The effect of developmental iron deficiency on TET proteins and DNA hydroxymethylation

发育性缺铁对 TET 蛋白和 DNA 羟甲基化的影响

• 批准号: 9394853
• 负责人: Amanda Kathryn Barks
• 金额: $ 4.36万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-28 至 2021-08-27
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9394853
• 关键词: Acute; Adolescence; Adult; Affect; Biological; Biological Assay; Brain; Cells; Child; Childhood; Chronic; Cognitive; Control Groups; Coupled; DNA; Development; Dioxygenases; Emotional; Epigenetic Process; Family; Functional disorder; Gene Expression; Gene Expression Regulation; Gene Targeting; Genes; Genetic; Genomic DNA; Goals; Health; Health Care Costs; Hippocampus (Brain); Iron; Learning; Life; Liquid Chromatography; Long-Term Effects; Longevity; Mass Spectrum Analysis; Memory impairment; Mixed Function Oxygenases; Modification; Molecular; Molecular Biology; Mus; Neonatal; Neuraxis; Neurocognitive; Neurodevelopmental Deficit; Neurons; Neurosciences; Nursery Schools; Outcome; Outcome Measure; Phenotype; Physicians; Pre-Clinical Model; Pregnant Women; Protein translocation; Public Health; Research; Research Personnel; Resolution; Risk; Rodent; Scientist; Structure; Synaptic plasticity; Techniques; Testing; Therapeutic; Time; Tissues; Work; aged; behavioral outcome; career; chromatin immunoprecipitation; chromatin modification; critical period; early childhood; effective therapy; fetal; histone demethylase; histone methylation; in vitro Model; insight; iron deficiency; micronutrient deficiency; mouse model; neurodevelopment; neuron development; neuropsychiatry; neurotransmission; new therapeutic target; postnatal; targeted treatment

PROJECT SUMMARY Fetal-neonatal iron deficiency (ID) has a lasting negative impact on neurodevelopment, resulting in significant cognitive, socio-emotional, and learning and memory deficits in adulthood. Given that ID is the most common micronutrient deficiency worldwide, and that pregnant women and young children are disproportionately affected, it presents a significant public health concern. Preclinical models have demonstrated that the developing hippocampus is particularly affected by ID, and that the deleterious neurodevelopmental and behavioral outcomes that follow are associated with dysregulation of hippocampal gene expression. Affected genes include many that are important for neurodevelopment and synaptic plasticity such as Bdnf, Dlg4 (PSD- 95), and Vamp1. If developmental ID is corrected by iron repletion within a critical period, correction of these deficits is possible. However, if iron repletion occurs outside of the critical period, the phenotypic and gene expression changes persist into adulthood despite correction of the deficiency. While changes in gene expression can be understood as the proximate cause of the ID neurocognitive phenotype, it is still unclear what the ultimate cause is. As such, there is a gap in our understanding of how developmental ID drives hippocampal gene expression changes. A potential mechanism by which iron could enact these changes is through Ten-Eleven Translocation (TET) proteins, a family of iron-dependent hydroxylases that generate the epigenetic modification 5-hydroxymethylcytosine. Epigenetic modifications such as DNA hydroxymethylation have the ability to stably influence gene expression throughout the lifespan, and are known to be labile to environmental influences. Of particular relevance, 5-hydroxyethylcytosine is more abundant in the brain than any other tissue type, and it increases in enrichment as neurodevelopment progresses, particularly in genes critical for neuronal development and function. The central hypothesis of this proposal is that dysregulation of TET protein activity and DNA hydroxymethylation by ID drive gene expression changes in hippocampal neurons that contribute to the long-term neurocognitive phenotype of developmental ID. To test this hypothesis, the following specific aims are proposed: 1) Determine how ID alters TET activity and hydroxymethylation of neurons in an in vitro model of hippocampal neurodevelopment, and 2) Determine the effect of developmental ID and subsequent iron repletion on hydroxymethylation in the developing mouse hippocampus. Completion of these aims will contribute to our long-term goal of understanding the cellular and molecular underpinnings of hippocampal dysfunction following developmental ID. Because the standard therapy of iron repletion incompletely rescues the neurodevelopmental phenotype of ID, there is a need for better therapeutic options. By better understanding the underlying mechanisms of ID-related hippocampal dysfunction, it may be possible to identify new therapeutic targets for more effective treatment of iron deficiency.

项目总结 胎儿-新生儿缺铁(ID)对神经发育有持久的负面影响，导致显著 成年期的认知、社会情绪、学习和记忆缺陷。鉴于ID是最常见的 世界范围内的微量营养素缺乏，孕妇和幼儿比例不成比例 受影响，它是一个重大的公共卫生问题。临床前模型已经证明， 发育中的海马体尤其受ID的影响，而有害的神经发育和 随后的行为结果与海马区基因表达的失调有关。受影响 基因包括许多对神经发育和突触可塑性很重要的基因，如BDNF、Dlg4(PSD- 95)和Vamp1。如果在关键时期内通过补充铁来纠正发育性ID，则纠正这些 赤字是可能的。然而，如果铁补充发生在临界期之外，表型和基因 尽管缺陷得到纠正，但表情变化仍会持续到成年。而基因的变化 表达可被理解为ID神经认知表型的直接原因，目前仍不清楚 最终的原因是什么。因此，我们对发育性ID是如何驱动的理解上存在差距 海马区基因表达的变化。铁可能导致这些变化的一个潜在机制是 通过Ten-Eleven易位(Tet)蛋白，一组铁依赖的羟基酶家族产生 表观遗传修饰5-羟甲基胞嘧啶。表观遗传修饰，如DNA羟甲基化 有能力在一生中稳定地影响基因表达，并且已知不稳定于 环境影响。特别重要的是，5-羟乙基胞嘧啶在大脑中的含量比 任何其他组织类型，随着神经发育的进展，尤其是在基因上，它的丰富程度会增加 对神经元的发育和功能至关重要。这一提议的中心假设是，对 ID驱动基因表达变化引起的海马区Tet蛋白活性和DNA羟甲基化 对发育性ID的长期神经认知表型有贡献的神经元。 假设，提出了以下具体目标：1)确定ID如何改变Tet活性和 在海马神经发育的体外模型中神经元的羟甲基化，以及2)确定 发育性缺铁和随后的铁补充对发育中小鼠羟甲基化的影响 海马体。完成这些目标将有助于我们的长期目标，了解细胞和 发育性ID后海马区功能障碍的分子基础。 铁补充治疗不能完全挽救ID的神经发育表型，需要 更好的治疗选择。通过更好地了解ID相关海马区的潜在机制 功能障碍，有可能确定新的治疗靶点，以更有效地治疗铁 缺乏症。