The study shows that taking vitamin D can turn on the gene that makes the antimicrobial peptide LL‑37 in lung cells, and that this effect is stronger when certain other proteins (PU.1 and CEBPα) are present. It also finds that drugs or nutrients that change how DNA is packaged (like HDAC inhibitors) can further boost LL‑37, while another protein (PRMT5) can dampen it. In plain terms, vitamin D helps the lungs make a natural antibiotic, and tweaking the cell's epigenetic machinery might make this effect bigger.

LL-37, the only known human cathelicidin which is encoded by the human antimicrobial peptide (CAMP) gene, plays a critical role in protection against bacterial infection. We previously demonstrated that cathelicidin is induced by 1,25-dihydroxyvitamin D₃ (1,25(OH) ₂ D ₃ ) in human airway epithelial cells with a resultant increase in bactericidal activity. In this study we identify key factors that co-operate with 1,25(OH) ₂ D ₃ in the regulation of CAMP. Our results show for the first time that PU.1, the myeloid transcription factor (which has also been identified in lung epithelial cells), co-operates with the vitamin D receptor and CCAAT/enhancer binding protein α (CEBPα) to enhance the induction of CAMP in lung epithelial cells. Our findings also indicate that enhancement of 1,25(OH) ₂ D ₃ regulation of CAMP by histone deacetylase inhibitors involves co-operation between acetylation and chromatin remodeling through Brahma-related gene 1 (BRG1; a component of the SWItch/sucrose nonfermentable [SWI/SNF] complex). BRG1 can be an activator or repressor depending on BRG1-associated factors. Protein arginine methyltransferase 5 (PRMT5), a methlytransferase which interacts with BRG1, represses 1,25(OH) ₂ D ₃ induced CAMP in part through dimethylation of H4R3. Our findings identify key mediators involved in the regulation of the CAMP gene in lung epithelial cells and suggest new approaches for therapeutic manipulation of gene expression to increase the antibacterial capability of the airway.