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

被引：128

作者：

Wang, Hu ^{[1
]}

Diao, Daojun ^{[1
]}

Shi, Zhencan ^{[1
]}

Zhu, Xudong ^{[1
]}

Gao, Yawei ^{[2
]}

Gao, Shaorong ^{[2
]}

Liu, Xiaoyu ^{[2
]}

Wu, You ^{[2
]}

Rudolph, K. Lenhard ^{[3
]}

Liu, Guanghui ^{[4
]}

Li, Tangliang ^{[1
]}

Ju, Zhenyu ^{[1
]}

机构：

[1] Hangzhou Normal Univ, Sch Med, Inst Aging Res, Hangzhou 311121, Zhejiang, Peoples R China

[2] Tongji Univ, Sch Life Sci & Technol, Shanghai Matern & Infant Hosp 1, Clin & Translat Res Ctr, Shanghai 200092, Peoples R China

[3] Fritz Lipmann Inst eV, Leibniz Inst Aging, Beutenbergstr 11, D-07745 Jena, Germany

[4] Chinese Acad Sci, Inst Biophys, Natl Lab Biomacromol, Beijing 100101, Peoples R China

来源：

CELL STEM CELL | 2016年 / 18卷 / 04期

基金：

中国国家自然科学基金;

关键词：

HISTONE DEACETYLASE SIRT6; SELF-RENEWAL; WNT/BETA-CATENIN; QUIESCENCE; PATHWAY; DIFFERENTIATION; ACTIVATION; RESISTANCE; DEFECTS; IMPAIRS;

D O I：

10.1016/j.stem.2016.03.005

中图分类号：

Q813 [细胞工程];

学科分类号：

100113 [医学细胞生物学];

摘要：

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.

引用

页码：495 / 507

页数：13

共 49 条

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