美国德克萨斯大学Yejing Ge研究团队发现，干细胞活性与内源性逆转录病毒抑制的结合主导成年组织再生。相关论文于2024年10月29日在线发表在《细胞》杂志上。
研究人员观察到组蛋白甲基转移酶SETDB1（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连。SETDB1缺失导致内源性逆转录病毒（ERV，一种逆转录转座子）的重新激活和类病毒颗粒的组装，导致脱发和干细胞耗竭，这一过程可以通过抗病毒药物逆转。
从机制上看，至少有两条在分子和空间上不同的途径发挥作用：由毛囊干细胞和祖细胞介导的抗病毒防御，以及因转瞬扩增细胞中的复制压力引发的抗病毒独立反应。DNA去甲基化酶TET（ten-eleven translocation ）介导的羟甲基化促进了ERV的重新激活，而通过去除细胞命运转录因子可以再现这一过程。
综合来看，研究人员证明了ERV的沉默与干细胞活性密切相关，并对成年毛发生长至关重要。
据悉，哺乳动物逆转录转座子占基因组的40%。在组织再生过程中，成年干细胞协调抑制逆转录转座子并激活谱系基因，但这种协调的控制机制尚不清楚。
附：英文原文
Title: Stem cell activity-coupled suppression of endogenous retrovirus governs adult tissue regeneration
Author: Ying Lyu, Soo Jin Kim, Ericka S. Humphrey, Richa Nayak, Yinglu Guan, Qingnan Liang, Kun Hee Kim, Yukun Tan, Jinzhuang Dou, Huandong Sun, Xingzhi Song, Priyadharsini Nagarajan, Kamryn N. Gerner-Mauro, Kevin Jin, Virginia Liu, Rehman H. Hassan, Miranda L. Johnson, Lisa P. Deliu, Yun You, Anurag Sharma, H. Amalia Pasolli, Yue Lu, Jianhua Zhang, Vakul Mohanty, Ken Chen, Youn Joo Yang, Taiping Chen, Yejing Ge
Issue&Volume: 2024-10-29
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.
DOI: 10.1016/j.cell.2024.10.007
Source: https://www.cell.com/cell/abstract/S0092-8674(24)01155-3