美國斯坦福大學Steven E. Artandi研究團隊發(fā)現(xiàn)，TERT的克隆失活損害干細胞競爭。這一研究成果于2024年7月17日在線發(fā)表在國際學術(shù)期刊《自然》上。
研究人員發(fā)現(xiàn)，在含有小鼠精原干細胞（SSC）群體中條件性刪除端粒酶逆轉(zhuǎn)錄酶（TERT）顯著削弱了競爭性克隆形成。通過從Tert基因座進行譜系追蹤，研究人員發(fā)現(xiàn)表達TERT的SSC會產(chǎn)生長壽命克隆，而TERT的克隆性失活促進了干細胞分化并在全基因組范圍內(nèi)減少開放染色質(zhì)。這種TERT在競爭性克隆形成中的作用獨立于其逆轉(zhuǎn)錄酶活性和典型端粒酶復合物。
TERT的失活導致MYC癌基因活性下降，而在TERT刪除的SSC群體中轉(zhuǎn)基因表達MYC則能有效恢復克隆形成。這些數(shù)據(jù)表明TERT在增強干細胞競爭中的催化活性非依賴性要求，揭示了TERT和MYC之間的遺傳聯(lián)系，并暗示高水平TERT的干細胞選擇優(yōu)勢有助于在穩(wěn)態(tài)和衰老過程中延長男性生殖系中的端粒。
據(jù)悉，端粒酶因其催化端粒延長而與干細胞和癌癥密切相關(guān)。端粒是保護染色體末端的核蛋白帽。TERT的過表達在無端粒依賴的情況下增強細胞增殖，但至今的功能缺失研究未能證明TERT在干細胞功能中的直接作用。在許多組織中，穩(wěn)態(tài)是由干細胞競爭形成的，這一過程中干細胞根據(jù)內(nèi)在的適應性進行競爭。
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.
來源：科學網(wǎng)
作者：小柯機器人
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