DNA methylation regulates the neonatal CD4 T-cell response to pneumonia in mice

Sharon A. McGrath-Morrow, Roland Ndeh, Kathryn A. Helmin, Shang Yang Chen, Kishore R. Anekalla, Hiam Abdala-Valencia, Franco R. D’Alessio, J. Michael Collaco, Benjamin D. Singer

Research output: Contribution to journalArticle

Abstract

Pediatric acute lung injury, usually because of pneumonia, has a mortality rate of more than 20% and an incidence that rivals that of all childhood cancers combined. CD4 T-cells coordinate the immune response to pneumonia but fail to function robustly among the very young, who have poor outcomes from lung infection. We hypothesized that DNA methylation represses a mature CD4 T-cell transcriptional program in neonates with pneumonia. Here, we found that neonatal mice (3– 4 days old) aspirated with Escherichia coli bacteria had a higher mortality rate than juvenile mice (11–14 days old). Transcriptional profiling with an unsupervised RNA-Seq approach revealed that neonates displayed an attenuated lung CD4 T-cell transcriptional response to pneumonia compared with juveniles. Unlike neonates, juveniles up-regulated a robust set of canonical T-cell immune response genes. DNA methylation profiling with modified reduced representation bisulfite sequencing revealed 44,119 differentially methylated CpGs, which preferentially clustered around transcriptional start sites and CpG islands. A methylation difference–filtering algorithm detected genes with a high likelihood of differential promoter methylation regulating their expression; these 731 loci encoded important immune response and tissue-protective T-cell pathway components. Disruption of DNA methylation with the hypomethylating agent decitabine induced plasticity in the lung CD4 T-cell marker phenotype. Altogether, multidimensional profiling suggested that DNA methylation within the promoters of a core set of CD4 T-cell pathway genes contributes to the hypore-sponsive neonatal immune response to pneumonia. These findings also suggest that DNA methylation could serve as a mechanistic target for disease-modifying therapies in pediatric lung infection and injury.

Original languageEnglish (US)
Pages (from-to)11772-11783
Number of pages12
JournalJournal of Biological Chemistry
Volume293
Issue number30
DOIs
StatePublished - Jul 27 2018

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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