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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.

SUBMITTER: Coarfa C

PROVIDER: S-EPMC7509469 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Epigenetic response to hyperoxia in the neonatal lung is sexually dimorphic.

Coarfa Cristian C Grimm Sandra L SL Katz Tiffany T Zhang Yuhao Y Jangid Rahul K RK Walker Cheryl L CL Moorthy Bhagavatula B Lingappan Krithika K

Redox biology 20200911

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 expose ...[more]

PMID: 32961439

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Project description:BackgroundSexual differentiation of the male brain, and specifically the stress circuitry in the hypothalamus, is primarily driven by estrogen exposure during the perinatal period. Surprisingly, this single hormone promotes diverse programs of sex-specific development that vary widely between different cell types and across the developing male brain. The complexity of this phenomenon suggests that additional layers of gene regulation, including microRNAs (miRNAs), must act downstream of estrogen to mediate this specificity.MethodsTo identify noncanonical mediators of estrogen-dependent sex-specific neural development, we assayed the miRNA complement of the mouse PN2 hypothalamus by microarray following an injection of vehicle or the aromatase inhibitor, formestane. Initially, multivariate analyses were used to test the influence of sex and experimental group on the miRNA environment as a whole. Then, we utilized traditional hypothesis testing to identify individual miRNA with significantly sex-biased expression. Finally, we performed a transcriptome-wide mapping of Argonaute footprints by high-throughput sequencing of RNA isolated by cross-linking immunoprecipitation (Ago HITS-CLIP) to empirically characterize targeting relationship between estrogen-responsive miRNAs and their messenger RNA (mRNA) targets.ResultsIn this study, we demonstrated that the neonatal hypothalamic miRNA environment has robust sex differences and is dynamically responsive to estrogen. Analyses identified 162 individual miRNAs with sex-biased expression, 92 of which were estrogen-responsive. Examining the genomic distribution of these miRNAs, we found three miRNA clusters encoded within a 175-kb region of chromosome 12 that appears to be co-regulated by estrogen, likely acting broadly to alter the epigenetic programming of this locus. Ago HITS-CLIP analysis uncovered novel miRNA-target interactions within prototypical mediators of estrogen-driven sexual differentiation of the brain, including Esr1 and Cyp19a1. Finally, using Gene Ontology annotations and empirically identified miRNA-mRNA connections, we identified a gene network regulated by estrogen-responsive miRNAs that converge on biological processes relevant to sexual differentiation of the brain.ConclusionsSexual differentiation of the perinatal brain, and that of stress circuitry in the hypothalamus specifically, seems to be particularly susceptible to environmental programming effects. Integrating miRNA into our conceptualization of factors, directing differentiation of this circuitry could be an informative next step in efforts to understand the complexities behind these processes.

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Epigenetic response to hyperoxia in the neonatal lung is sexually dimorphic.

Publications

Epigenetic response to hyperoxia in the neonatal lung is sexually dimorphic.

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