Center for Research on Reproduction and Women's Health, Perelman School of Medicine, The University of Pennsylvania, Philadelphia, PA 19104, USA.
Department of Pediatrics, University of Minnesota School of Medicine, Minneapolis, MN 55455, USA.
Nutrients. 2019 May 27;11(5):1191. doi: 10.3390/nu11051191.
Early-life iron deficiency results in long-term abnormalities in cognitive function and affective behavior in adulthood. In preclinical models, these effects have been associated with long-term dysregulation of key neuronal genes. While limited evidence suggests histone methylation as an epigenetic mechanism underlying gene dysregulation, the role of DNA methylation remains unknown. To determine whether DNA methylation is a potential mechanism by which early-life iron deficiency induces gene dysregulation, we performed whole genome bisulfite sequencing to identify loci with altered DNA methylation in the postnatal day (P) 15 iron-deficient (ID) rat hippocampus, a time point at which the highest level of hippocampal iron deficiency is concurrent with peak iron demand for axonal and dendritic growth. We identified 229 differentially methylated loci and they were mapped within 108 genes. Among them, 63 and 45 genes showed significantly increased and decreased DNA methylation in the P15 ID hippocampus, respectively. To establish a correlation between differentially methylated loci and gene dysregulation, the methylome data were compared to our published P15 hippocampal transcriptome. Both datasets showed alteration of similar functional networks regulating nervous system development and cell-to-cell signaling that are critical for learning and behavior. Collectively, the present findings support a role for DNA methylation in neural gene dysregulation following early-life iron deficiency.
早期铁缺乏会导致成年后认知功能和情感行为的长期异常。在临床前模型中，这些影响与关键神经元基因的长期失调有关。虽然有限的证据表明组蛋白甲基化为基因失调的表观遗传机制，但 DNA 甲基化的作用仍然未知。为了确定 DNA 甲基化是否是早期铁缺乏诱导基因失调的潜在机制，我们进行了全基因组亚硫酸氢盐测序，以确定出生后第 15 天（P15）缺铁（ID）大鼠海马体中 DNA 甲基化改变的基因座，此时海马体中铁缺乏的最高水平与轴突和树突生长所需的铁峰值同时发生。我们确定了 229 个差异甲基化基因座，它们映射到 108 个基因中。其中，63 个和 45 个基因在 P15 ID 海马体中分别表现出显著增加和减少的 DNA 甲基化。为了建立差异甲基化基因座与基因失调之间的相关性，将甲基组数据与我们发表的 P15 海马转录组进行了比较。这两个数据集都显示出调节神经系统发育和细胞间信号转导的相似功能网络的改变，这些网络对学习和行为至关重要。综上所述，本研究结果支持 DNA 甲基化在早期铁缺乏后神经基因失调中的作用。
