Of mice and men: correlations between microRNA-17∼92 cluster expression and promoter methylation in severe bronchopulmonary dysplasia.
We previously demonstrated that decreased miR-17∼92 cluster expression was 1) present in lungs from human infants who died with bronchopulmonary dysplasia (BPD); 2) inversely correlated with DNA methyltransferase (DNMT) expression and promoter methylation; and 3) correlated with a subsequent diagnosis of BPD at 36 wk gestational age. We tested the hypothesis that plasma miR-17 levels would be lowest in infants who ultimately develop severe BPD. Secondly, we utilized our well-characterized murine model of severe BPD that combines perinatal inflammation with postnatal hyperoxia to test the hypothesis that alterations in lung miR-17∼92, DNMT, and promoter methylation in our model would mirror our findings in tissues from premature human infants. Plasma was obtained during the first 5 days of life from premature infants born ≤32 wk gestation. Lung tissues were harvested from mice exposed to maternal inflammation and neonatal hyperoxia for 14 days after birth. miR-17∼92 cluster expression and DNA methyltransferase expression were measured by qRT-PCR, and promoter methylation was assessed by Methyl-Profiler assay. Plasma miR-17 levels are significantly lower in the first week of life in human infants who develop severe BPD compared with mild or moderate BPD. Data from our severe BPD murine model reveal that lung miR-17∼92 cluster expression is significantly attenuated, and levels inversely correlated with DNMT expression and miR-17∼92 cluster promoter methylation. Collectively, our data support a plausible role for epigenetically altered miR-17∼92 cluster in the pathogenesis of severe BPD.
Division of Neonatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
Mary E
ME
Robbins
Departments of Microbiology, Immunology, and Cell Biology, West Virginia University, Morgantown, West Virginia.
Duaa
D
Dakhlallah
Departments of Microbiology, Immunology, and Cell Biology, West Virginia University, Morgantown, West Virginia.
Clay B
CB
Marsh
Center for Perinatal Research, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio; and.
Lynette K
LK
Rogers
Division of Neonatology, University of Alabama at Birmingham School of Medicine, Birmingham, Alabama ttipple@peds.uab.edu.
Trent E
TE
Tipple
D000818:Animals; D001997:Bronchopulmonary Dysplasia / Q000097:blood / Q000235:genetics*; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism; D019175:DNA Methylation / Q000235:genetics*; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D018496:Hyperoxia / Q000235:genetics / Q000473:pathology; D007231:Infant, Newborn; D007249:Inflammation / Q000235:genetics / Q000473:pathology; D008168:Lung / Q000201:enzymology / Q000473:pathology; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000097:blood / Q000235:genetics*; D011401:Promoter Regions, Genetic; D062085:RNA, Long Noncoding
C568997:MIR17HG, human; C575895:MIRN17-92 microRNA, mouse; D035683:MicroRNAs; D062085:RNA, Long Noncoding; D004248:DNA (Cytosine-5-)-Methyltransferases
DNMT; bronchopulmonary dysplasia; methylation; miR-17∼92; microRNA
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