Department of Pediatrics, University of Minnesota, Minneapolis, MN, 55455, USA.
Department of Psychology, University of Minnesota, Minneapolis, MN, 55455, USA.
BMC Genomics. 2024 Mar 21;25(1):301. doi: 10.1186/s12864-024-10230-4.
Iron deficiency (ID) during the fetal-neonatal period results in long-term neurodevelopmental impairments associated with pervasive hippocampal gene dysregulation. Prenatal choline supplementation partially normalizes these effects, suggesting an interaction between iron and choline in hippocampal transcriptome regulation. To understand the regulatory mechanisms, we investigated epigenetic marks of genes with altered chromatin accessibility (ATAC-seq) or poised to be repressed (H3K9me3 ChIP-seq) in iron-repleted adult rats having experienced fetal-neonatal ID exposure with or without prenatal choline supplementation.
Fetal-neonatal ID was induced by limiting maternal iron intake from gestational day (G) 2 through postnatal day (P) 7. Half of the pregnant dams were given supplemental choline (5.0 g/kg) from G11-18. This resulted in 4 groups at P65 (Iron-sufficient [IS], Formerly Iron-deficient [FID], IS with choline [ISch], and FID with choline [FIDch]). Hippocampi were collected from P65 iron-repleted male offspring and analyzed for chromatin accessibility and H3K9me3 enrichment. 22% and 24% of differentially transcribed genes in FID- and FIDch-groups, respectively, exhibited significant differences in chromatin accessibility, whereas 1.7% and 13% exhibited significant differences in H3K9me3 enrichment. These changes mapped onto gene networks regulating synaptic plasticity, neuroinflammation, and reward circuits. Motif analysis of differentially modified genomic sites revealed significantly stronger choline effects than early-life ID and identified multiple epigenetically modified transcription factor binding sites.
This study reveals genome-wide, stable epigenetic changes and epigenetically modifiable gene networks associated with specific chromatin marks in the hippocampus, and lays a foundation to further elucidate iron-dependent epigenetic mechanisms that underlie the long-term effects of fetal-neonatal ID, choline, and their interactions.
胎儿-新生儿期的缺铁（ID）会导致长期的神经发育障碍，与广泛的海马基因调控失调有关。产前补充胆碱可部分纠正这些影响，提示铁和胆碱在海马转录组调控中存在相互作用。为了了解调控机制，我们研究了经历过胎儿-新生儿期 ID 暴露且有或没有产前补充胆碱的铁充足的成年大鼠中海马体中改变染色质可及性的基因（ATAC-seq）或准备被抑制的基因（H3K9me3 ChIP-seq）的表观遗传标记。
通过限制妊娠第 2 天（G）至产后第 7 天（P）的母体铁摄入来诱导胎儿-新生儿 ID。一半的孕鼠从 G11-18 开始给予补充胆碱（5.0g/kg）。这导致 P65 时有 4 组（铁充足 [IS]、曾经缺铁 [FID]、IS 加胆碱 [ISch] 和 FID 加胆碱 [FIDch]）。从铁充足的雄性后代的 P65 海马中收集组织并分析染色质可及性和 H3K9me3 富集情况。FID-和 FIDch-组分别有 22%和 24%的差异转录基因的染色质可及性存在显著差异，而 1.7%和 13%的基因的 H3K9me3 富集存在显著差异。这些变化映射到调节突触可塑性、神经炎症和奖励回路的基因网络上。差异修饰基因组位点的基序分析表明，胆碱的作用比早期生命 ID 更强，并确定了多个受表观遗传修饰的转录因子结合位点。
这项研究揭示了与海马体特定染色质标记相关的全基因组、稳定的表观遗传变化和受表观遗传修饰的基因网络，并为进一步阐明铁依赖性表观遗传机制奠定了基础，这些机制是胎儿-新生儿 ID、胆碱及其相互作用的长期影响的基础。
