Department of Biological Chemistry, School of Medicine, University of California, Irvine, CA 92697; and.
Departments of Molecular, Cellular and Developmental Biology and Dermatology, Yale University, New Haven, CT 06520.
Proc Natl Acad Sci U S A. 2014 Jul 15;111(28):10215-20. doi: 10.1073/pnas.1311395111. Epub 2014 Jun 30.
Understanding the epigenetic mechanisms that control the activation of adult stem cells holds the promise of tissue and organ regeneration. Hair follicle stem cells have emerged as a prime model to study stem cell activation. Wnt/β-catenin signaling controls multiple aspects of skin epithelial regeneration, with its excessive activity promoting the hyperactivation of hair follicle stem/progenitor cells and tumorigenesis. The contribution of chromatin factors in regulating Wnt/β-catenin pathway function in these processes is unknown. Here, we show that chromatin effector Pygopus homolog 2 (Pygo2) produced by the epithelial cells facilitates depilation-induced hair regeneration, as well as β-catenin-induced activation of hair follicle stem/early progenitor cells and trichofolliculoma-like skin hyperplasia. Pygo2 maximizes the expression of Wnt/β-catenin targets, but is dispensable for β-catenin-mediated expansion of LIM/homeobox protein Lhx2(+) cells, in the stem/early progenitor cell compartment of the hair follicle. Moreover, β-catenin and Pygo2 converge to induce the accumulation and acetylation of tumor suppressor protein p53 upon the cell cycle entry of hair follicle early progenitor cells and in cultured keratinocytes. These findings identify Pygo2 as an important regulator of Wnt/β-catenin function in skin epithelia and p53 activation as a prominent downstream event of β-catenin/Pygo2 action in stem cell activation.
了解控制成体干细胞激活的表观遗传机制有望实现组织和器官再生。毛囊干细胞已成为研究干细胞激活的主要模型。Wnt/β-catenin 信号通路控制着皮肤上皮细胞再生的多个方面，其过度活跃会促进毛囊干细胞/祖细胞的过度激活和肿瘤发生。染色质因子在调节这些过程中 Wnt/β-catenin 通路功能中的贡献尚不清楚。在这里，我们表明，由上皮细胞产生的染色质效应因子 Pygopus 同源物 2（Pygo2）促进了脱毛诱导的毛发再生，以及β-catenin 诱导的毛囊干细胞/早期祖细胞激活和毛滤泡样皮肤过度增生。Pygo2 最大限度地表达 Wnt/β-catenin 靶标，但在毛囊干细胞/早期祖细胞区室中对β-catenin 介导的 LIM/homeobox 蛋白 Lhx2(+)细胞扩增是可有可无的。此外，β-catenin 和 Pygo2 会在毛囊早期祖细胞进入细胞周期时，以及在培养的角质形成细胞中，共同诱导肿瘤抑制蛋白 p53 的积累和乙酰化。这些发现表明 Pygo2 是皮肤上皮细胞中 Wnt/β-catenin 功能的重要调节剂，并且 p53 激活是β-catenin/Pygo2 作用于干细胞激活中的突出下游事件。
