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

1. Weiqi Zhang1,*, 
2. Jingyi Li2,*, 
3. Keiichiro Suzuki3,*, 
4. Jing Qu4,*, 
5. Ping Wang1, 
6. Junzhi Zhou1, 
7. Xiaomeng Liu2,
8. Ruotong Ren1, 
9. Xiuling Xu1, 
10. Alejandro Ocampo3, 
11. Tingting Yuan1, 
12. Jiping Yang1, 
13. Ying Li1, 
14. Liang Shi6, 
15. Dee Guan1,
16. Huize Pan1, 
17. Shunlei Duan1, 
18. Zhichao Ding1, 
19. Mo Li3, 
20. Fei Yi5, 
21. Ruijun Bai4, 
22. Yayu Wang6, 
23. Chang Chen1, 
24. Fuquan Yang1,
25. Xiaoyu Li7, 
26. Zimei Wang8, 
27. Emi Aizawa3, 
28. April Goebl3,9, 
29. Rupa Devi Soligalla3, 
30. Pradeep Reddy3,
31. Concepcion Rodriguez Esteban3, 
32. Fuchou Tang2,10,11,12,†, 
33. Guang-Hui Liu1,8,11,13,†,
34. Juan Carlos Izpisua Belmonte3,†

+Author Affiliations

1. ¹National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
2. ²Biodynamic Optical Imaging Center, College of Life Sciences, Peking University, Beijing 100871, China.
3. ³Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
4. ⁴State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
5. ⁵Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA.
6. ⁶Diagnosis and Treatment Center for Oral Disease, the 306th Hospital of the PLA, Beijing, China.
7. ⁷College of Life Sciences, Peking University, Beijing 100871, China.
8. ⁸The Center for Anti-aging and Regenerative Medicine, Shenzhen University, Shenzhen 518060, China.
9. ⁹Universidad Católica San Antonio de Murcia, Campus de los Jerónimos s/n, 30107 Guadalupe, Murcia, Spain.
10. ¹⁰Ministry of Education Key Laboratory of Cell Proliferation and Differentiation, Beijing 100871, China.
11. ¹¹Center for Molecular and Translational Medicine (CMTM), Beijing 100101, China.
12. ¹²Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China.
13. ¹³Beijing Institute for Brain Disorders, Beijing100069, China.

1. ↵†Corresponding author. E-mail: ghliu@ibp.ac.cn (G.-H.L.); tangfuchou@pku.edu.cn (F.T.); belmonte@salk.edu (J.C.I.B.)

1. ↵* These authors contributed equally to this work.

• 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.