Zunpeng Liu
Xiaoqian Liu
Si Wang
Yiyuan Zhang
Xiaojuan He
Shuhui Sun
Shuai Ma
Ng Shyh-Chang
Feng Liu
Qiang Wang
Xiaoqun Wang
Lin Liu
Weiqi Zhang
Moshi Song
Guang-Hui Liu
Jing Qu
1 State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China;
2 Advanced Innovation Center for Human Brain Protection, National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing 100053, China;
3 National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China;
4 State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin 300071, China;
5 State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China;
6 University of Chinese Academy of Sciences, Beijing 100049, China;
7 Institute for Stem cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China;
8 Key Laboratory of Regenerative Medicine of Ministry of Education, Institute of Aging and Regenerative Medicine, Jinan University, Guangzhou 510632, China;
9 Beijing Institute for Brain Disorders, Capital Medical University, Beijing 100069, China
Funds: This work was supported by the National Key Research and Development Program of China (2018YFA0107001), the Strategic Priority Research Program of the Chinese Academy of Sciences (XDA16010100), the National Key Research and Development Program of China (2018YFC2000100, 2018YFA0107203, 2017YFA0103304, 2017 YFA0102802, 2015CB964800, 2014CB910503), the National Natural Science Foundation of China (81625009, 81330008, 91749202, 91749123, 31671429, 81671377, 81771515, 31601109, 31601158, 81701388, 81422017, 81601233, 81471414, 81870228, 81822018, 81801399, 31801010, 81801370 and 81861168034), Program of Beijing Municipal Science and Technology Commission (Z151100003915072), Key Research Program of the Chinese Academy of Sciences (KJZDEWTZ-L05), Beijing Municipal Commission of Health and Family Planning (PXM2018_026283_000002), Advanced Innovation Center for Human Brain Protection (117212) and the State Key Laboratory of Membrane Biology.
Received Date: 2018-12-02
Rev Recd Date:2019-01-03
Abstract
Abstract
RAP1 is a well-known telomere-binding protein, but its functions in human stem cells have remained unclear. Here we generated RAP1-deficient human embryonic stem cells (hESCs) by using CRISPR/Cas9 technique and obtained RAP1-deficient human mesenchymal stem cells (hMSCs) and neural stem cells (hNSCs) via directed differentiation. In both hMSCs and hNSCs, RAP1 not only negatively regulated telomere length but also acted as a transcriptional regulator of RELN by tuning the methylation status of its gene promoter. RAP1 deficiency enhanced self-renewal and delayed senescence in hMSCs, but not in hNSCs, suggesting complicated lineage-specific effects of RAP1 in adult stem cells. Altogether, these results demonstrate for the first time that RAP1 plays both telomeric and nontelomeric roles in regulating human stem cell homeostasis.Keywords: RAP1,
stem cell,
telomere,
RELN,
methylation
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