Telomere dysfunction impairs epidermal stem cell specification and differentiation by disrupting BMP/pSmad/P63 signaling

Telomere shortening is associated with aging and age-associated diseases. Additionally, telomere dysfunction resulting from telomerase gene mutation can lead to premature aging, such as apparent skin atrophy and hair loss. However, the molecular signaling linking telomere dysfunction to skin atrophy remains elusive. Here we show that dysfunctional telomere disrupts BMP/pSmad/P63 signaling, impairing epidermal stem cell specification and differentiation of skin and hair follicles. We find that telomere shortening mediated by Terc loss up-regulates Follistatin (Fst), inhibiting pSmad signaling and down-regulating P63 and epidermal keratins in an ESC differentiation model as well as in adult development of telomere-shortened mice. Mechanistically, short telomeres disrupt PRC2/H3K27me3-mediated repression of Fst. Our findings reveal that skin atrophy due to telomere dysfunction is caused by a previously unappreciated link with Fst and BMP signaling that could be explored in the development of therapies.端粒（telomere）缩短与衰老及年龄相关疾病密切相关。此外，端粒酶基因突变引发的端粒功能异常可导致早衰，例如显著的皮肤萎缩与脱发。然而，连接端粒功能异常与皮肤萎缩的分子信号通路仍未明确。本研究表明，功能异常的端粒会干扰骨形态发生蛋白/磷酸化Smad/P63信号通路（BMP/pSmad/P63 signaling），损害皮肤及毛囊的表皮干细胞特化与分化过程。研究发现，在胚胎干细胞（ESC）分化模型以及端粒缩短的成年小鼠体内，由端粒酶RNA（Terc）缺失介导的端粒缩短会上调卵泡抑素（Follistatin，Fst）的表达，进而抑制磷酸化Smad信号通路（pSmad signaling），并下调P63与表皮角蛋白的水平。从机制层面来看，短端粒会破坏多梳抑制复合体2/组蛋白H3赖氨酸27三甲基化（PRC2/H3K27me3）介导的卵泡抑素基因抑制作用。本研究结果揭示，端粒功能异常引发的皮肤萎缩，是通过此前未被阐明的卵泡抑素与骨形态发生蛋白信号通路关联所导致的，这一发现可为相关治疗策略的开发提供新的研究方向。