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Metabolism and epigenetics in the nervous system: Creating cellular fitness and resistance to neuronal death in neurological conditions via modulation of oxygen- iron- and 2-oxoglutarate-dependent dioxygenases

机译:神经系统中的代谢和表观遗传学:通过调节氧铁和2-氧戊二酸依赖性双加氧酶创造细胞适应性并在神经系统疾病中抵抗神经元死亡

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摘要

Modern definitions of epigenetics incorporate models for transient but biologically important changes in gene expression that are unrelated to DNA code but responsive to environmental changes such as injury-induced stress. In this scheme, changes in oxygen levels (hypoxia) and/or metabolic co-factors (iron deficiency or diminished 2-oxoglutarate levels) are transduced into broad genetic programs that return the cell and the organism to a homeostatic set point. Over the past two decades, exciting studies have identified a superfamily of iron-, oxygen-, and 2-oxoglutarate-dependent dioxygenases that sit in the nucleus as modulators of transcription factor stability, co-activator function, histone demethylases, and DNA demethylases. These studies have provided a concrete molecular scheme for how changes in metabolism observed in a host of neurological conditions, including stroke, traumatic brain injury, and Alzheimer’s disease, could be transduced into adaptive gene expression to protect the nervous system. We will discuss these enzymes in this short review, focusing primarily on the ten eleven translocation (TET) DNA demethylases, the jumonji (JmJc) histone demethylases, and the oxygen-sensing prolyl hydroxylase domain enzymes (HIF PHDs).
机译:表观遗传学的现代定义包含了基因表达的短暂但生物学上重要的变化的模型,这些变化与DNA编码无关,但对环境变化(如伤害引起的压力)有反应。在该方案中,将氧水平(缺氧)和/或代谢辅因子(铁缺乏症或2-氧戊二酸水平降低)的变化转导为广泛的遗传程序,这些程序可使细胞和生物体恢复体内稳态。在过去的二十年中,激动人心的研究已经确定了依赖铁,氧和2-氧戊二酸的双加氧酶的超家族,它们位于细胞核中,作为转录因子稳定性,共激活功能,组蛋白脱甲基酶和DNA脱甲基酶的调节剂。这些研究提供了一个具体的分子方案,以说明如何将在包括中风,脑外伤和阿尔茨海默氏病在内的许多神经系统疾病中观察到的代谢变化转化为适应性基因表达,以保护神经系统。我们将在这篇简短的评论中讨论这些酶,主要集中在十一个11易位(TET)DNA脱甲基酶,jumonji(JmJc)组蛋白脱甲基酶和氧敏感的脯氨酰羟化酶结构域酶(HIF PHD)。

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