Department of Human Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
Faculty of Medicine, Technion - Israel Institute of Technology, Haifa 3200003, Israel.
Mol Cell. 2018 Nov 1;72(3):444-456.e7. doi: 10.1016/j.molcel.2018.09.022. Epub 2018 Oct 25.
Skin sun exposure induces two protection programs: stress responses and pigmentation, the former within minutes and the latter only hours afterward. Although serving the same physiological purpose, it is not known whether and how these programs are coordinated. Here, we report that UVB exposure every other day induces significantly more skin pigmentation than the higher frequency of daily exposure, without an associated increase in stress responses. Using mathematical modeling and empirical studies, we show that the melanocyte master regulator, MITF, serves to synchronize stress responses and pigmentation and, furthermore, functions as a UV-protection timer via damped oscillatory dynamics, thereby conferring a trade-off between the two programs. MITF oscillations are controlled by multiple negative regulatory loops, one at the transcriptional level involving HIF1α and another post-transcriptional loop involving microRNA-148a. These findings support trait linkage between the two skin protection programs, which, we speculate, arose during furless skin evolution to minimize skin damage.
应激反应和色素沉着，前者在数分钟内发生，后者仅在数小时后发生。虽然这两种程序服务于相同的生理目的，但尚不清楚它们是否以及如何协调。在这里，我们报告说，每隔一天接受 UVB 照射会比每天更高的频率产生更显著的皮肤色素沉着，而不会增加应激反应。我们使用数学建模和实证研究表明，黑素细胞主调节因子 MITF 可用于同步应激反应和色素沉着，并且，通过阻尼振荡动力学，它还作为 UV 保护定时器发挥作用，从而在这两个程序之间产生权衡。MITF 振荡受多个负反馈环控制，一个是涉及 HIF1α 的转录水平，另一个是涉及 microRNA-148a 的转录后环。这些发现支持这两种皮肤保护程序之间的特征联系，我们推测，这种联系是在无毛发皮肤进化过程中出现的，以最小化皮肤损伤。
