IRX5 promotes DNA damage repair and activation of hair follicle stem cells [ms_epidermis]. IRX5 promotes DNA damage repair and activation of hair follicle stem cells [ms_epidermis]

Here, we identify the transcription factor IRX5 as a promoter of HFSC activation. Irx5-/- mice display delayed onset of first postnatal anagen, with increased DNA damage and diminished HFSC proliferation. Through transcriptomic and epigenetic analysis, we discover the formation of open chromatin regions near key cell cycle progression- and DNA damage repair genes in Irx5-/- HFSC. We also identify DNA damage repair factors BRCA1 and BARD1 as IRX5 downstream targets. Inhibition of FGF18 kinase signaling partially rescues the anagen delay in Irx5-/- mice, indicating that the Irx5-/- HFSC quiescent phenotype is in part due to failure to suppress Fgf18 expression. Our findings identify IRX5 as a required promoter of DNA damage repair in HFSC activation and hair cycle initiation. Overall design: Whole epidermis from postnatal (P) day 20 Irx5-/- (n=2) and Irx5+/+ (n=2) mice was mechanically and enzymatically dissociated into single cell suspension for bulk RNA sequencing

本研究鉴定出转录因子IRX5可作为毛囊干细胞（Hair Follicle Stem Cells, HFSC）激活的促进因子。Irx5基因敲除（Irx5-/-）小鼠的首次出生后毛囊生长期（anagen）启动延迟，同时伴随DNA损伤水平升高以及毛囊干细胞增殖能力减弱。通过转录组学与表观遗传学分析，我们在Irx5-/-毛囊干细胞中发现，关键细胞周期进程相关基因与DNA损伤修复基因附近形成了开放染色质区域。本研究同时鉴定出DNA损伤修复因子BRCA1与BARD1为IRX5的下游靶标。抑制FGF18激酶信号通路可部分逆转Irx5-/-小鼠的毛囊生长期延迟表型，这表明Irx5-/-毛囊干细胞的静息表型部分源于无法抑制Fgf18的表达。本研究结果证实，IRX5是毛囊干细胞激活与毛囊周期启动过程中DNA损伤修复的必需促进因子。实验设计概况：取出生后第20天（P20）的Irx5-/-（样本量n=2）与Irx5+/+（样本量n=2）小鼠的全表皮组织，通过机械解离与酶解制备单细胞悬液，随后进行批量RNA测序（bulk RNA sequencing）。