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Cell Stem Cell. 2016 Apr 7;18(4):495-507. doi: 10.1016/j.stem.2016.03.005.

SIRT6 Controls Hematopoietic Stem Cell Homeostasis through Epigenetic Regulation of Wnt Signaling.

Author information

1
Institute of Aging Research, Hangzhou Normal University School of Medicine, Hangzhou 311121, China. Electronic address: wanghu19860315@163.com.
2
Institute of Aging Research, Hangzhou Normal University School of Medicine, Hangzhou 311121, China.
3
Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China.
4
Leibniz Institute on Aging, Fritz Lipmann Institute e.V., Beutenbergstrasse 11, 07745 Jena, Germany.
5
National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
6
Institute of Aging Research, Hangzhou Normal University School of Medicine, Hangzhou 311121, China. Electronic address: zhenyuju@163.com.

Abstract

Proper regulation of Wnt signaling is critical for the maintenance of hematopoietic stem cell (HSC) homeostasis. The epigenetic regulation of Wnt signaling in HSCs remains largely unknown. Here, we report that the histone deacetylase SIRT6 regulates HSC homeostasis through the transcriptional repression of Wnt target genes. Sirt6 deletion promoted HSC proliferation through aberrant activation of Wnt signaling. SIRT6-deficient HSCs exhibited impaired self-renewal ability in serial competitive transplantation assay. Mechanistically, SIRT6 inhibits the transcription of Wnt target genes by interacting with transcription factor LEF1 and deacetylating histone 3 at lysine 56. Pharmacological inhibition of the Wnt pathway rescued the aberrant proliferation and functional defect in SIRT6-deficient HSCs. Taken together, these findings disclose a new link between SIRT6 and Wnt signaling in the regulation of adult stem cell homeostasis and self-renewal capacity.

KEYWORDS:

SIRT6; Wnt; epigenetic modification; hematopoietic stem cell

PMID:
27058938
DOI:
10.1016/j.stem.2016.03.005
[Indexed for MEDLINE]
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