Strawn Monica, Behura Susanta K
Division of Animal Sciences, University of Missouri, Columbia Missouri 65211.
Division of Animal Sciences, University of Missouri, Columbia Missouri 65211; MU Institute for Data Science and Informatics, University of Missouri, Columbia Missouri 65211; Interdisciplenary Neuroscience Program, University of Missouri, Columbia Missouri 65211.
Gene. 2022 Nov 30;844:146823. doi: 10.1016/j.gene.2022.146823. Epub 2022 Aug 19.
How fetal brain development is regulated at the molecular level is not well understood. Due to ethical challenges associated with research on the human fetus, large animals particularly pigs are increasingly used to study development and disorders of fetal brain. The pig fetal brain grows rapidly during the last ∼ 50 days before birth which is around day 60 (d60) of pig gestation. But what regulates the onset of accelerated growth of the brain is unknown. The current study tests the hypothesis that epigenetic alteration around d60 is involved in the onset of rapid growth of fetal brain of pig. To test this hypothesis, DNA methylation changes of fetal brain was assessed in a genome-wide manner by Enzymatic Methyl-seq (EM-seq) during two gestational periods (GP): d45 vs. d60 (GP1) and d60 vs. d90 (GP2). The cytosine-guanine (CpG) methylation data was analyzed in an integrative manner with the RNA-seq data generated from the same brain samples from our earlier study. A neural network based modeling approach was implemented to learn changes in methylation patterns of the differentially expressed genes, and then predict methylations of the brain in a genome-wide manner during rapid growth. This approach identified specific methylations that changed in a mutually informative manner during rapid growth of the fetal brain. These methylations were significantly overrepresented in specific genic as well as intergenic features including CpG islands, introns, and untranslated regions. In addition, sex-bias methylations of known single nucleotide polymorphic sites were also identified in the fetal brain ide during rapid growth.
胎儿大脑发育在分子水平上是如何调控的，目前还不太清楚。由于对人类胎儿进行研究存在伦理挑战，大型动物尤其是猪越来越多地被用于研究胎儿大脑的发育和疾病。猪胎儿大脑在出生前约50天（即猪妊娠第60天左右）迅速生长。但大脑加速生长的起始调控因素尚不清楚。当前的研究检验了这样一个假设，即妊娠第60天左右的表观遗传改变参与了猪胎儿大脑快速生长的起始过程。为了验证这一假设，在两个妊娠期（GP），即妊娠第45天与第60天（GP1）以及妊娠第60天与第90天（GP2），通过酶促甲基化测序（EM-seq）以全基因组方式评估了胎儿大脑的DNA甲基化变化。将胞嘧啶-鸟嘌呤（CpG）甲基化数据与我们早期研究中从相同大脑样本生成的RNA-seq数据进行综合分析。采用基于神经网络的建模方法来了解差异表达基因甲基化模式的变化，然后在快速生长期间以全基因组方式预测大脑的甲基化情况。这种方法识别出了在胎儿大脑快速生长期间以相互信息丰富的方式发生变化的特定甲基化。这些甲基化在特定的基因以及基因间特征（包括CpG岛、内含子和非翻译区）中显著富集。此外，在胎儿大脑快速生长期间，还识别出了已知单核苷酸多态性位点的性别偏向甲基化。
