richa Nayak  3 , Yinglu Guan  1 , Qingnan Liang  4 , Kun Hee Kim  5 , Yukun Tan  4 , Jinzhuang Dou  4 , Huandong Sun  6 , Xingzhi Song  6 , Priyadharsini Nagarajan  7 , Kamryn N Gerner-Mauro  8 , Kevin Jin  9 , Virginia Liu  9 , Rehman H Hassan  1 , Miranda L Johnson  1 , Lisa P Deliu  1 , Yun You  1 , Anurag Sharma  10 , H Amalia Pasolli  10 , Yue Lu  2 , Jianhua Zhang  6 , Vakul Mohanty  4 , Ken Chen  5 , Youn Joo Yang  1 , Taiping Chen  11 , Yejing Ge  12
Affiliations

Stem cell activity-coupled suppression of endogenous retrovirus governs adult tissue regeneration

Ying Lyu et al. Cell. .

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: DNA demethylation; adult stem cells; antiviral response; endogenous retroviruses; hair follicle stem cell exhaustion; hair loss; heterochromatin; replication stress; retrotransposons; skin.

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Conflict of interest statement

Declaration of interests The authors declare no competing interests.

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