Periodic Reporting for period 3 - UVdynamicsProtection (Aligning pigmentation and repair: a holistic approach for UV protection dynamics)
Reporting period: 2020-04-01 to 2021-09-30
Since these two systems serve the same physiological purpose, but on different time scales (DNA repair takes minutes, while pigmentation lasts hours to days), I propose to take the novel approach of focusing on their timing as an opportunity to uncover their regulation. As a first step, we exposed human and mouse skin to UV and found that UV exposure at 48hr intervals resulted in higher skin pigmentation than did exposure at 24hr intervals, even after controlling for total UV dosage. Furthermore, we found that the expression level of the melanocyte central regulator, MITF, exhibits damped oscillatory behaviour during this 48hr interval. I therefore hypothesize that the dynamic behaviour of the central regulator dictates the UV–response timing of the two protection systems. In the proposed research, I will take a holistic approach and address this issue from three complementary perspectives: (1) transcriptional dynamics, (2) temporal effects on cellular output, and (3) DNA repair after UV. This will be achieved by utilizing and developing new experimental and analytical tools that will allow us to correlate the temporal behaviours of a wide set of molecular markers. Reaching our goals will provide a breakthrough in our understanding of skin protection from UV and the underlying mechanisms that control it. These findings may offer exciting new avenues for future skin cancer prevention. UV exposure is a major risk factor for all common cutaneous malignancies. Skin cancer incidence increases by ~3% per year worldwide. Only in melanoma, the most lethal and treatment-resistant of human skin cancers, there are 132,000 new cases per year. New treatment and prevention approaches are needed for all skin cancers. Here I build a strong framework to uncover, for the first time, the dynamic regulatory mechanisms of skin protection against UVB.
We have generated useful high throughput data for the scientific community, including full transcriptome data of 10 time points upon UV stimulation at the skin (GEO server: GSE114764) and full miRNAs profiling upon DNA methylation manipulation (GEO server: GSE124879). Moreover, we have discovered a gender depended response to UV exposure in terms of DNA damage repair and systemic effect. We aim to further investigate these point and publish several article in the near future.