Volume 26, No 2, Feb 2016
ISSN: 1001-0602
EISSN: 1748-7838 2018
impact factor 17.848*
(Clarivate Analytics, 2019)
Volume 26 Issue 2, February 2016: 190-205 | Open Access
ORIGINAL ARTICLES
SIRT6 safeguards human mesenchymal stem cells from oxidative stress by coactivating NRF2
Huize Pan1,*, Di Guan1,*, Xiaomeng Liu2,*, Jingyi Li2, Lixia Wang1,3,4, Jun Wu5, Junzhi Zhou1, Weizhou Zhang6, Ruotong Ren1,3, Weiqi Zhang1,3, Ying Li1, Jiping Yang1, Ying Hao3,4, Tingting Yuan1, Guohong Yuan1, Hu Wang7, Zhenyu Ju7, Zhiyong Mao8, Jian Li9, Jing Qu4, Fuchou Tang2,10,11,12 and Guang-Hui Liu1,3,12,13
1National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
2Biodynamic Optical Imaging Center, College of Life Sciences, Peking University, Beijing 100871, China
3FSU-CAS Innovation Institute, Foshan, Guangdong 528000, China
4State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
5Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA
6Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
7Institute of Aging Research, Leibniz Link Partner Group on Stem Cell Aging, Hangzhou Normal University School of Medicine, Hangzhou, Zhejiang 310036, China
8School of life sciences and technology, Tongji University, Shanghai 200092, China
9The Key Laboratory of Geriatrics, Beijing Hospital & Beijing Institute of Geriatrics, Ministry of Health, Beijing 100730, China
10Ministry of Education Key Laboratory of Cell Proliferation and Differentiation, Beijing 100871, China
11Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China
12Center for Molecular and Translational Medicine, CMTM, Beijing 100101, China
13Beijing Institute for Brain Disorders, Beijing 100069, China
Correspondence: Guang-Hui Liu, E-mail: ghliu@ibp.ac.cn; Fuchou Tang, E-mail: tangfuchou@pku.edu.cn; Jing Qu,(qujing@ioz.ac.cn)
SIRT6 belongs to the mammalian homologs of Sir2 histone NAD+-dependent deacylase family. In rodents, SIRT6 deficiency leads to aging-associated degeneration of mesodermal tissues. It remains unknown whether human SIRT6 has a direct role in maintaining the homeostasis of mesodermal tissues. To this end, we generated SIRT6 knockout human mesenchymal stem cells (hMSCs) by targeted gene editing. SIRT6-deficient hMSCs exhibited accelerated functional decay, a feature distinct from typical premature cellular senescence. Rather than compromised chromosomal stability, SIRT6-null hMSCs were predominately characterized by dysregulated redox metabolism and increased sensitivity to the oxidative stress. In addition, we found SIRT6 in a protein complex with both nuclear factor erythroid 2-related factor 2 (NRF2) and RNA polymerase II, which was required for the transactivation of NRF2-regulated antioxidant genes, including heme oxygenase 1 (HO-1). Overexpression of HO-1 in SIRT6-null hMSCs rescued premature cellular attrition. Our study uncovers a novel function of SIRT6 in maintaining hMSC homeostasis by serving as a NRF2 coactivator, which represents a new layer of regulation of oxidative stress-associated stem cell decay.
10.1038/cr.2016.4
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