Humanization of the mouse Tert gene reset telomeres to human length.
De ChengFan ZhangKenneth I PorterShuwen WangHui ZhangChristopher J DavisGavin P RobertsonJiyue ZhuPublished in: Research square (2024)
Telomeres undergo shortening with each cell division, serving as biomarkers of human aging, which is characterized by short telomeres and restricted telomerase expression in adult tissues. Contrarily, mice, featuring their longer telomeres and widespread telomerase activity, present limitations as models for understanding telomere-related human biology and diseases. To bridge this gap, we engineered a mouse strain with a humanized mTert gene, hmTert , wherein specific non-coding sequences were replaced with their human counterparts. The hmTert gene, encoding the wildtype mTert protein, was repressed in adult tissues beyond the gonads and thymus, closely resembling the regulatory pattern of the human TERT gene. Remarkably, the hmTert gene rescued telomere dysfunction in late generations of mTert -knockout mice. Through successive intercrosses of Tert h /- mice, telomere length progressively declined, stabilizing below 10-kb. Tert h/h mice achieved a human-like average telomere length of 10-12 kb, contrasting with the 50-kb length in wildtype C57BL/6J mice. Despite shortened telomeres, Tert h/h mice maintained normal body weight and cell homeostasis in highly proliferative tissues. Notably, colonocyte proliferation decreased significantly in Tert h/h mice during dextran sodium sulfate-induced ulcerative colitis-like pathology, suggesting limitations on cellular renewal due to short telomeres. Our findings underscore the genetic determination of telomere homeostasis in mice by the Tert gene. These mice, exhibiting humanized telomere homeostasis, serve as a valuable model for exploring fundamental questions related to human aging and cancer.
Keyphrases
- endothelial cells
- high fat diet induced
- induced pluripotent stem cells
- genome wide
- pluripotent stem cells
- copy number
- gene expression
- high glucose
- squamous cell carcinoma
- skeletal muscle
- stem cells
- single cell
- oxidative stress
- adipose tissue
- drug induced
- transcription factor
- mesenchymal stem cells
- signaling pathway
- small molecule
- lymph node metastasis
- tandem mass spectrometry