PDF(Pubmed)
Abstract：
Epidermal stem cells orchestrate epidermal renewal and timely wound repair through a tight regulation of self-renewal, proliferation, and differentiation. In culture, human epidermal stem cells generate a clonal type referred to as holoclone, which give rise to transient amplifying progenitors (meroclone and paraclone-forming cells) eventually generating terminally differentiated cells. Leveraging single-cell transcriptomic data, we explored the FOXM1-dependent biochemical signals controlling self-renewal and differentiation in epidermal stem cells aimed at improving regenerative medicine applications. We report that the expression of H1 linker histone subtypes decrease during serial cultivation. At clonal level we observed that H1B is the most expressed isoform, particularly in epidermal stem cells, as compared to transient amplifying progenitors. Indeed, its expression decreases in primary epithelial culture where stem cells are exhausted due to FOXM1 downregulation. Conversely, H1B expression increases when the stem cells compartment is sustained by enforced FOXM1 expression, both in primary epithelial cultures derived from healthy donors and JEB patient. Moreover, we demonstrated that FOXM1 binds the promotorial region of H1B, hence regulates its expression. We also show that H1B is bound to the promotorial region of differentiation-related genes and negatively regulates their expression in epidermal stem cells. We propose a novel mechanism wherein the H1B acts downstream of FOXM1, contributing to the fine interplay between self-renewal and differentiation in human epidermal stem cells. These findings further define the networks that sustain self-renewal along the previously identified YAP-FOXM1 axis.
摘要：
表皮干细胞通过严格的自我更新调节协调表皮更新和及时的伤口修复，扩散,和差异化。在文化中,人表皮干细胞产生一种称为全克隆的克隆类型，产生瞬时扩增的祖细胞（meroclone和paraclone形成细胞），最终产生最终分化的细胞。利用单细胞转录组数据，我们探索了FOXM1依赖的控制表皮干细胞自我更新和分化的生化信号,旨在改善再生医学应用.我们报道，H1接头组蛋白亚型的表达在连续培养过程中降低。在克隆水平，我们观察到H1B是表达最多的同工型，特别是在表皮干细胞中，与瞬时放大祖细胞相比。的确,在干细胞耗尽的原代上皮培养物中，由于FOXM1下调，其表达降低。相反，当通过强制FOXM1表达维持干细胞区室时，H1B表达增加，来自健康供体和JEB患者的原发性上皮培养物。此外，我们证明FOXM1结合H1B的启动子区，因此调节其表达。我们还表明，H1B与分化相关基因的启动子区域结合，并负调节其在表皮干细胞中的表达。我们提出了一种新机制，其中H1B在FOXM1下游起作用，有助于人表皮干细胞自我更新和分化之间的精细相互作用。这些发现进一步定义了沿着先前确定的YAP-FOXM1轴维持自我更新的网络。
