机构：[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首都医科大学宣武医院衰老与再生研究中心[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
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.
基金：
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.
第一作者机构：[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[6]University of Chinese Academy of Sciences, Beijing 100049, China
共同第一作者：
通讯作者：
推荐引用方式(GB/T 7714)：
Xing Zhang,Zunpeng Liu,Xiaoqian Liu,et al.Telomere-dependent and telomere-independent roles of RAP1 in regulating human stem cell homeostasis.[J].PROTEIN & CELL.2019,10(9):649-667.doi:10.1007/s13238-019-0610-7.
APA：
Xing Zhang,Zunpeng Liu,Xiaoqian Liu,Si Wang,Yiyuan Zhang...&Jing Qu.(2019).Telomere-dependent and telomere-independent roles of RAP1 in regulating human stem cell homeostasis..PROTEIN & CELL,10,(9)
MLA：
Xing Zhang,et al."Telomere-dependent and telomere-independent roles of RAP1 in regulating human stem cell homeostasis.".PROTEIN & CELL 10..9(2019):649-667
