美国斯坦福大学Steven E. Artandi研究团队发现，TERT的克隆失活损害干细胞竞争。这一研究成果于2024年7月17日在线发表在国际学术期刊《自然》上。
研究人员发现，在含有小鼠精原干细胞（SSC）群体中条件性删除端粒酶逆转录酶（TERT）显著削弱了竞争性克隆形成。通过从Tert基因座进行谱系追踪，研究人员发现表达TERT的SSC会产生长寿命克隆，而TERT的克隆性失活促进了干细胞分化并在全基因组范围内减少开放染色质。这种TERT在竞争性克隆形成中的作用独立于其逆转录酶活性和典型端粒酶复合物。
TERT的失活导致MYC癌基因活性下降，而在TERT删除的SSC群体中转基因表达MYC则能有效恢复克隆形成。这些数据表明TERT在增强干细胞竞争中的催化活性非依赖性要求，揭示了TERT和MYC之间的遗传联系，并暗示高水平TERT的干细胞选择优势有助于在稳态和衰老过程中延长男性生殖系中的端粒。
据悉，端粒酶因其催化端粒延长而与干细胞和癌症密切相关。端粒是保护染色体末端的核蛋白帽。TERT的过表达在无端粒依赖的情况下增强细胞增殖，但至今的功能缺失研究未能证明TERT在干细胞功能中的直接作用。在许多组织中，稳态是由干细胞竞争形成的，这一过程中干细胞根据内在的适应性进行竞争。
附：英文原文
Title: Clonal inactivation of TERT impairs stem cell competition
Author: Hasegawa, Kazuteru, Zhao, Yang, Garbuzov, Alina, Corces, M. Ryan, Neuhfer, Patrick, Gillespie, Victoria M., Cheung, Peggie, Belk, Julia A., Huang, Yung-Hsin, Wei, Yuning, Chen, Lu, Chang, Howard Y., Artandi, Steven E.
Issue&Volume: 2024-07-17
Abstract: Telomerase is intimately associated with stem cells and cancer, because it catalytically elongates telomeres—nucleoprotein caps that protect chromosome ends1. Overexpression of telomerase reverse transcriptase (TERT) enhances the proliferation of cells in a telomere-independent manner2,3,4,5,6,7,8, but so far, loss-of-function studies have provided no evidence that TERT has a direct role in stem cell function. In many tissues, homeostasis is shaped by stem cell competition, a process in which stem cells compete on the basis of inherent fitness. Here we show that conditional deletion of Tert in the spermatogonial stem cell (SSC)-containing population in mice markedly impairs competitive clone formation. Using lineage tracing from the Tert locus, we find that TERT-expressing SSCs yield long-lived clones, but that clonal inactivation of TERT promotes stem cell differentiation and a genome-wide reduction in open chromatin. This role for TERT in competitive clone formation occurs independently of both its reverse transcriptase activity and the canonical telomerase complex. Inactivation of TERT causes reduced activity of the MYC oncogene, and transgenic expression of MYC in the TERT-deleted pool of SSCs efficiently rescues clone formation. Together, these data reveal a catalytic-activity-independent requirement for TERT in enhancing stem cell competition, uncover a genetic connection between TERT and MYC and suggest that a selective advantage for stem cells with high levels of TERT contributes to telomere elongation in the male germline during homeostasis and ageing.
来源：科学网
作者：小柯机器人
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