Intrauterine Hypoxia and Epigenetic Programming in Lung Development and Disease

Abstract

Clinically, intrauterine hypoxia is the foremost cause of perinatal morbidity and developmental plasticity in the fetus and newborn infant. Under hypoxia, deviations occur in the lung cell epigenome. Epigenetic mechanisms (e.g., DNA methylation, histone modification, and miRNA expression) control phenotypic programming and are associated with physiological responses and the risk of developmental disorders, such as bronchopulmonary dysplasia. This developmental disorder is the most frequent chronic pulmonary complication in preterm labor. The pathogenesis of this disease involves many factors, including aberrant oxygen conditions and mechanical ventilation-mediated lung injury, infection/inflammation, and epigenetic/genetic risk factors. This review is focused on various aspects related to intrauterine hypoxia and epigenetic programming in lung development and disease, summarizes our current knowledge of hypoxia-induced epigenetic programming and discusses potential therapeutic interventions for lung disease.

Mapping fetal myeloid differentiation in airway samples from premature neonates with single-cell profiling

“…Out of 6,113 genes that were differentially expressed along either trajectory at an FDR of 0.5, we identified 2,509 shared genes, 2,007 genes specific to the Alveolar trajectory, and 1,597 genes specific to the Interstitial trajectory (Table S6). Gene ontology analysis of genes specific to a given trajectory or shared (Table S8) revealed that the Alveolar trajectory-specific genes were enriched for "Chromatin organization" (adjusted p-value = 2.3x10 -8 ) and "histone H4-K16 acetylation" (adjusted p-value = 3.6x10 -7 ), consistent with studies showing that dysregulation of chromatin remodeling is implicated in experimental models and patients with hypoxia lung injury [48] and that H4K16ac regulates differentiation and apoptosis in embryonic myeloid cells [49]. Genes specific to the Interstitial trajectory remained enriched for pathways in relevant cellular metabolism terms like "mitochondrial translational elongation" (adjusted p-value = 2.2x10 -16 ; [50]) and "rRNA processing" (adjusted p-value = 3.9x10 -7 ; [51]).…”

Time Domains of Hypoxia Responses and -Omics Insights

“…Specifically, the allele that predominates at high altitude is associated with an elevated heart rate under hypoxia and reduced expression of genes involved in catecholamine biosynthesis and secretion. Many of these effects seem to be attributable to a single non-synonymous substitution that disrupts the interaction between HIF-2 alpha and its transcriptional co-activator, CREB-binding protein (Song et al, 2021). Further evidence for convergent adaptation is reported at the Hb gene region across various species and impacts Hb-O 2 affinity, as mentioned in Section 2.2 (Storz 2019).…”

“…Such modifications may lead to notable physiological changes and/or distinct gene expression, proteomic, and metabolomic profiles as discussed further in this Section and the final Section of this review. Indeed, recent reports describe epigenetic changes with hypoxia exposure in neonates ( Bustelo et al, 2020 ; Tong et al, 2021 ), and epigenetic modifications in peripheral chemoreceptors have been induced with hypoxia exposure ( Nanduri et al, 2012 , 2017a , 2017b ; Prabhakar, 2013 ). These findings highlight the crucial impact of O 2 levels in early stages.…”

Association of immune cell recruitment and BPD development

“…The consequences of misdirected lung development persist into adulthood, and although the advances in neonatal intensive care decreased the rate of overall mortality after premature birth, the prevalence of chronic complications like BPD remained [ 2 , 3 ]. Different prenatal and postnatal factors have been introduced as contributors to BPD development, including genetic/epigenetic risk factors, intrauterine hypoxia and growth retardation, infection, mechanical ventilation (MV), and oxygen supplementation [ 4 , 5 ]. Clinically, BPD is classified into three severity grades according to the need for oxygen supplementation or MV 28 days after birth and near term age, i.e., 36 weeks gestational age (GA) [ 6 ].…”