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.

中文翻译：

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干细胞活性偶联抑制内源性逆转录病毒控制成体组织再生


哺乳动物反转录转座子占基因组的 40%。在组织再生过程中，成体干细胞协调抑制反转录转座子并激活谱系基因，但如何控制这种协调尚不清楚。在这里，我们观察到组蛋白甲基转移酶 SETDB1 （一种反转录转座子阻遏物） 的动态表达与小鼠皮肤中的干细胞活性密切相关。SETDB1 消融导致内源性逆转录病毒（ERV，一种逆转录转座子）的再激活和病毒样颗粒的组装，导致脱发和干细胞耗竭，这些都可以通过抗病毒药物逆转。从机制上讲，至少有两个分子和空间不同的途径是负责的：由毛囊干细胞和祖细胞介导的抗病毒防御，以及由于瞬时扩增细胞中的复制应激引起的抗病毒非依赖性反应。ERV 再激活由 DNA 去甲基化酶 ten-eleven 易位 （TET） 介导的羟甲基化促进，并通过消融细胞命运转录因子概括。我们一起证明了 ERV 沉默与干细胞活性相结合，对成人头发再生至关重要。