Critically short telomeres derepress retrotransposons to promote genome instability in embryonic stem cells

Nannan Zhao; Guoxing Yin; Chun Liu; Weiyu Zhang; Yang Shen; Dan Wang; Zhenzhen Lin; Jiao Yang; Jian Mao; Renpeng Guo; Yongwang Zhang; Feng Wang; Zhe Liu; Xinyi Lu; Lin Liu

doi:10.1038/s41421-023-00538-y

Critically short telomeres derepress retrotransposons to promote genome instability in embryonic stem cells

Cell Discov. 2023 May 2;9(1):45. doi: 10.1038/s41421-023-00538-y.

Authors

Nannan Zhao^#^{1

2}, Guoxing Yin^#^{1

2}, Chun Liu^#^{1

2}, Weiyu Zhang^{1

3}, Yang Shen⁴, Dan Wang⁵, Zhenzhen Lin⁵, Jiao Yang^{1

2}, Jian Mao^{1

2}, Renpeng Guo^{1

2}, Yongwang Zhang^{1

3}, Feng Wang⁶, Zhe Liu⁷, Xinyi Lu^{8

9}, Lin Liu^{10

11

12

13}

Affiliations

¹ State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, China.
² Frontiers Science Center for Cell Responses, College of Life Sciences, Nankai University, Tianjin, China.
³ College of Pharmacy, Nankai University, Tianjin, China.
⁴ Genome Institute of Singapore, Singapore, Singapore.
⁵ 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Tianjin Key Laboratory of Medical Epigenetics, Department of Immunology, Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.
⁶ Department of Genetics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.
⁷ 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Tianjin Key Laboratory of Medical Epigenetics, Department of Immunology, Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China. zheliu@tmu.edu.cn.
⁸ State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, China. luxy@nankai.edu.cn.
⁹ College of Pharmacy, Nankai University, Tianjin, China. luxy@nankai.edu.cn.
¹⁰ State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, China. liulin@nankai.edu.cn.
¹¹ Frontiers Science Center for Cell Responses, College of Life Sciences, Nankai University, Tianjin, China. liulin@nankai.edu.cn.
¹² Haihe Laboratory of Cell Ecosystem, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China. liulin@nankai.edu.cn.
¹³ Institute of Translational Medicine, Tianjin Union Medical Center, Nankai University, Tianjin, China. liulin@nankai.edu.cn.

^# Contributed equally.

Abstract

Telomeres, at the ends of chromosomes, protect chromosomes from fusion and preserve genomic stability. However, the molecular mechanisms underlying telomere attrition-induced genome instability remain to be understood. We systematically analyzed the expression of retrotransposons and performed genomic sequencing of different cell and tissue types with telomeres of varying lengths due to telomerase deficiency. We found that critically short telomeres altered retrotransposon activity to promote genomic instability in mouse embryonic stem cells, as evidenced by elevated numbers of single nucleotide variants, indels and copy number variations (CNVs). Transpositions of retrotransposons such as LINE1 resulting from the short telomeres can also be found in these genomes with elevated number of mutations and CNVs. Retrotransposon activation is linked to increased chromatin accessibility, and reduced heterochromatin abundance correlates with short telomeres. Re-elongation of telomeres upon recovery of telomerase partly represses retrotransposons and heterochromatin accumulation. Together, our findings suggest a potential mechanism by which telomeres maintain genomic stability by suppressing chromatin accessibility and retrotransposon activity.

Abstract

Grants and funding