Departments of Biological Chemistry and Medicine, Division of Endocrinology, School of Medicine, University of California, Irvine, Irvine, CA, USA.
Departments of Biological Chemistry and Medicine, Division of Endocrinology, School of Medicine, University of California, Irvine, Irvine, CA, USA; Mathematical, Computational and Systems Biology (MCSB) Program, University of California, Irvine, Irvine, CA, USA.
Stem Cell Reports. 2023 May 9;18(5):1227-1243. doi: 10.1016/j.stemcr.2023.03.013. Epub 2023 Apr 20.
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 Irx5mice. 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.
毛囊周期性激活其干细胞（HFSCs）的分子机制尚未完全阐明。在这里，我们鉴定转录因子 IRX5 为 HFSC 激活的启动子。Irx5 小鼠的毛发生长期延迟，DNA 损伤增加，HFSC 增殖减少。Irx5 HFSCs 中，接近细胞周期进程和 DNA 损伤修复基因的开放染色质区域形成。DNA 损伤修复因子 BRCA1 是 IRX5 的下游靶标。抑制 FGF 激酶信号可部分挽救 Irx5 小鼠的毛发生长期延迟，表明 Irx5 HFSC 静止表型部分归因于未能抑制 Fgf18 的表达。Irx5 小鼠的毛囊间表皮干细胞也表现出增殖减少和 DNA 损伤增加。与 IRX5 作为 DNA 损伤修复促进子的作用一致，我们发现许多癌症类型中 IRX 基因上调，并且在乳腺癌中存在 IRX5 和 BRCA1 表达之间的相关性。
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