Roles of Iron-Dependent PHD and JARID in Early-Life Iron Deficiency-Induced Adult Neural Gene Dysregulation

摘要 全世界约20-30%的孕妇及其后代患有早期铁缺乏症（ID）， 尽管接受了铁剂治疗，但仍会导致成年期认知和社会情感行为的长期损害 在婴儿期诊断出ID后。这些持续的异常给社会带来了巨大的成本， 失去教育、工作潜力和心理健康。持续性脑梗死的潜在病理学 行为异常仅归因于异常的神经发育和功能（例如， 代谢、树突发生和突触发生），这些过程在生命早期的关键时期进行， 功能遵循形式假说（Function follows form hypothesis）。然而，在知识方面仍然存在重大差距，其中之一是 属于铁依赖性细胞机制，通过该机制，早期ID诱导基因失调 对成年期的神经元功能至关重要。这些知识对于在治疗方面推进该领域至关重要。 防止早期ID对发育中的大脑产生长期负面影响的策略。 目前的建议调查如何细胞途径驱动的含铁双加氧酶改变 主要突触分化和可塑性基因的长期神经元表达，包括脑源性 神经营养因子（BDNF）。我们利用铁对两种已知的催化活性的必要性， 双加氧酶、脯氨酰羟化酶（PHD）和含组蛋白脱甲基酶的JmjC ARID结构域家族 （JARID），以分析早期生命ID对神经组织中这些蛋白质的功能影响。我们的新型 概念化是这两种途径通过PHD调节HIF 1 α联系在一起，而HIF 1 α又靶向 JARID。根据我们最近发表的研究结果和新的初步数据，我们将表明，早期生活ID改变 PHD和JARID的功能，导致稳定的表观遗传修饰和随后的基因 成年期的失调我们将使用我们独特的慢性缺铁原发性 培养的海马-锥体神经元模型和我们的显性阴性（DN）TfR 1转基因小鼠模型 它被设计成以时间依赖的方式在发育中的神经元中特异性诱导ID， 系统性贫血或全脑ID。我们将进一步证明这一概念的翻译价值，使用 饮食性ID贫血大鼠模型，非常类似于人类的情况。 拟议的工作将通过解决两个重要的知识差距对实地产生重大影响： (1)PHD和JARID是否是直接导致染色质变化的关键含铁因素 结构，导致对学习和记忆至关重要的基因的持续失调;以及（2）是否 及时补铁可以减轻这些变化。缩小这些差距对于制定战略至关重要， 包括在怀孕期间维持铁的充足，并设计潜在的治疗方法， 表观遗传景观（例如，胆碱），以减轻数百万患有早期ID的儿童的终身负担。

ABSTRACT Early-life iron deficiency (ID) affects ~20-30% of all pregnant women and their offspring worldwide and causes long-term impairments in cognition and socio-emotional behaviors in adulthood despite iron therapy after the diagnosis of ID in infancy. These persistent abnormalities constitute a significant cost to society in terms of loss of education, job potential, and mental health. The underlying pathobiology for the persistent behavioral abnormalities has been ascribed solely to abnormal neural development and function (e.g., metabolism, dendritogenesis, and synaptogenesis) during critical periods in early life that are carried forward into adulthood (function follows form hypothesis). However, major gaps in knowledge remain, one of which pertains to the iron-dependent cellular mechanisms, by which early-life ID induces the dysregulation of genes critical for neuronal function in adulthood. Such knowledge is critical to advance the field in terms of therapeutic strategies to prevent the long-term negative effects of early-life ID on the developing brain. The present proposal investigates how cellular pathways driven by iron-containing dioxygenases alter long-term neuronal expression of major synaptic differentiation and plasticity genes, including brain-derived neurotrophic factor (BDNF). We leverage the necessity of iron for the catalytic activity of two well-known families of dioxygenases, prolyl hydroxylases (PHDs) and JmjC ARID-domain containing histone demethylases (JARIDs), to analyze the functional effect of early-life ID on these proteins in neural tissues. Our novel conceptualization is that the two pathways are linked through PHD regulation of HIF1α, which in turns targets JARIDs. Based on our recent published findings and new preliminary data, we will show that early-life ID alters the function of both PHD and JARID, leading to stable epigenetic modifications and consequent gene dysregulation in adulthood. We will test this novel hypothesis using our unique chronic iron-deficient primary cultured hippocampal-pyramidal neuron model and our dominant-negative (DN) TfR1 transgenic mouse model that was engineered to induce ID specifically in the developing neurons in a time-dependent manner without systemic anemia or global brain ID. We will further demonstrate the translational value of this concept using the dietary ID anemia rat model that closely resembles the human condition. The proposed work will have a major impact on the field by addressing two important gaps in knowledge: (1) whether PHDs and JARIDs are key iron-containing factors directly responsible for the changes in chromatin structures, resulting in the persistent dysregulation of genes critical for learning and memory; and (2) whether timely iron restoration can attenuate these modifications. Closing these gaps is crucial in designing strategies, including maintenance of iron sufficiency during pregnancy and devising potential therapies that restore the epigenetic landscape (e.g., choline), to lessen the life-long burden of millions of children with early-life ID.