Modification of the telomerase gene with human regulatory sequences resets mouse telomeres to human length
Abstract 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 bi...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-02-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-56559-6 |
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| author | Fan Zhang De Cheng Kenneth I. Porter Emily A. Heck Shuwen Wang Hui Zhang Christopher J. Davis Gavin P. Robertson Jiyue Zhu |
| author_facet | Fan Zhang De Cheng Kenneth I. Porter Emily A. Heck Shuwen Wang Hui Zhang Christopher J. Davis Gavin P. Robertson Jiyue Zhu |
| author_sort | Fan Zhang |
| collection | DOAJ |
| description | Abstract 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 h/- mice stabilized telomere length below 10 kb, while Tert h/h mice achieve a human-like average length of 10–12 kb, compared to 50 kb in wildtype mice. Despite shortened telomeres, Tert h/h mice maintain normal body weight and cell homeostasis. These mice, with humanized telomere regulation, represent a valuable model to study human aging and cancer. |
| format | Article |
| id | doaj-art-660f73c576b34318ae803f19ec806dbb |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-660f73c576b34318ae803f19ec806dbb2025-02-09T12:45:09ZengNature PortfolioNature Communications2041-17232025-02-0116111610.1038/s41467-025-56559-6Modification of the telomerase gene with human regulatory sequences resets mouse telomeres to human lengthFan Zhang0De Cheng1Kenneth I. Porter2Emily A. Heck3Shuwen Wang4Hui Zhang5Christopher J. Davis6Gavin P. Robertson7Jiyue Zhu8Department of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Washington State UniversityDepartment of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Washington State UniversityDepartment of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Washington State UniversityDepartment of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Washington State UniversityDepartment of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Washington State UniversityDepartment of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Washington State UniversityDepartment of Translational Medicine and Physiology, Elson S. Floyd College of Medicine, Washington State UniversityDepartment of Pharmacology, Pathology, Dermatology, and Surgery, Pennsylvania State University College of MedicineDepartment of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Washington State UniversityAbstract 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 h/- mice stabilized telomere length below 10 kb, while Tert h/h mice achieve a human-like average length of 10–12 kb, compared to 50 kb in wildtype mice. Despite shortened telomeres, Tert h/h mice maintain normal body weight and cell homeostasis. These mice, with humanized telomere regulation, represent a valuable model to study human aging and cancer.https://doi.org/10.1038/s41467-025-56559-6 |
| spellingShingle | Fan Zhang De Cheng Kenneth I. Porter Emily A. Heck Shuwen Wang Hui Zhang Christopher J. Davis Gavin P. Robertson Jiyue Zhu Modification of the telomerase gene with human regulatory sequences resets mouse telomeres to human length Nature Communications |
| title | Modification of the telomerase gene with human regulatory sequences resets mouse telomeres to human length |
| title_full | Modification of the telomerase gene with human regulatory sequences resets mouse telomeres to human length |
| title_fullStr | Modification of the telomerase gene with human regulatory sequences resets mouse telomeres to human length |
| title_full_unstemmed | Modification of the telomerase gene with human regulatory sequences resets mouse telomeres to human length |
| title_short | Modification of the telomerase gene with human regulatory sequences resets mouse telomeres to human length |
| title_sort | modification of the telomerase gene with human regulatory sequences resets mouse telomeres to human length |
| url | https://doi.org/10.1038/s41467-025-56559-6 |
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