Epigenetic response to hyperoxia in the neonatal lung is sexually dimorphic

Abstract

Sex as a biological variable plays a critical role both during lung development and in modulating postnatal hyperoxic lung injury and repair. The molecular mechanisms behind these sex-specific differences need to be elucidated. Our objective was to determine if the neonatal lung epigenomic landscape reconfiguration has profound effects on gene expression and could underlie sex-biased differences in protection from or susceptibility to diseases. Neonatal male and female mice (C57BL/6) were exposed to hyperoxia (95% FiO, PND 1–5: saccular stage) or room air and euthanized on PND 7 and 21. Pulmonary gene expression was studied using RNA-seq on Illumina HiSeq 2500 platform and quantified. Epigenomic landscape was assessed using Chromatin Immunoprecipitation (ChIP-Seq) of the H3K27ac histone modification mark, associated with active genes, enhancers, and super-enhancers. These data were then integrated, pathways identified and validated. Sex-biased epigenetic modulation of gene expression leads to differential regulation of biological processes in the developing lung at baseline and after exposure to hyperoxia. The female lung exhibits a more robust epigenomic response for the H3K27ac mark in response to hyperoxia. Epigenomic changes distribute over genomic and epigenomic domains in a sex-specific manner. The differential epigenomic responses also enrich for key transcription regulators crucial for lung development. In addition, by utilizing H3K27ac as the target epigenomic change we were also able to identify new epigenomic reprogramming at super-enhancers. Finally, we report for the first time that the upregulation of p21 (Cdkn1a) in the injured neonatal lung could be mediated through gain of H3K27ac. These data demonstrate that modulation of transcription via epigenomic landscape alterations may contribute to the sex-specific differences in preterm neonatal hyperoxic lung injury and repair.

Effect of sex chromosomes versus hormones in neonatal lung injury

“…Prolonging the hyperoxia exposure to 14 days would correlate with human patients receiving hyperoxia throughout their first year of life and beyond. Our previous publications (27,28) as well as publications from other labs (29)(30)(31)(32) have shown the long-term effects of hyperoxia exposure during the saccular stage of lung development on the developing lung. However, the use of high FiO2 may replicate the clinical course of babies with severe lung disease who need higher FiO2 and are at greatest risk to develop severe BPD.…”

Oxygen Toxicity to the Immature Lung—Part I: Pathomechanistic Understanding and Preclinical Perspectives

“…While exposure to hyperoxia downregulated both miRNA 29b levels and histone 3 and 4 methylation patterns, nanoparticle delivery of miR-29b on day 3 reverted these changes and partially reversed lung histopathology, with reduced septal wall thickness but unchanged alveolar air space [57]. One further dimension arises from the observed specific epigenetic regulation of genes implicated in cell cycle control, pulmonary vessel formation, vascular remodeling, and mesenchymal stem cell function in female mice, while in male mice, endothelium developmental pathways were specifically altered [58].…”

Down-Regulation of CXXC5 De-Represses MYCL1 to Promote Hepatic Stellate Cell Activation

“…Chromatin Immunoprecipitation (ChIP) assays were performed essentially as described before ( Coarfa et al, 2020 ; Maity et al, 2020 ; Wang J.N. et al, 2020 ; Wang S. et al, 2020 ; Marti et al, 2021 ).…”