The fetal brain is adapted to the hypoxic conditions present during normal in utero development. Relatively more hypoxic states, either chronic or acute, are pathologic and can lead to significant long-term neurodevelopmental sequelae. In utero hypoxic injury is associated with neonatal mortality and millions of lives lived with varying degrees of disability. Genetic studies of children with neurodevelopmental disease indicate that epigenetic modifiers regulating DNA methylation and histone remodeling are critical for normal brain development. Epigenetic modifiers are also regulated by environmental stimuli, such as hypoxia. Indeed, epigenetic modifiers that are mutated in children with genetic neurodevelopmental diseases are regulated by hypoxia in a number of preclinical models and may be part of the mechanism for the long-term neurodevelopmental sequelae seem in children with hypoxic brain injury. Thus, a comprehensive understanding the role of DNA methylation and histone modifications in hypoxic injury is critical for developing novel strategies to treat children with hypoxic injury. This review focuses on our current understanding of the intersection between epigenetics, brain development, and hypoxia. Opportunities for the use of epigenetics as biomarkers of neurodevelopmental disease after hypoxic injury and potential clinical epigenetics targets to improve outcomes after injury are also discussed. While there have been many published studies on the epigenetics of hypoxia, more are needed in the developing brain in order to determine which epigenetic pathways may be most important for mitigating the long-term consequences of hypoxic brain injury.

中文翻译：

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表观遗传学修饰剂：理解和治疗缺氧损伤引起的神经发育障碍的潜在中心

胎儿大脑适应子宫正常发育过程中出现的缺氧条件。相对较多的缺氧状态，无论是慢性还是急性，都是病理性的，可能导致严重的长期神经发育后遗症。子宫内缺氧损伤与新生儿死亡率有关，数百万人患有不同程度的残疾。对患有神经发育疾病的儿童的遗传学研究表明，调节 DNA 甲基化和组蛋白重塑的表观遗传修饰剂对于正常的大脑发育至关重要。表观遗传修饰因子也受到环境刺激的调节，例如缺氧。事实上，在许多临床前模型中，患有遗传性神经发育疾病的儿童中发生突变的表观遗传修饰因子受到缺氧的调节，并且可能是缺氧性脑损伤儿童中出现长期神经发育后遗症的机制的一部分。因此，全面了解 DNA 甲基化和组蛋白修饰在缺氧损伤中的作用对于制定治疗儿童缺氧损伤的新策略至关重要。这篇综述重点关注我们目前对表观遗传学、大脑发育和缺氧之间的交叉点的理解。还讨论了使用表观遗传学作为缺氧损伤后神经发育疾病生物标志物的机会以及改善损伤后结果的潜在临床表观遗传学目标。虽然已经发表了许多关于缺氧表观遗传学的研究，但在发育中的大脑中还需要更多的研究，以确定哪些表观遗传途径对于减轻缺氧性脑损伤的长期后果可能最重要。