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

Protein Cell. 2019 Sep;10(9):649-667. doi: 10.1007/s13238-019-0610-7. Epub 2019 Feb 22.

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; RELN; methylation; stem cell; telomere.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Adhesion Molecules, Neuronal / metabolism*
  • Extracellular Matrix Proteins / metabolism*
  • Human Embryonic Stem Cells / cytology*
  • Humans
  • Male
  • Mesenchymal Stem Cells / cytology*
  • Methylation
  • Mice, Inbred NOD
  • Mice, SCID
  • Nerve Tissue Proteins / metabolism*
  • Neural Stem Cells / cytology*
  • Reelin Protein
  • Serine Endopeptidases / metabolism*
  • Shelterin Complex
  • Telomere / metabolism*
  • Telomere-Binding Proteins / physiology*

Substances

  • Cell Adhesion Molecules, Neuronal
  • Extracellular Matrix Proteins
  • Nerve Tissue Proteins
  • Reelin Protein
  • Shelterin Complex
  • TERF2IP protein, human
  • Telomere-Binding Proteins
  • RELN protein, human
  • Reln protein, mouse
  • Serine Endopeptidases