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

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…

• NN
  National Natural Science Foundation of China

  Awards: 81300261, 81271266, 81401159, 81330008, 81471414, 81422017, 81471407, 81371342, 31222039, 81300677, 31322037, 31201111
• CP
  China Postdoctoral Science Foundation

  Award: 2013M530751
• NS
  Natural Science Foundation of Beijing Municipality

  Awards: 5142016, 7141005
• NK
  National Key Research and Development Program of China

  Awards: 2014CB964600, 2015CB964800, 2014CB910500, 2012CB966704