PRKCZ methylation is associated with sunlight exposure in a North American but not a Mediterranean population

Authors: ASLIBEKYAN, STELLA - University Of Alabama; DASHTI, HASSAN - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; TANAKA, TOSHIKO - National Institute On Aging (NIA, NIH); SHA, JIN - University Of Alabama; FERRUCCI, LUIGI - National Institute On Aging (NIA, NIH); ZHI, DEGUI - University Of Alabama; BANDINELLI, STEFANIA - Azienda Sanitaria Di Firenze; BORECKI, INGRID - Washington University; ABSHER, DEVIN - Hudsonalpha Institute For Biotechnology; ARNETT, DONNA - University Of Alabama; ORDOVAS, JOSE - Jean Mayer Human Nutrition Research Center On Aging At Tufts University

Submitted to: Chronobiology International
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/9/2014
Publication Date: 11/15/2014
Citation: Aslibekyan, S., Dashti, H., Tanaka, T., Sha, J., Ferrucci, L., Zhi, D., Bandinelli, S., Borecki, I., Absher, D.M., Arnett, D.K., Ordovas, J.M. 2014. PRKCZ methylation is associated with sunlight exposure in a North American but not a Mediterranean population. Chronobiology International. 31(9):1034-1040. https://doi.org/10.3109/07420528.2014.944266.

Interpretive Summary: Sunlight exposure has previously been shown to influence human DNA in different cell types, and one of the mechanisms whereby this happens is through changes in methylation patterns. DNA methylation works like a light switch for genes: when genes switch "on" they are expressed, and when genes switch "off" they are not expressed. We were interested in investigating how sunlight exposure influences methylation patterns across the entire human genome as well as which genes are influenced by those changes in methylation patterns. In particular, we were interested in the CD4+ T-cell methylation patterns because of their role in human health, especially with regard to immunity and tumor growth suppression. We tested the hypothesis that differences in sunlight exposure result in changes in DNA methylation in human CD4+ T-cells in a North American population of European origin. In addition to sunlight duration, we investigated what genes could also contribute to changes in the methylation of sites we identified to be sensitive to sunlight duration. We observed that sunlight exposure significantly alters the methylation pattern at one particular site on a gene. Interestingly, this gene was previously shown to be influenced by light in mice. In addition to sunlight exposure, our analysis suggested that two other genetic regions further influenced methylation at this site. However, we were unable to replicate the associations we observed in the North American population in an independent Mediterranean cohort for numerous reasons. Our preliminary results support the role of sunlight exposure in regulating gene expression and lay the groundwork for future studies of the molecular link between sunlight and physiologic processes, such as tumorigenesis and metabolism.

Technical Abstract: Sunlight exposure has been shown to alter DNA methylation patterns across several human cell-types, including T-lymphocytes. Since epigenetic changes establish gene expression profiles, changes in DNA methylation induced by sunlight exposure warrant investigation. The purpose of this study was to assess the effects of sunlight exposure on CD4+ T-cell methylation patterns on an epigenome-wide scale in a North American population of European origin (n = 991). Additionally, we investigated the genetic contribution to epigenetic variation (methylQTL). We used linear regression to test the associations between methylation scores at 461 281 cytosine-phosphate-guanine (CpG) sites and sunlight exposure, followed by a genome-wide association analysis (methylQTL) to test for associations between methylation at the top CpG locus and common genetic variants, assuming an additive genetic model. We observed an epigenome-wide significant association between sunlight exposure and methylation status at cg26930596 (P = 9.2 x 10^-8), a CpG site located in PRKCZ (protein kinase C zeta), a gene previously shown to be entrained by light. MethylQTL analysis resulted in significant associations between cg26930596 and two intergenic SNPs on chromosome 3, rs4574216 (P = 1.5 x 10^-10) and rs4405858 (P = 1.9 x 10^-9). These common genetic variants reside downstream of WWTR1, a transcriptional co-activator of PRKCZ. Associations observed in the North American population, however, did not replicate in an independent Mediterranean cohort. Our preliminary results support the role of sunlight exposure in epigenetic processes, and lay the groundwork for future studies of the molecular link between sunlight and physiologic processes such as tumorigenesis and metabolism.