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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

37 Scopus citations

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

Funding

Acknowledgments—We acknowledge Dr. Alexander V. Misharin for the thoughtful review of this manuscript. We also acknowledge the Sidney Kimmel Cancer Center Experimental and Computational Genomics Core (supported by National Institutes of Health award P30CA006973), the Northwestern University RNA-Seq Center of the Pulmonary and Critical Care Medicine and Rheumatology Divisions, and the Johns Hopkins Bayview Flow Cytometry Core (supported by National Institutes of Health award P30AR053503). This research was supported in part through the computational resources and staff contributions provided by the Genomics Compute Cluster, which is jointly supported by the Feinberg School of Medicine, the Center for Genetic Medicine, and Feinberg’s Department of Biochemistry and Molecular Genetics, the Office of the Provost, the Office for Research, and Northwestern Information Technology. The Genomics Compute Cluster is part of Quest, Northwestern University’s high performance computing facility, with the purpose to advance research in genomics. This work was supported by National Institutes of Health Grants R01HL114800 (to S. A. M.-M.) and K08HL128867 (to B. D. S.) and by the Francis Family Foundation’s Parker B. Francis Research Opportunity Award (to B. D. S.). The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or the Francis Family Foundation. We acknowledge Dr. Alexander V. Misharin for the thoughtful review of this manuscript. We also acknowledge the Sidney Kimmel Cancer Center Experimental and Computational Genomics Core (supported by National Institutes of Health award P30CA006973), the Northwestern University RNA-Seq Center of the Pulmonary and Critical Care Medicine and Rheumatology Divisions, and the Johns Hopkins Bayview Flow Cytometry Core (supported by National Institutes of Health award P30AR053503). This research was supported in part through the computational resources and staff contributions provided by the Genomics Compute Cluster, which is jointly supported by the Feinberg School of Medicine, the Center for Genetic Medicine, and Feinberg’s Department of Biochemistry and Molecular Genetics, the Office of the Provost, the Office for Research, and Northwestern Information Technology. The Genomics Compute Cluster is part of Quest, Northwestern University’s high performance computing facility, with the purpose to advance research in genomics. This work was supported by National Institutes of Health Grants R01HL114800 (to S. A. M.-M.) and K08HL128867 (to B. D. S.) and by the Francis Family Foundation’s Parker B. Francis Research Opportunity Award (to B. D. S.). The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or the Francis Family Foundation.

ASJC Scopus subject areas

  • Molecular Biology
  • Biochemistry
  • Cell Biology

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