Prenatal Iron Deficiency and Choline Supplementation Interact to Epigenetically Regulate Jarid1b and Bdnf in the Rat Hippocampus into Adulthood.
Prenatal Iron Deficiency and Choline Supplementation Interact to Epigenetically Regulate Jarid1b and Bdnf in the Rat Hippocampus into Adulthood.
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产前铁缺乏症和补充胆碱与大鼠海马中的jARID1b和BDNF相互作用。
DOI：
10.3390/nu13124527
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发表时间：
2021-12-17
期刊：
影响因子：
5.9
通讯作者：
Tran PV
中科院分区：
文献类型：
--
作者：
Liu SX;Barks AK;Lunos S;Gewirtz JC;Georgieff MK;Tran PV
早期缺铁（ID）会导致长期的神经认知障碍和基因失调，产前补充胆碱可以部分缓解。长期的基因失调被假设为认知功能障碍的基础。然而，铁和胆碱介导长期基因失调的机制仍然未知。在本研究中，我们使用一个成熟的胎儿-新生儿ID大鼠模型，证明ID下调海马编码JmjC-ARID结构域蛋白1B（JARID 1B）的基因表达，JARID 1B是一种铁依赖性组蛋白H3 K4脱甲基酶，与较高的组蛋白脱乙酰酶1（HDAC 1）富集和较低的乙酰化组蛋白H3 K9（H3 K9 ac）和磷酸化cAMP反应元件富集相关。结合蛋白（pCREB）。同样，ID降低了编码脑源性神经营养因子（BDNF）的基因的转录能力，这是JARID 1B的靶点，与抑制性组蛋白修饰相关，例如在成年大鼠海马中BDNF启动子处H3 K9 ac和pCREB富集较低。产前胆碱补充剂并没有阻止ID诱导的染色质修饰在这些位点，但诱导持久的抑制性染色质修饰在铁充足的成年大鼠。总的来说，这些研究结果表明，铁依赖性表观遗传机制介导的JARID 1B占长期BDNF失调的早期生活ID。胆碱补充剂利用一个单独的机制，以挽救ID对神经基因调控的影响。在铁充足的大鼠海马中补充胆碱的负面表观遗传效应需要在其用作治疗剂之前进行额外的研究。
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 Bdnf 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 Bdnf 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.
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