Laboratory of Epithelial Biology, Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI 48109, USA.
Odontology Sciences Postgraduate Program, Dentistry Department, Federal University of Rio Grande do Norte, Natal 59056, RN, Brazil.
Int J Mol Sci. 2020 Jan 30;21(3):901. doi: 10.3390/ijms21030901.
The circadian rhythm regulates the physiology and behavior of living organisms in a time-dependent manner. Clock genes have distinct roles including the control over gene expression mediated by the transcriptional activators CLOCK and BMAL1, and the suppression of gene expression mediated by the transcriptional repressors PER1/2 and CRY1/2. The balance between gene expression and repression is key to the maintenance of tissue homeostasis that is disrupted in the event of an injury. In the skin, a compromised epithelial barrier triggers a cascade of events that culminate in the mobilization of epithelial cells and stem cells. Recruited epithelial cells migrate towards the wound and reestablish the protective epithelial layer of the skin. Although we have recently demonstrated the involvement of BMAL and the PI3K signaling in wound healing, the role of the circadian clock genes in tissue repair remains poorly understood. Here, we sought to understand the role of BMAL1 on skin healing in response to injury. We found that genetic depletion of BMAL1 resulted in delayed healing of the skin as compared to wild-type control mice. Furthermore, we found that loss of Bmal1 was associated with the accumulation of Reactive Oxygen Species Modulator 1 (ROMO1), a protein responsible for inducing the production of intracellular reactive oxygen species (ROS). The slow healing was associated with ROS and superoxide dismutase (SOD) production, and pharmacological inhibition of the oxidative stress signaling (ROS/SOD) led to cellular proliferation, upregulation of Sirtuin 1 (SIRT1), and rescued the skin healing phenotype of mice. Overall, our study points to BMAL1 as a key player in tissue regeneration and as a critical regulator of ROMO1 and oxidative stress in the skin.
昼夜节律以时间依赖的方式调节生物体的生理和行为。时钟基因具有不同的作用，包括对转录激活因子 CLOCK 和 BMAL1 介导的基因表达的控制，以及对转录抑制因子 PER1/2 和 CRY1/2 介导的基因表达的抑制。基因表达和抑制之间的平衡是维持组织内稳态的关键，而组织内稳态在受到损伤时会被打破。在皮肤中，受损的上皮屏障会引发一系列事件，最终导致上皮细胞和干细胞的动员。募集的上皮细胞向伤口迁移，并重新建立皮肤的保护性上皮层。尽管我们最近已经证明了 BMAL 和 PI3K 信号通路在伤口愈合中的参与，但昼夜节律钟基因在组织修复中的作用仍知之甚少。在这里，我们试图了解 BMAL1 在皮肤损伤愈合中的作用。我们发现，与野生型对照小鼠相比，BMAL1 的基因缺失导致皮肤愈合延迟。此外，我们发现 Bmal1 的缺失与活性氧调节剂 1（ROMO1）的积累有关，ROMO1 是一种负责诱导细胞内活性氧（ROS）产生的蛋白质。愈合缓慢与 ROS 和超氧化物歧化酶（SOD）的产生有关，氧化应激信号（ROS/SOD）的药理学抑制导致细胞增殖、Sirtuin 1（SIRT1）的上调，并挽救了 小鼠的皮肤愈合表型。总的来说，我们的研究表明 BMAL1 是组织再生的关键参与者，也是皮肤中 ROMO1 和氧化应激的关键调节因子。
