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

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 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE227078 | GEO | 2024/10/17

REPOSITORIES: GEO

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Stem Cell Activity-Coupled Suppression of Endogenous Retrovirus Governs Adult Tissue Regeneration

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Project description:The RNA modification N6-methyladenosine (m6A) has critical roles in many biological processes. However, the function of m6A in the early phase of mammalian development remains poorly understood. Here we show that the m6A reader YT521-B homology-domain-containing protein 1 (YTHDC1) is required for the maintenance of mouse embryonic stem (ES) cells in an m6A-dependent manner, and that its deletion initiates cellular reprogramming to a 2C-like state. Mechanistically, YTHDC1 binds to the transcripts of retrotransposons (such as intracisternal A particles, ERVK and LINE1) in mouse ES cells and its depletion results in the reactivation of these silenced retrotransposons, accompanied by a global decrease in SETDB1-mediated trimethylation at lysine 9 of histone H3 (H3K9me3). We further demonstrate that YTHDC1 and its target m6A RNAs act upstream of SETDB1 to repress retrotransposons and Dux, the master inducer of the two-cell stage (2C)-like program. This study reveals an essential role for m6A RNA and YTHDC1 in chromatin modification and retrotransposon repression. This SuperSeries is composed of the SubSeries listed below.

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