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Open AccessArticle

BMAL1 Modulates Epidermal Healing in a Process Involving the Antioxidative Defense Mechanism

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
The Michigan Medicine Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(3), 901;
Received: 18 December 2019 / Revised: 23 January 2020 / Accepted: 27 January 2020 / Published: 30 January 2020
(This article belongs to the Collection Feature Papers in Molecular Biology)
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 Bmal1−/− 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. View Full-Text
Keywords: ROMO1; clock genes; skin; SOD1; BMAL1 ROMO1; clock genes; skin; SOD1; BMAL1
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Silveira, E.J.D.; Nascimento Filho, C.H.V.; Yujra, V.Q.; Webber, L.P.; Castilho, R.M.; Squarize, C.H. BMAL1 Modulates Epidermal Healing in a Process Involving the Antioxidative Defense Mechanism. Int. J. Mol. Sci. 2020, 21, 901.

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