Zhang Fan, Cheng De, Porter Kenneth I, Heck Emily A, Wang Shuwen, Zhang Hui, Davis Christopher J, Robertson Gavin P, Zhu Jiyue
Department of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, WA, 99202, USA.
268 Linxin Road, Suite 11, Shanghai, 200335, China.
Nat Commun. 2025 Feb 4;16(1):1211. doi: 10.1038/s41467-025-56559-6.
Telomeres shorten with each cell division, serving as biomarkers of aging, with human tissues exhibiting short telomeres and restricted telomerase expression. In contrast, mice have longer telomeres and widespread telomerase activity, limiting their relevance as models for human telomere biology. To address this, we engineer a mouse strain with a humanized mTert gene (hmTert), replacing specific non-coding sequences with human counterparts. The hmTert gene, which is repressed in adult tissues except the gonads and thymus, closely mimics human TERT regulation. This modification rescues telomere dysfunction in mTert-knockout mice. Successive intercrosses of Tert mice stabilized telomere length below 10 kb, while Tert mice achieve a human-like average length of 10-12 kb, compared to 50 kb in wildtype mice. Despite shortened telomeres, Tert mice maintain normal body weight and cell homeostasis. These mice, with humanized telomere regulation, represent a valuable model to study human aging and cancer.
端粒会随着每次细胞分裂而缩短，作为衰老的生物标志物，人体组织表现出短端粒和有限的端粒酶表达。相比之下，小鼠具有更长的端粒和广泛的端粒酶活性，这限制了它们作为人类端粒生物学模型的相关性。为了解决这个问题，我们构建了一种带有人类化mTert基因（hmTert）的小鼠品系，用人类对应序列替换特定的非编码序列。hmTert基因在除性腺和胸腺外的成年组织中受到抑制， closely mimics human TERT regulation. 这种修饰挽救了mTert基因敲除小鼠的端粒功能障碍。Tert小鼠的连续回交使端粒长度稳定在10 kb以下，而Tert小鼠的平均长度达到10 - 12 kb，类似于人类，而野生型小鼠为50 kb。尽管端粒缩短，但Tert小鼠保持正常体重和细胞内稳态。这些具有人类化端粒调控的小鼠是研究人类衰老和癌症的宝贵模型。 （原文中“closely mimics human TERT regulation”表述似乎有误，可能影响准确理解，以上译文按正确逻辑翻译了大部分内容）
