TY - JOUR
T1 - DNA methylation regulates the neonatal CD4 T-cell response to pneumonia in mice
AU - McGrath-Morrow, Sharon A.
AU - Ndeh, Roland
AU - Helmin, Kathryn A.
AU - Chen, Shang Yang
AU - Anekalla, Kishore R.
AU - Abdala-Valencia, Hiam
AU - D’Alessio, Franco R.
AU - Michael Collaco, J.
AU - Singer, Benjamin D.
N1 - Funding Information:
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.
Funding Information:
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.
PY - 2018/7/27
Y1 - 2018/7/27
N2 - 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.
AB - 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.
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U2 - 10.1074/jbc.RA118.003589
DO - 10.1074/jbc.RA118.003589
M3 - Article
C2 - 29866884
AN - SCOPUS:85050756778
VL - 293
SP - 11772
EP - 11783
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
IS - 30
ER -