PU.1 and epigenetic signals modulate 1,25-dihydroxyvitamin D3 and C/EBPα regulation of the human cathelicidin antimicrobial peptide gene in lung epithelial cells.

Abstract

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.

• Authors: Ran Wei, Puneet Dhawan, Robert A Baiocchi, Ki-Yoon Kim, Sylvia Christakos
• Journal: Journal of cellular physiology (J Cell Physiol) Vol. 234 Issue 7 Pg. 10345-10359 (07 2019) ISSN: 1097-4652 [Electronic] United States
• PMID: 30387140 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: © 2018 Wiley Periodicals, Inc.

Chemical References

• Antimicrobial Cationic Peptides
• CCAAT-Enhancer-Binding Proteins
• CEBPA protein, human
• Proto-Oncogene Proteins
• Receptors, Calcitriol
• Trans-Activators
• Transcription Factors
• proto-oncogene protein Spi-1
• Vitamin D
• 1,25-dihydroxyvitamin D
• Cathelicidins

Topics

• Acetylation
• Antimicrobial Cationic Peptides (genetics)
• CCAAT-Enhancer-Binding Proteins (genetics)
• Chromatin Assembly and Disassembly (genetics)
• Epigenesis, Genetic (genetics)
• Epithelial Cells
• Gene Expression Regulation (genetics)
• HEK293 Cells
• Humans
• Lung
• Proto-Oncogene Proteins (genetics)
• Receptors, Calcitriol (genetics)
• Trans-Activators (genetics)
• Transcription Factors (genetics)
• Transcription, Genetic (genetics)
• Vitamin D (analogs & derivatives, genetics)
• Cathelicidins