Prenatal hypoxia exposure induced methylomic and transcriptomic alterations in rat hearts [RNA-seq]

Antenatal hypoxia has critial impacts on fetal heart development. The molecular mechanism of the antenaltal hypoxia effect on the heart development is still unknown. We performed DNA methylome and transcriptome analyses of antenatal hypoxia induced rat fetal and adult offspring hearts to understand the hypoxia-mediated epigenomic programming in the heart development. Heart tissue from fetal (E21) and adult rat (5 months old) were collected. mRNA and genomic DNA methylation profiles of the heart tissue were generated by RNAseq and reduced representation bisulfite seuqencing (RRBS) techniques. We found 323 and 112 differential expressed genes between control and hypoxia groups in the fetal and adult hearts, respectively. Meanwhile, 2828 and 2193 differential methylated regions were identified in the fetal and adult hearts. Furthermore, opposite gobal DNA methylation pattern changes in transcription start site regions (TSS ± 1kb) were observed between fetal and adult hearts. Combining transcriptome, data indicates a significant difference in the responding genes and pathways between fetal and adult hearts in responding to the antenatal hypoxia. Our study provides an initial framework and new insights into fetal hypoxia-mediated epigenetic programming of pro-inflammatory phenotype in the heart development, linking antenatal stress, and developmental programming of heart vulnerability to disease later in life. Overall design: Fetal (E21) heart tissues from control (n=3) and hypoxia (n=3) Sprague-Dawley (SD) rats were collected for transcriptome analysis. Adult male and female (5 months old) heart tissues from control (n=5 per gender) and hypoxia (n=5 per gender ) SD rats were used for transcriptome analysis.

产前缺氧对胎儿心脏发育具有关键影响，但其调控心脏发育的分子机制至今仍未阐明。为解析缺氧介导的心脏发育表观基因组编程机制，本研究对产前缺氧诱导的大鼠胎鼠及成年子代心脏开展了DNA甲基化组（DNA methylome）与转录组（transcriptome）联合分析。本研究采集了胎龄21天（E21）的胎鼠与5月龄成年大鼠的心脏组织，通过RNA测序（RNAseq）与简化代表性亚硫酸氢盐测序（reduced representation bisulfite sequencing, RRBS）技术，获取了心脏组织的mRNA表达谱与基因组DNA甲基化谱。结果显示，胎鼠与成年大鼠心脏的对照组与缺氧组之间，分别存在323个与112个差异表达基因；同时分别鉴定得到2828个与2193个差异甲基化区域。此外，胎鼠与成年大鼠心脏在转录起始位点区域（TSS ±1kb）的全局DNA甲基化模式变化呈现完全相反的趋势。结合转录组数据可知，胎鼠与成年大鼠心脏在响应产前缺氧时，其差异应答基因及富集通路存在显著差异。本研究为阐明产前缺氧介导的心脏发育促炎表型表观遗传编程提供了初步研究框架与全新视角，同时揭示了产前应激与心脏成年后疾病易感性发育编程之间的关联。实验设计：本研究采集了对照组（n=3）与缺氧组（n=3）斯普拉-道来（SD）大鼠的胎龄21天（E21）心脏组织用于转录组分析；同时采集了5月龄成年SD大鼠（雌雄各半）的心脏组织，其中对照组与缺氧组均为每性别5只样本，同样用于转录组分析。