Assistant Professor of Pediatrics Ann & Robert H. Lurie Children's Hospital of Chicago CHICAGO, Illinois, United States
Background: Bronchopulmonary dysplasia (BPD) is the most common respiratory disease in preterm infants born at less than 28 weeks gestation. Most existing clinical prediction models for BPD show limited accuracy in predicting BPD development when validated using external data, stressing the need for novel biomarkers to identify at-risk infants for early and effective interventions. Our previous study demonstrated that lung tissues from patients with BPD have increased expression of methyltransferase DMNT3a/b and DMNT1, suggesting that methylation-associated epigenetic regulation may be involved in BPD development. Nevertheless, whether specific epigenetic and transcriptomic signals at birth predict BPD development remains unclear. Objective: The objective of this study was to investigate transcriptional and methylation signatures in cord blood that are associated with BPD development. Design/Methods: We leveraged the existing buffy coat of the frozen umbilical cord blood samples from the Northwestern University Cord Blood Biobank (NUCord) to perform parallel RNA and DNA extraction. Transcriptional profiling was performed using bulk RNAseq and libraries were generated using the Takara SMARTer Stranded Total RNA-Seq Kit v2 with integrated rRNA removal. Methylation profiling was performed using our in-house modified reduced representation bisulfite sequencing (mRRBS) pipelines. Our patient cohorts include term infants, preterm infants with no BPD, and preterm infants who later developed BPD. These three cohorts were also controlled for chorioamnionitis infection, a well-established risk factor for BPD development. Results: BPD-associated differentially expressed genes (DEGs) were related to disrupted regulation of methylation, DNA damage, cellular senescence, and NF-κB signaling. By integrating RNAseq and mRRBS data, we identified that IL-1, a previously described modulator for BPD development, is both differentially expressed and differentially methylated at birth in infants who later developed BPD.
Conclusion(s): Our results suggest that BPD development is associated with distinct epigenetic and transcriptomic signatures when compared to healthy term infants and preterm infants. These signatures may represent biomarkers measurable at birth that predict BPD development during a time window when preventative or therapeutic interventions could be applied.
