Seasonal and Vitamin D3 mediated methylome reprogramming of peripheral immune cells and anti-viral responses

Seasonality of inflammatory and infectious diseases is associated with several factors, including serum vitamin D fluctuations and immunological state. We longitudinally investigated peripheral blood mononuclear cell (PBMC) methylomes of healthy South African adults in summer, winter, and after high-dose winter vitamin D3 supplementation to determine whether vitamin D3 modulates seasonal epigenetic variations and whether these underpin reported seasonal transcriptional oscillations. PBMC DNA methylomes were more variable in winter compared to summer, with winter variability decreased following vitamin D3 supplementation. Summer and vitamin D3 shared differential methylation of genes involved in transcription, metabolism, and epigenome regulation. Seasonal methylome changes mapped to gene targets of viral effector proteins and pathways related to pathogenic responses, including ferroptosis. Differential methylation patterns were validated against seasonal transcriptome, accessible chromatin changes, and vitamin D receptor-independent 1,25(OH)D3-induced transcription in three orthogonal datasets and upon in vitro HIV-1 infection. These findings reveal novel epigenetic regulation of seasonal immunity and may inform new treatments for seasonal diseases.