DNA methyltransferase inhibition induces dynamic gene expression changes in lung CD4+ T cells of neonatal mice with E. coli pneumonia

• Published in: bioRxiv
• Main Authors: Michki, Nigel S, Ndeh, Roland, Helmin, Kathryn A, Singer, Benjamin D, Mcgrath-Morrow, Sharon A
• Format: Paper
• Language: English
• Published: Cold Spring Harbor Cold Spring Harbor Laboratory Press 01.10.2022
• Subjects: 5-aza-2'-deoxycytidine; Bronchopulmonary infection; CD4 antigen; Demethylation; DNA fingerprinting; DNA methylation; DNA methyltransferase; E coli; Epigenetics; Gene expression; Genomes; Interferon; Juveniles; Lungs; Lymphocytes; Lymphocytes T; Minors; Morbidity; Neonates; United States > US
• DOI: 10.1101/2022.09.30.510315

Introduction: Bacterial pulmonary infections are a major cause of morbidity and mortality in neonates, with less severity in older children. Previous studies demonstrated that the DNA of CD4+ T cells in the mouse lung, whose primary responsibility is to coordinate the immune response foreign pathogens, is differentially methylated in neonates compared with juveniles. Nevertheless, the effect of this differential DNA methylation on CD4+ T cell gene expression and response to infection remains unclear. Methods: We treated E. coli-infected neonatal (4-day-old) and juvenile (13-day-old) mice with decitabine (DAC), a DNA methyltransferase inhibitor with broad-spectrum DNA demethylating activity, and performed simultaneous genome-wide DNA methylation and transcriptional profiling on lung CD4+ T cells. Results: Juvenile and neonatal mice experienced differential demethylation in response to DAC treatment, with larger methylation differences observed in neonates. By cross-filtering differentially expressed genes between juveniles and neonates with those sites that were demethylated in neonates, we found that interferon-responsive genes such as Ifit1 are the most down-regulated methylation-sensitive genes in neonatal mice. DAC treatment shifted neonatal lung CD4+ T cells toward a gene expression program similar to that of juveniles. Conclusion: Following lung infection with E. coli, lung CD4+ T cells in neonatal mice exhibit epigenetic repression of important host defense pathways, which are activated by inhibition of DNA methyltransferase activity to resemble a more mature profile. Competing Interest Statement B.D.S. holds United States Patent No. US 10,905,706 B2, Compositions and Methods to Accelerate Resolution of Acute Lung Inflammation, and serves on the Scientific Advisory Board of Zoe Biosciences, outside of the submitted work.