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表观遗传机制、创伤与精神病理学:靶向染色质重塑复合物。

Epigenetic mechanisms, trauma, and psychopathology: targeting chromatin remodeling complexes.

机构信息

Department of Psychiatry, Wroclaw Medical University, 10 Pasteur Street, 50-367 Wroclaw, Poland.

Department of Genetics, Wroclaw Medical University, 1 Marcinkowski Street, 50-368 Wroclaw, Poland.

出版信息

Rev Neurosci. 2019 Jul 26;30(6):595-604. doi: 10.1515/revneuro-2018-0055.

Abstract

Environmental pressure affects the genotype throughout different epigenetic processes. There is currently ample evidence on the role of epigenetics in developing various mental disorders. A burden of environmental pressure, such as psychological trauma, and its influence on genotype can lead to a variety of psychopathologies. Thus, this study focuses on the epigenetic activity of the complex protein machinery operating on chromatin - the ATP-dependent chromatin remodeling complexes. Although there are several recent studies on the molecular structure, functions, and taxonomy of ATP-dependent chromatin remodeling complexes, the focus of this paper is to highlight the importance of those 'protein machines' in developing psychiatric disorders. Data were obtained from human preclinical and clinical studies. The results of this review indicate an importance of ATP-dependent chromatin remodeling complexes in the interaction between environmental factors, including traumatic events, and genetic vulnerability to stress. Several studies indicate that ATP-dependent chromatin remodeling complexes play a crucial role in the development and consolidation of memory, in neurodevelopmental processes, and in etiology depressive-like behavior. Thus, the activity of those 'protein machines' emerges as a key factor in the pathophysiology of various psychiatric diseases. It can also be concluded that the limitations of clinical studies may be explained by inappropriate laboratory methods and research paradigms due to the delayed timeframe of biochemical responses to environmental stimuli. Future research in this field may enable a better understanding of the pathophysiology of psychiatric diseases and contribute to the development of novel molecular treatment targets.

摘要

环境压力会通过不同的表观遗传过程影响基因型。目前有大量证据表明,表观遗传在各种精神障碍的发展中起作用。环境压力(如心理创伤)及其对基因型的影响可导致多种精神病理。因此,本研究侧重于在染色质上操作的复杂蛋白机器的表观遗传活性-ATP 依赖性染色质重塑复合物。尽管最近有几项关于 ATP 依赖性染色质重塑复合物的分子结构、功能和分类的研究,但本文的重点是强调这些“蛋白机器”在发展精神疾病中的重要性。数据来自人类临床前和临床研究。本综述的结果表明,ATP 依赖性染色质重塑复合物在环境因素(包括创伤事件)与应激遗传易感性之间的相互作用中具有重要作用。几项研究表明,ATP 依赖性染色质重塑复合物在记忆的形成和巩固、神经发育过程以及抑郁样行为的病因学中起着至关重要的作用。因此,这些“蛋白机器”的活性成为各种精神疾病病理生理学的关键因素。还可以得出结论,由于对环境刺激的生化反应的时间延迟,临床研究的局限性可能是由于实验室方法和研究范式不恰当所致。该领域的未来研究可能有助于更好地理解精神疾病的病理生理学,并有助于开发新的分子治疗靶点。

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