Aging stem cells. A Werner syndrome stem cell model unveils heterochromatin alterations as a driver of human aging

Science. 2015 Jun 5;348(6239):1160-3. doi: 10.1126/science.aaa1356. Epub 2015 Apr 30.

Abstract

Werner syndrome (WS) is a premature aging disorder caused by WRN protein deficiency. Here, we report on the generation of a human WS model in human embryonic stem cells (ESCs). Differentiation of WRN-null ESCs to mesenchymal stem cells (MSCs) recapitulates features of premature cellular aging, a global loss of H3K9me3, and changes in heterochromatin architecture. We show that WRN associates with heterochromatin proteins SUV39H1 and HP1α and nuclear lamina-heterochromatin anchoring protein LAP2β. Targeted knock-in of catalytically inactive SUV39H1 in wild-type MSCs recapitulates accelerated cellular senescence, resembling WRN-deficient MSCs. Moreover, decrease in WRN and heterochromatin marks are detected in MSCs from older individuals. Our observations uncover a role for WRN in maintaining heterochromatin stability and highlight heterochromatin disorganization as a potential determinant of human aging.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / genetics
  • Aging / metabolism*
  • Animals
  • Cell Differentiation
  • Cellular Senescence*
  • Centromere / metabolism
  • Chromosomal Proteins, Non-Histone / metabolism
  • DNA-Binding Proteins / metabolism
  • Epigenesis, Genetic
  • Exodeoxyribonucleases / genetics
  • Exodeoxyribonucleases / metabolism*
  • Gene Knockout Techniques
  • HEK293 Cells
  • Heterochromatin / chemistry
  • Heterochromatin / metabolism*
  • Humans
  • Membrane Proteins / metabolism
  • Mesenchymal Stem Cells / metabolism*
  • Methyltransferases / genetics
  • Methyltransferases / metabolism
  • Mice
  • Models, Biological
  • RecQ Helicases / genetics
  • RecQ Helicases / metabolism*
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism
  • Werner Syndrome / genetics
  • Werner Syndrome / metabolism*
  • Werner Syndrome Helicase

Substances

  • Chromosomal Proteins, Non-Histone
  • DNA-Binding Proteins
  • Heterochromatin
  • Membrane Proteins
  • Repressor Proteins
  • lamina-associated polypeptide 2
  • heterochromatin-specific nonhistone chromosomal protein HP-1
  • SUV39H1 protein, human
  • Methyltransferases
  • Exodeoxyribonucleases
  • RecQ Helicases
  • WRN protein, human
  • Werner Syndrome Helicase