Department of Pediatrics, University of Minnesota, Minneapolis, MN 55455, USA.
Department of Psychology, University of Minnesota, Minneapolis, MN 55455, USA.
Nutrients. 2021 Dec 17;13(12):4527. doi: 10.3390/nu13124527.
Early-life iron deficiency (ID) causes long-term neurocognitive impairments and gene dysregulation that can be partially mitigated by prenatal choline supplementation. The long-term gene dysregulation is hypothesized to underlie cognitive dysfunction. However, mechanisms by which iron and choline mediate long-term gene dysregulation remain unknown. In the present study, using a well-established rat model of fetal-neonatal ID, we demonstrated that ID downregulated hippocampal expression of the gene encoding JmjC-ARID domain-containing protein 1B (JARID1B), an iron-dependent histone H3K4 demethylase, associated with a higher histone deacetylase 1 (HDAC1) enrichment and a lower enrichment of acetylated histone H3K9 (H3K9ac) and phosphorylated cAMP response element-binding protein (pCREB). Likewise, ID reduced transcriptional capacity of the gene encoding brain-derived neurotrophic factor (BDNF), a target of JARID1B, associated with repressive histone modifications such as lower H3K9ac and pCREB enrichments at the promoters in the adult rat hippocampus. Prenatal choline supplementation did not prevent the ID-induced chromatin modifications at these loci but induced long-lasting repressive chromatin modifications in the iron-sufficient adult rats. Collectively, these findings demonstrated that the iron-dependent epigenetic mechanism mediated by JARID1B accounted for long-term dysregulation by early-life ID. Choline supplementation utilized a separate mechanism to rescue the effect of ID on neural gene regulation. The negative epigenetic effects of choline supplementation in the iron-sufficient rat hippocampus necessitate additional investigations prior to its use as an adjunctive therapeutic agent.
早期生活铁缺乏（ID）导致长期的神经认知障碍和基因调控异常，而产前胆碱补充可以部分缓解这种情况。长期的基因调控异常被认为是认知功能障碍的基础。然而，铁和胆碱介导长期基因调控异常的机制尚不清楚。在本研究中，我们使用了一种成熟的胎儿-新生儿 ID 大鼠模型，证明 ID 下调了海马体中编码 JmjC-ARID 结构域包含蛋白 1B（JARID1B）的基因表达，JARID1B 是一种铁依赖性组蛋白 H3K4 去甲基化酶，与组蛋白去乙酰化酶 1（HDAC1）的富集增加和乙酰化组蛋白 H3K9（H3K9ac）和磷酸化 cAMP 反应元件结合蛋白（pCREB）的富集减少有关。同样，ID 降低了脑源性神经营养因子（BDNF）的基因表达，BDNF 是 JARID1B 的靶基因，与抑制性组蛋白修饰有关，如成年大鼠海马体中基因启动子处的 H3K9ac 和 pCREB 富集减少。产前胆碱补充并没有预防 ID 在这些基因座引起的染色质修饰，但在铁充足的成年大鼠中诱导了持久的抑制性染色质修饰。总之，这些发现表明，JARID1B 介导的铁依赖性表观遗传机制解释了早期生活 ID 引起的长期失调。胆碱补充利用了一种独立的机制来挽救 ID 对神经基因调节的影响。胆碱补充在铁充足的大鼠海马体中的负性表观遗传效应需要进一步研究，才能将其作为辅助治疗剂使用。
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