Brain and muscle Arnt-like protein-1 (BMAL1) controls circadian cell proliferation and susceptibility to UVB-induced DNA damage in the epidermis
Brain and muscle Arnt-like protein-1 (BMAL1) controls circadian cell proliferation and susceptibility to UVB-induced DNA damage in the epidermis
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DOI：
10.1073/pnas.1209592109
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发表时间：
2012-07-17
影响因子：
11.1
通讯作者：
Andersen, Bogi
中科院分区：
文献类型：
--
作者：
Geyfman, Mikhail;Kumar, Vivek;Andersen, Bogi
生物钟在皮肤中的作用以及参与其生物钟学的基因身份在很大程度上仍然未知，这促使我们确定毛发生长周期两个不同阶段（休止期和生长期）小鼠皮肤的生物钟转录组。休止期和生长期皮肤的生物钟转录组有很大差异，前者主要由参与细胞增殖和代谢的基因主导。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。一致地，活性氧（氧化磷酸化的副产物）的积累和S期在休止期皮肤中彼此呈反相。此外，S期的生物钟变化由角质形成细胞内在的BMAL1控制，因为角质形成细胞特异性缺失Bmal1会消除表皮中细胞分裂的时间依赖性同步性，导致细胞增殖持续升高。与S期细胞对紫外线诱导的DNA损伤具有更高的敏感性一致，我们发现小鼠在夜间对紫外线B诱导的表皮DNA损伤最为敏感。因为在人类表皮中，最多数量的角质形成细胞在下午晚些时候经历S期，我们推测在人类中，生物钟对表皮细胞增殖进行调节，使得皮肤在紫外线暴露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病率。
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.