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

Academic Article

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 HP1a 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.
  • Authors

    Published In

  • Science  Journal
  • Digital Object Identifier (doi)

    Author List

  • Zhang W; Li J; Suzuki K; Qu J; Wang P; Zhou J; Liu X; Ren R; Xu X; Ocampo A
  • Start Page

  • 1160
  • End Page

  • 1163
  • Volume

  • 348
  • Issue

  • 6239