In vivo transcriptional governance of hair follicle stem cells by canonical Wnt regulators.
In vivo transcriptional governance of hair follicle stem cells by canonical Wnt regulators.
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DOI：
10.1038/ncb2903
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发表时间：
2014-02
影响因子：
21.3
通讯作者：
中科院分区：
文献类型：
--
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毛囊干细胞（HFSC）响应Wnt信号而再生毛发。在这里，我们展开全基因组的β-连环蛋白-TCF 3/4-TLE电路的转录和染色质景观，并从遗传学上剖析其在天然HFSC生态位中的生物学作用。我们发现在HFSC静止期，TCF 3，TCF 4和TLE（Groucho）协同结合并转录抑制Wnt靶基因。我们还发现β-连环蛋白对HFSC的存活率有抑制作用，如果TCF 3/4水平充分降低，它对HFSC的增殖也有抑制作用。然而，β-连环蛋白对于激活启动毛囊命运和抑制皮脂细胞命运决定的基因至关重要。TCF 3/4缺陷模拟这些毛囊命运靶点的Wnt-β-连环蛋白依赖性激活; TCF 3过表达与它们的TLE 4依赖性抑制平行。我们的研究揭示了TCF 3/4-TLE组蛋白去乙酰化酶作为一种抑制性变阻器，其作用可以通过Wnt-β-catenin信号转导来缓解。当TCF 3/4和TLE水平高时，HFSCs可以保持干性，但保持静止。当这些水平下降或当Wnt-β-catenin水平上升时，这种平衡被转移，毛发再生开始。
Hair follicle stem cells (HFSCs) regenerate hair in response to Wnt signalling. Here, we unfold genome-wide transcriptional and chromatin landscapes of β-catenin–TCF3/4–TLE circuitry, and genetically dissect their biological roles within the native HFSC niche. We show that during HFSC quiescence, TCF3, TCF4 and TLE (Groucho) bind coordinately and transcriptionally repress Wnt target genes. We also show that β-catenin is dispensable for HFSC viability, and that if TCF3/4 levels are sufficiently reduced, it is dispensable for proliferation. However, β-catenin is essential to activate genes that launch hair follicle fate and suppress sebocyte fate determination. TCF3/4 deficiency mimics Wnt–β-catenin-dependent activation of these hair follicle fate targets; TCF3 overexpression parallels their TLE4-dependent suppression. Our studies unveil TCF3/4–TLE histone deacetylases as a repressive rheostat, whose action can be relieved by Wnt–β-catenin signalling. When TCF3/4 and TLE levels are high, HFSCs can maintain stemness, but remain quiescent. When these levels drop or when Wnt–β-catenin levels rise, this balance is shifted and hair regeneration initiates.
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作者：
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