Aging stem cells. A Werner syndrome stem cell model unveils heterochromatin alterations as a driver of human aging.
Détails
ID Serval
serval:BIB_7E1288D26ABF
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
Aging stem cells. A Werner syndrome stem cell model unveils heterochromatin alterations as a driver of human aging.
Périodique
Science
ISSN
1095-9203 (Electronic)
ISSN-L
0036-8075
Statut éditorial
Publié
Date de publication
05/06/2015
Peer-reviewed
Oui
Volume
348
Numéro
6239
Pages
1160-1163
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Publication Status: ppublish
Résumé
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.
Mots-clé
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 Stromal 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
Pubmed
Web of science
Création de la notice
14/08/2018 10:34
Dernière modification de la notice
20/08/2019 15:39