DNA methyltransferase inhibition induces dynamic gene expression changes in lung CD4+ T cells of neonatal mice with E. coli pneumonia
Abstract 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 to foreign pathogens...
Saved in:
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2023-03-01
|
| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-023-31285-5 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850172413552099328 |
|---|---|
| author | Sylvia N. Michki Roland Ndeh Kathryn A. Helmin Benjamin D. Singer Sharon A. McGrath-Morrow |
| author_facet | Sylvia N. Michki Roland Ndeh Kathryn A. Helmin Benjamin D. Singer Sharon A. McGrath-Morrow |
| author_sort | Sylvia N. Michki |
| collection | DOAJ |
| description | Abstract 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 to 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. Here 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. We show that 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 find 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. 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. |
| format | Article |
| id | doaj-art-94fe431f22c34bdeb705ffc74f345c59 |
| institution | OA Journals |
| issn | 2045-2322 |
| language | English |
| publishDate | 2023-03-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj-art-94fe431f22c34bdeb705ffc74f345c592025-08-20T02:20:06ZengNature PortfolioScientific Reports2045-23222023-03-0113111110.1038/s41598-023-31285-5DNA methyltransferase inhibition induces dynamic gene expression changes in lung CD4+ T cells of neonatal mice with E. coli pneumoniaSylvia N. Michki0Roland Ndeh1Kathryn A. Helmin2Benjamin D. Singer3Sharon A. McGrath-Morrow4Children’s Hospital of Philadelphia Division of Pulmonary and Sleep MedicineEudowood Division of Pediatric Respiratory Sciences, Johns Hopkins UniversityDivision of Pulmonary and Critical Care Medicine, Department of Medicine, Northwestern University Feinberg School of Medicine ChicagoDivision of Pulmonary and Critical Care Medicine, Department of Medicine, Northwestern University Feinberg School of Medicine ChicagoChildren’s Hospital of Philadelphia Division of Pulmonary and Sleep MedicineAbstract 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 to 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. Here 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. We show that 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 find 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. 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.https://doi.org/10.1038/s41598-023-31285-5 |
| spellingShingle | Sylvia N. Michki Roland Ndeh Kathryn A. Helmin Benjamin D. Singer Sharon A. McGrath-Morrow DNA methyltransferase inhibition induces dynamic gene expression changes in lung CD4+ T cells of neonatal mice with E. coli pneumonia Scientific Reports |
| title | DNA methyltransferase inhibition induces dynamic gene expression changes in lung CD4+ T cells of neonatal mice with E. coli pneumonia |
| title_full | DNA methyltransferase inhibition induces dynamic gene expression changes in lung CD4+ T cells of neonatal mice with E. coli pneumonia |
| title_fullStr | DNA methyltransferase inhibition induces dynamic gene expression changes in lung CD4+ T cells of neonatal mice with E. coli pneumonia |
| title_full_unstemmed | DNA methyltransferase inhibition induces dynamic gene expression changes in lung CD4+ T cells of neonatal mice with E. coli pneumonia |
| title_short | DNA methyltransferase inhibition induces dynamic gene expression changes in lung CD4+ T cells of neonatal mice with E. coli pneumonia |
| title_sort | dna methyltransferase inhibition induces dynamic gene expression changes in lung cd4 t cells of neonatal mice with e coli pneumonia |
| url | https://doi.org/10.1038/s41598-023-31285-5 |
| work_keys_str_mv | AT sylvianmichki dnamethyltransferaseinhibitioninducesdynamicgeneexpressionchangesinlungcd4tcellsofneonatalmicewithecolipneumonia AT rolandndeh dnamethyltransferaseinhibitioninducesdynamicgeneexpressionchangesinlungcd4tcellsofneonatalmicewithecolipneumonia AT kathrynahelmin dnamethyltransferaseinhibitioninducesdynamicgeneexpressionchangesinlungcd4tcellsofneonatalmicewithecolipneumonia AT benjamindsinger dnamethyltransferaseinhibitioninducesdynamicgeneexpressionchangesinlungcd4tcellsofneonatalmicewithecolipneumonia AT sharonamcgrathmorrow dnamethyltransferaseinhibitioninducesdynamicgeneexpressionchangesinlungcd4tcellsofneonatalmicewithecolipneumonia |