Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, USA; Center for Precision Environmental Health, Baylor College of Medicine, Houston, USA; Molecular and Cellular Biology Department, Baylor College of Medicine, Houston, USA.
Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, USA.
Redox Biol. 2020 Oct;37:101718. doi: 10.1016/j.redox.2020.101718. Epub 2020 Sep 11.
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.
性别作为一个生物学变量，在肺发育过程中以及调节出生后高氧肺损伤和修复中起着关键作用。需要阐明这些性别特异性差异背后的分子机制。我们的目标是确定新生儿肺表观基因组景观的重新配置是否对基因表达有深远影响，并可能是导致疾病保护或易感性存在性别差异的基础。将新生雄性和雌性小鼠（C57BL/6）暴露于高氧（95%FiO，PND 1-5：囊泡期）或空气，并于 PND 7 和 21 时安乐死。使用 Illumina HiSeq 2500 平台上的 RNA-seq 研究肺基因表达，并进行定量。使用 H3K27ac 组蛋白修饰标记的染色质免疫沉淀（ChIP-Seq）评估表观基因组景观，该标记与活性基因、增强子和超级增强子相关联。然后整合这些数据，识别和验证途径。性别对基因表达的表观遗传调控导致发育中肺在基线和暴露于高氧后的生物学过程的差异调节。与高氧暴露相比，雌性肺的 H3K27ac 标记表现出更强的表观遗传反应。表观遗传变化以性别特异性的方式分布在基因组和表观基因组区域上。差异的表观遗传反应也富集了对肺发育至关重要的关键转录调节剂。此外，通过利用 H3K27ac 作为目标表观遗传变化，我们还能够在超级增强子上识别新的表观遗传重编程。最后，我们首次报道，受伤的新生肺中 p21（Cdkn1a）的上调可能是通过 H3K27ac 的获得介导的。这些数据表明，通过表观基因组景观改变调节转录可能有助于早产儿高氧性肺损伤和修复中的性别特异性差异。
