Perinatal Inflammation Results in Altered Histone 3 and Histone 4 Methylation Patterns

Abstract

BackgroundBronchopulmonary dysplasia (BPD) continues to be a significant pulmonary complication for preterm infants, but the mechanisms associated with altered lung development remain poorly understood. Our mouse model of perinatal inflammation mimics the pathophysiology observed in infants with severe BPD. We have previously reported decreased pulmonary miR‐29b and miR~17–92 cluster expression and increased global DNA methylation. These studies tested the hypothesis that histone methylation may also be responsible for the lung pathophysiology observed in this model. First, we investigated protein arginine methyltransferase (PRMT)‐mediated changes in H4R3me2 (symmetrical and asymmetrical). Second, we explored lysine methylation, specifically H3K4me3, H3K9me2, and H3K27me3.MethodsPregnant C3H/HeN mice received an intraperitoneal LPS injection on E16 and newborn pups were exposed in 85% oxygen from birth to 14 days of life. On postnatal day 14 or 28, mouse lung tissues were harvested. Tissue homogenates were analyzed by western blot for PRMT‐1, PRMT‐5, and H4R3me2 symmetrical and asymmetrical and by ELISA for H3K4me3, H3K9me2, and H3K27me3 (Epigentek).ResultsPerinatal inflammation resulted in decreased expression of PRMT‐1 (1.0 v 0.45 arbitrary units, p<0.0001) and PRMT‐5 (1.0 v 0.48 arbitrary units, p=0.02) which corresponded to decreases in H4R3me2 symmetrical methylation (1.3 v 0.39 arbitrary units, p=0.04). H3K9me2 (39.8 vs 25.0 ug/mL, p=0.03) and H3K4me3 (41.1 vs 30.3 ug/mL, p<0.05) were also decreased in the exposed group while H3K27me3 was not significant.ConclusionOur data suggest that maternal inflammation combined with neonatal hyperoxia influences expression of proteins involved in histone methylation and alters specific histone methylation marks. Further investigations will explore expression of histone lysine methyltransferases and demethylases. Overall the changes observed suggest a disruption in chromatin structure which may be responsible for altered gene expression in this model.Support or Funding InformationNIH NICHD R01HD088033This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.