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 D'Alessio, 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 - Jan 1 2018

Fingerprint

T-cells
DNA Methylation
Pneumonia
T-Lymphocytes
Pediatrics
Methylation
Genes
decitabine
Lung
CpG Islands
DNA Fingerprinting
Mortality
Acute Lung Injury
Lung Injury
Cellular Structures
Infection
Escherichia coli
Plasticity
Bacteria
RNA

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

McGrath-Morrow, S. A., Ndeh, R., Helmin, K. A., Chen, S. Y., Anekalla, K. R., Abdala-Valencia, H., ... Singer, B. D. (2018). DNA methylation regulates the neonatal CD4 T-cell response to pneumonia in mice. Journal of Biological Chemistry, 293(30), 11772-11783. https://doi.org/10.1074/jbc.RA118.003589

DNA methylation regulates the neonatal CD4 T-cell response to pneumonia in mice. / McGrath-Morrow, Sharon A; Ndeh, Roland; Helmin, Kathryn A.; Chen, Shang Yang; Anekalla, Kishore R.; Abdala-Valencia, Hiam; D'Alessio, Franco; Collaco, Michael; Singer, Benjamin D.

In: Journal of Biological Chemistry, Vol. 293, No. 30, 01.01.2018, p. 11772-11783.

Research output: Contribution to journalArticle

McGrath-Morrow, Sharon A ; Ndeh, Roland ; Helmin, Kathryn A. ; Chen, Shang Yang ; Anekalla, Kishore R. ; Abdala-Valencia, Hiam ; D'Alessio, Franco ; Collaco, Michael ; Singer, Benjamin D. / DNA methylation regulates the neonatal CD4 T-cell response to pneumonia in mice. In: Journal of Biological Chemistry. 2018 ; Vol. 293, No. 30. pp. 11772-11783.
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