title: SIRT6 Controls Hematopoietic Stem Cell Homeostasis through Epigenetic Regulation of Wnt Signaling.
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.
authors.affiliation: Institute of Aging Research, Hangzhou Normal University School of Medicine, Hangzhou 311121, China. Electronic address: wanghu19860315@163.com.
authors.forename: Hu
authors.initials: H
authors.lastname: Wang
authors.affiliation: Institute of Aging Research, Hangzhou Normal University School of Medicine, Hangzhou 311121, China.
authors.forename: Daojun
authors.initials: D
authors.lastname: Diao
authors.affiliation: Institute of Aging Research, Hangzhou Normal University School of Medicine, Hangzhou 311121, China.
authors.forename: Zhencan
authors.initials: Z
authors.lastname: Shi
authors.affiliation: Institute of Aging Research, Hangzhou Normal University School of Medicine, Hangzhou 311121, China.
authors.forename: Xudong
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China.
authors.forename: Yawei
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China.
authors.forename: Shaorong
authors.initials: S
authors.lastname: Gao
authors.affiliation: Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China.
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Liu
authors.affiliation: Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China.
authors.forename: You
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Leibniz Institute on Aging, Fritz Lipmann Institute e.V., Beutenbergstrasse 11, 07745 Jena, Germany.
authors.forename: K Lenhard
authors.initials: KL
authors.lastname: Rudolph
authors.affiliation: National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Guanghui
authors.initials: G
authors.lastname: Liu
authors.affiliation: Institute of Aging Research, Hangzhou Normal University School of Medicine, Hangzhou 311121, China.
authors.forename: Tangliang
authors.initials: T
authors.lastname: Li
authors.affiliation: Institute of Aging Research, Hangzhou Normal University School of Medicine, Hangzhou 311121, China. Electronic address: zhenyuju@163.com.
authors.forename: Zhenyu
authors.initials: Z
authors.lastname: Ju
mesh_terms: D000818:Animals; D044127:Epigenesis, Genetic; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D006706:Homeostasis; D051379:Mice; D008810:Mice, Inbred C57BL; D037761:Sirtuins / Q000378:metabolism*; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D060449:Wnt Signaling Pathway
chemical_list: D051153:Wnt Proteins; C501860:Sirt6 protein, mouse; D037761:Sirtuins
keywords: SIRT6; Wnt; epigenetic modification; hematopoietic stem cell