Skin sun exposure induces two protection programs, stress responses and pigmentation, the former within minutes and the latter only hours afterwards. Although serving the same physiological purpose, it is not known if and how these programs are coordinated. Here we report that UVB exposure every-other-day induces significantly more skin pigmentation than the higher frequency of daily exposure, without an associated increase in stress responses. Using mathematical modelling and empirical studies we show that the melanocyte master regulator, MITF, serves to synchronize stress responses and pigmentation and furthermore, functions as a UV-protection timer via damped oscillatory dynamics, thereby conferring a tradeoff between the two programs. MITF oscillations are controlled by multiple negative regulatory loops, one at the transcriptional level involving HIF1a and another post-transcriptional loop involving microRNA-148a. Additionally, we found that miRNA biogenesis depends on DNA methylation. When the regions flanking the miRNA coding sequence are highly methylated, the miRNAs are more highly expressed, have greater sequence conservation, and are more likely to drive cancer-related phenotypes than miRNAs encoded by unmethylated loci. These findings support trait linkage between the two skin protection programs, which we speculate arose during furless skin evolution to minimize skin damage.
Further, we present a classification of melanoma tumors into four subtypes with different survival profiles based on three distinct gene expression signatures: keratin, immune, and melanogenesis. The melanogenesis expression pattern includes several genes that are characteristic of the melanosome organelle and correlates
with worse survival, suggesting the involvement of melanosomes in melanoma aggression.
Additionally, we discover that ultraviolet B (UVB) exposure enhances the levels of sex-steroid hormones and sexual
behavior, which are mediated by the skin. Conditional knockout of p53 specifically in skin keratinocytes abolishes
the effects of UVB. Thus, UVB triggers a skin-brain-gonadal axis through skin p53 activation. In humans,
solar exposure enhances romantic passion in both genders and aggressiveness in men.
Finally, we reveal that solar exposure induces food-seeking behavior, food intake and weight gain in males, but not in females. The underlying mechanism entails increased ghrelin secretion from skin adipocytes into the circulation. UVB irradiation led to p53 transcriptional activation of ghrelin in skin adipocytes, with mouse conditional p53-knockout abolishing UVB-induced ghrelin expression and food-seeking behavior. In females, estrogen interferes with the p53–chromatin interaction on the ghrelin promotor, thus blocking ghrelin and, consequently, food-seeking behavior in response to UVB exposure.
