Department of Biological Chemistry, University of California, Irvine, CA 92697, USA.
Proc Natl Acad Sci U S A. 2012 Jul 17;109(29):11758-63. doi: 10.1073/pnas.1209592109. Epub 2012 Jul 2.
The role of the circadian clock in skin and the identity of genes participating in its chronobiology remain largely unknown, leading us to define the circadian transcriptome of mouse skin at two different stages of the hair cycle, telogen and anagen. The circadian transcriptomes of telogen and anagen skin are largely distinct, with the former dominated by genes involved in cell proliferation and metabolism. The expression of many metabolic genes is antiphasic to cell cycle-related genes, the former peaking during the day and the latter at night. Consistently, accumulation of reactive oxygen species, a byproduct of oxidative phosphorylation, and S-phase are antiphasic to each other in telogen skin. Furthermore, the circadian variation in S-phase is controlled by BMAL1 intrinsic to keratinocytes, because keratinocyte-specific deletion of Bmal1 obliterates time-of-day-dependent synchronicity of cell division in the epidermis leading to a constitutively elevated cell proliferation. In agreement with higher cellular susceptibility to UV-induced DNA damage during S-phase, we found that mice are most sensitive to UVB-induced DNA damage in the epidermis at night. Because in the human epidermis maximum numbers of keratinocytes go through S-phase in the late afternoon, we speculate that in humans the circadian clock imposes regulation of epidermal cell proliferation so that skin is at a particularly vulnerable stage during times of maximum UV exposure, thus contributing to the high incidence of human skin cancers.
昼夜节律钟在皮肤中的作用及其参与生物钟的基因身份在很大程度上仍是未知的，这促使我们在两个不同的毛发生长周期阶段（休止期和生长期）定义小鼠皮肤的昼夜转录组。休止期和生长期皮肤的昼夜转录组有很大的不同，前者主要由参与细胞增殖和代谢的基因组成。许多代谢基因的表达与细胞周期相关基因呈反相，前者在白天达到峰值，后者在夜间达到峰值。同样，在休止期皮肤中，活性氧（氧化磷酸化的副产物）的积累和 S 期彼此呈反相。此外，S 期的昼夜变化受角质形成细胞内源性的 BMAL1 控制，因为角质形成细胞特异性敲除 Bmal1 会消除表皮细胞分裂的昼夜同步性，导致细胞增殖持续升高。与 S 期细胞对紫外线诱导的 DNA 损伤的敏感性更高一致，我们发现，在夜间，小鼠对 UVB 诱导的表皮 DNA 损伤最为敏感。由于在人类表皮中，大多数角质形成细胞在下午晚些时候进入 S 期，我们推测在人类中，昼夜节律钟对表皮细胞增殖进行调节，使皮肤在紫外线照射最强的时间段处于特别脆弱的阶段，从而导致人类皮肤癌的高发。
