Protein Cell. 2019 Feb 22. doi: 10.1007/s13238-019-0610-7. [Epub ahead of print]

Telomere-dependent and telomere-independent roles of RAP1 in regulating human stem cell homeostasis.

Zhang X^1,2,3, Liu Z^1,3, Liu X¹, Wang S^2,4,5, Zhang Y^4,3, He X², Sun S⁴, Ma S⁴, Shyh-Chang N^1,3,5, Liu F^6,3,5, Wang Q^6,3,5, Wang X^4,3,5, Liu L⁷, Zhang W^8,9,10,11, Song M^12,13,14, Liu GH^{15,16,17,18,19,20}, Qu J^21,22,23.

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.