1] Howard Hughes Medical Institute, Laboratory of Mammalian Cell Biology and Development, The Rockefeller UniversityNew York New York 10065 USA [2].
Howard Hughes Medical Institute, Laboratory of Mammalian Cell Biology and Development, The Rockefeller UniversityNew York New York 10065 USA.
Nat Cell Biol. 2014 Feb;16(2):179-90. doi: 10.1038/ncb2903. Epub 2014 Jan 26.
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 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.
毛囊干细胞 (HFSCs) 通过 Wnt 信号再生毛发。在这里，我们揭示了 β-catenin-TCF3/4-TLE 电路的全基因组转录和染色质图谱，并在其天然 HFSC 生态位中遗传剖析了它们的生物学作用。我们表明，在 HFSC 静止期间，TCF3、TCF4 和 TLE（Groucho）协调结合并转录抑制 Wnt 靶基因。我们还表明，β-catenin 对于 HFSC 的存活不是必需的，如果 TCF3/4 水平足够降低，则对于增殖也不是必需的。然而，β-catenin 对于激活启动毛囊命运并抑制皮脂腺命运决定的基因是必需的。TCF3/4 缺失模拟了 Wnt-β-catenin 依赖性对这些毛囊命运靶标的激活；TCF3 的过表达与其 TLE4 依赖性抑制平行。我们的研究揭示了 TCF3/4-TLE 组蛋白去乙酰化酶作为一种抑制变阻器，其作用可以通过 Wnt-β-catenin 信号得到缓解。当 TCF3/4 和 TLE 水平较高时，HFSCs 可以维持干细胞特性，但仍处于静止状态。当这些水平下降或当 Wnt-β-catenin 水平上升时，这种平衡被打破，毛发再生开始。
