RAP1 is a well-known telomere-binding protein, but its functions in human stem cells have remained unclea匚 Here we generated RAP1 -deficient human embryonic stem cells (hESCs) by using CRISPR/Cas9 technique and obtai...RAP1 is a well-known telomere-binding protein, but its functions in human stem cells have remained unclea匚 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.展开更多
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)+5 种基金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 Mun icipal 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.
文摘RAP1 is a well-known telomere-binding protein, but its functions in human stem cells have remained unclea匚 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.
