Lyu Ying, Kim Soo Jin, Humphrey Ericka S, Nayak Richa, Guan Yinglu, Liang Qingnan, Kim Kun Hee, Tan Yukun, Dou Jinzhuang, Sun Huandong, Song Xingzhi, Nagarajan Priyadharsini, Gerner-Mauro Kamryn N, Jin Kevin, Liu Virginia, Hassan Rehman H, Johnson Miranda L, Deliu Lisa P, You Yun, Sharma Anurag, Pasolli H Amalia, Lu Yue, Zhang Jianhua, Mohanty Vakul, Chen Ken, Yang Youn Joo, Chen Taiping, Ge Yejing
Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Department of Epigenetics and Molecular Carcinogenesis, UT MD Anderson Cancer Center UTHealth Houston, Houston, TX, USA.
Cell. 2024 Dec 26;187(26):7414-7432.e26. doi: 10.1016/j.cell.2024.10.007. Epub 2024 Oct 29.
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.
哺乳动物逆转录转座子占基因组的40%。在组织再生过程中，成体干细胞协同抑制逆转录转座子并激活谱系基因，但这种协调是如何控制的却知之甚少。在这里，我们观察到组蛋白甲基转移酶SETDB1（一种逆转录转座子抑制因子）的动态表达与小鼠皮肤中的干细胞活性密切相关。SETDB1缺失导致内源性逆转录病毒（ERVs，一种逆转录转座子）重新激活和病毒样颗粒的组装，导致脱发和干细胞耗竭，而抗病毒药物可使其逆转。从机制上讲，至少有两条分子和空间上不同的途径起作用：毛囊干细胞和祖细胞介导的抗病毒防御以及由于短暂扩增细胞中的复制应激导致的抗病毒非依赖性反应。DNA去甲基化酶十-十一易位（TET）介导的羟甲基化促进了ERV的重新激活，并且通过去除细胞命运转录因子得以重现。总之，我们证明了ERV沉默与干细胞活性相关联，并且对成年毛发再生至关重要。
