PDF(Pubmed)
Abstract：
The molecular mechanisms allowing hair follicles to periodically activate their stem cells (HFSCs) are incompletely characterized. Here, we identify the transcription factor IRX5 as a promoter of HFSC activation. Irx5-/- mice have delayed anagen onset, with increased DNA damage and diminished HFSC proliferation. Open chromatin regions form near cell cycle progression and DNA damage repair genes in Irx5-/- HFSCs. DNA damage repair factor BRCA1 is an IRX5 downstream target. Inhibition of FGF kinase signaling partially rescues the anagen delay in Irx5-/- mice, suggesting that the Irx5-/- HFSC quiescent phenotype is partly due to failure to suppress Fgf18 expression. Interfollicular epidermal stem cells also show decreased proliferation and increased DNA damage in Irx5-/-mice. Consistent with a role for IRX5 as a promoter of DNA damage repair, we find that IRX genes are upregulated in many cancer types and that there is a correlation between IRX5 and BRCA1 expression in breast cancer.
摘要：
允许毛囊周期性地激活其干细胞(HFSC)的分子机制是不完全表征的。这里,我们确定转录因子IRX5是HFSC激活的启动子。Irx5-/-小鼠有延迟的生长期发作，增加的DNA损伤和减少HFSC增殖。在Irx5-/-HFSC中形成接近细胞周期进程和DNA损伤修复基因的开放染色质区。DNA毁伤修复因子BRCA1是IRX5的下游靶点。FGF激酶信号传导的抑制部分挽救了Irx5-/-小鼠的生长期延迟，表明Irx5-/-HFSC静止表型部分是由于未能抑制Fgf18表达。在Irx5-/-小鼠中,滤泡间表皮干细胞也显示增殖减少和DNA损伤增加。与IRX5作为DNA损伤修复的启动子的作用一致，我们发现IRX基因在许多癌症类型中上调，并且在乳腺癌中IRX5和BRCA1表达之间存在相关性。
