IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v16y2025i1d10.1038_s41467-025-56559-6.html
   My bibliography  Save this article

Modification of the telomerase gene with human regulatory sequences resets mouse telomeres to human length

Author

Listed:
  • Fan Zhang

    (Washington State University)

  • De Cheng

    (Washington State University
    Suite 11)

  • Kenneth I. Porter

    (Washington State University)

  • Emily A. Heck

    (Washington State University)

  • Shuwen Wang

    (Washington State University)

  • Hui Zhang

    (Washington State University)

  • Christopher J. Davis

    (Washington State University)

  • Gavin P. Robertson

    (Pennsylvania State University College of Medicine)

  • Jiyue Zhu

    (Washington State University)

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 Terth/- mice stabilized telomere length below 10 kb, while Terth/h mice achieve a human-like average length of 10–12 kb, compared to 50 kb in wildtype mice. Despite shortened telomeres, Terth/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.

Suggested Citation

  • Fan Zhang & De Cheng & Kenneth I. Porter & Emily A. Heck & Shuwen Wang & Hui Zhang & Christopher J. Davis & Gavin P. Robertson & Jiyue Zhu, 2025. "Modification of the telomerase gene with human regulatory sequences resets mouse telomeres to human length," Nature Communications, Nature, vol. 16(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-56559-6
    DOI: 10.1038/s41467-025-56559-6
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-025-56559-6
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-025-56559-6?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Saher Sue Hammoud & David A. Nix & Haiying Zhang & Jahnvi Purwar & Douglas T. Carrell & Bradley R. Cairns, 2009. "Distinctive chromatin in human sperm packages genes for embryo development," Nature, Nature, vol. 460(7254), pages 473-478, July.
    2. Riham Smoom & Catherine Lee May & Vivian Ortiz & Mark Tigue & Hannah M. Kolev & Melissa Rowe & Yitzhak Reizel & Ashleigh Morgan & Nachshon Egyes & Dan Lichtental & Emmanuel Skordalakes & Klaus H. Kaes, 2023. "Telomouse—a mouse model with human-length telomeres generated by a single amino acid change in RTEL1," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    3. Han-Woong Lee & Maria A. Blasco & Geoffrey J. Gottlieb & James W. Horner & Carol W. Greider & Ronald A. DePinho, 1998. "Essential role of mouse telomerase in highly proliferative organs," Nature, Nature, vol. 392(6676), pages 569-574, April.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Grigorios Fanourgakis & Laura Gaspa-Toneu & Pavel A. Komarov & Panagiotis Papasaikas & Evgeniy A. Ozonov & Sebastien A. Smallwood & Antoine H. F. M. Peters, 2025. "DNA methylation modulates nucleosome retention in sperm and H3K4 methylation deposition in early mouse embryos," Nature Communications, Nature, vol. 16(1), pages 1-22, December.
    2. Pasquale Perrone & Gennaro Lettieri & Carmela Marinaro & Valentina Longo & Simonetta Capone & Angiola Forleo & Sebastiana Pappalardo & Luigi Montano & Marina Piscopo, 2022. "Molecular Alterations and Severe Abnormalities in Spermatozoa of Young Men Living in the “Valley of Sacco River” (Latium, Italy): A Preliminary Study," IJERPH, MDPI, vol. 19(17), pages 1-18, September.
    3. Xuedi Zhang & Ju Peng & Menghua Wu & Angyang Sun & Xiangyu Wu & Jie Zheng & Wangfei Shi & Guanjun Gao, 2023. "Broad phosphorylation mediated by testis-specific serine/threonine kinases contributes to spermiogenesis and male fertility," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    4. Tobias T. Schmidt & Carly Tyer & Preeyesh Rughani & Candy Haggblom & Jeffrey R. Jones & Xiaoguang Dai & Kelly A. Frazer & Fred H. Gage & Sissel Juul & Scott Hickey & Jan Karlseder, 2024. "High resolution long-read telomere sequencing reveals dynamic mechanisms in aging and cancer," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    5. Ariane Lismer & Sarah Kimmins, 2023. "Emerging evidence that the mammalian sperm epigenome serves as a template for embryo development," Nature Communications, Nature, vol. 14(1), pages 1-22, December.
    6. Riham Smoom & Catherine Lee May & Vivian Ortiz & Mark Tigue & Hannah M. Kolev & Melissa Rowe & Yitzhak Reizel & Ashleigh Morgan & Nachshon Egyes & Dan Lichtental & Emmanuel Skordalakes & Klaus H. Kaes, 2023. "Telomouse—a mouse model with human-length telomeres generated by a single amino acid change in RTEL1," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    7. Filomena Mazzeo & Rosaria Meccariello, 2023. "Cannabis and Paternal Epigenetic Inheritance," IJERPH, MDPI, vol. 20(9), pages 1-14, April.
    8. Bertrand Theulot & Alan Tourancheau & Emma Simonin Chavignier & Etienne Jean & Jean-Michel Arbona & Benjamin Audit & Olivier Hyrien & Laurent Lacroix & Benoît Tallec, 2025. "Telomere-to-telomere DNA replication timing profiling using single-molecule sequencing with Nanotiming," Nature Communications, Nature, vol. 16(1), pages 1-13, December.
    9. Natthakan Thongon & Feiyang Ma & Andrea Santoni & Matteo Marchesini & Elena Fiorini & Ashley Rose & Vera Adema & Irene Ganan-Gomez & Emma M. Groarke & Fernanda Gutierrez-Rodrigues & Shuaitong Chen & P, 2021. "Hematopoiesis under telomere attrition at the single-cell resolution," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
    10. Carlos Olmeda-Gómez & Carlos Romá-Mateo & Maria-Antonia Ovalle-Perandones, 2019. "Overview of trends in global epigenetic research (2009–2017)," Scientometrics, Springer;Akadémiai Kiadó, vol. 119(3), pages 1545-1574, June.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-56559-6. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.