SIRT6 Controls Hematopoietic Stem Cell Homeostasis through Epigenetic Regulation of Wnt Signaling
SIRT6 Controls Hematopoietic Stem Cell Homeostasis through Epigenetic Regulation of Wnt Signaling
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SIRT6 通过 Wnt 信号传导的表观遗传调控来控制造血干细胞稳态。
DOI：
10.1016/j.stem.2016.03.005
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发表时间：
2016-04-07
期刊：
影响因子：
23.9
通讯作者：
Ju, Zhenyu
中科院分区：
文献类型：
--
作者：
Wang, Hu;Diao, Daojun;Ju, Zhenyu
Wnt信号的适当调节对于维持造血干细胞（HSC）的稳态是至关重要的。HSC中Wnt信号传导的表观遗传调控在很大程度上仍然未知。在这里，我们报告组蛋白去乙酰化酶SIRT6通过Wnt靶基因的转录抑制来调节HSC的稳态。Sirt6缺失通过Wnt信号异常激活促进HSC增殖。SIRT6缺陷的HSC在系列竞争移植试验中表现出受损的自我更新能力。SIRT6通过与转录因子LEF1相互作用并使组蛋白3在赖氨酸56处脱乙酰化来抑制Wnt靶基因的转录。Wnt通路的药理学抑制挽救了SIRT6缺陷型HSC的异常增殖和功能缺陷。总之，这些发现揭示了SIRT6和Wnt信号在调节成体干细胞稳态和自我更新能力中的新联系。
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.