Epigenetic mechanisms in mood disorders: targeting neuroplasticity.
Epigenetic mechanisms in mood disorders: targeting neuroplasticity.
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DOI：
10.1016/j.neuroscience.2013.01.041
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发表时间：
2014-04-04
期刊：
影响因子：
3.3
通讯作者：
Haggarty SJ
中科院分区：
文献类型：
--
作者：
Fass DM;Schroeder FA;Perlis RH;Haggarty SJ
基于对神经可塑性的理解开发新的治疗和诊断工具对于改善治疗并最终预防广泛的神经系统疾病至关重要。对于情绪障碍，例如重度抑郁症和双相情感障碍，其诊断仅基于疾病学而不是病理生理学，因此存在明显的未满足的医学需求，以增进我们对潜在分子机制的理解，并开发具有改进功效的全新机制实验药物。在这种背景下，最近的临床前分子、细胞和行为发现已经开始揭示表观遗传机制的重要性，这些机制改变染色质结构并动态调节基因表达模式，可能在情绪障碍的病理生理学中发挥关键作用。在这里，我们将回顾最近的进展，涉及使用动物模型结合遗传和药理学探针来剖析针对这种染色质介导的神经可塑性的潜在分子机制和神经生物学后果。我们讨论了情绪稳定剂、抗抑郁药和抗精神病药的直接和间接影响的证据，以及它们的许多其他影响，对染色质修饰酶和特定基因组位点、特定细胞类型和大脑特定区域的表观遗传状态的影响。这些数据以及来自患者组织的研究结果也开始揭示情绪障碍的病理生理学和治疗中表观遗传机制的改变。我们总结了越来越多的证据，支持这一观点：选择性靶向染色质修饰复合物，包括含有组蛋白脱乙酰酶 (HDAC) 的复合物，提供了一种可逆地改变神经元染色质乙酰化状态的方法，并有益地影响神经元活动调节的基因转录和情绪相关行为。超越现有知识，我们讨论高分辨率全基因组方法，例如用于转录组分析的 RNA 测序 (RNA-Seq) 和用于分析染色质相关因子的全基因组占用率的染色质免疫沉淀测序 (ChIP-Seq)，如何开始提供关于神经系统中特定基因组位点以及染色质整体特性的前所未有的视图。当这些方法应用于模型系统的表征时，包括患者来源的诱导多能（iPS）细胞和诱导神经元（iN）的模型系统，将极大地影响我们对表观遗传机制以及遗传变异对人类基因组调节区域（可影响神经可塑性）的影响的理解。最后，我们指出了尚未解答的关键问题和需要额外数据的领域，以便更好地了解染色质介导的神经可塑性的靶向机制对于情绪和其他精神疾病的新治疗的潜力。
Developing novel therapeutics and diagnostic tools based upon an understanding of neuroplasticity is critical in order to improve the treatment and ultimately the prevention of a broad range of nervous system disorders. In the case of mood disorders, such as major depressive disorder and bipolar disorder, where diagnoses are based solely on nosology rather than pathophysiology, there exists a clear unmet medical need to advance our understanding of the underlying molecular mechanisms and to develop fundamentally new mechanism experimental medicines with improved efficacy. In this context, recent preclinical molecular, cellular, and behavioral findings have begun to reveal the importance of epigenetic mechanisms that alter chromatin structure and dynamically regulate patterns of gene expression that may play a critical role in the pathophysiology of mood disorders. Here, we will review recent advances involving the use of animal models in combination with genetic and pharmacological probes to dissect the underlying molecular mechanisms and neurobiological consequence of targeting this chromatin-mediated neuroplasticity. We discuss evidence for the direct and indirect effects of mood stabilizers, antidepressants, and antipsychotics, among their many other effects, on chromatin-modifying enzmyes and on the epigenetic state of defined genomic loci, in defined cell types and in specific regions of the brain. These data, as well as findings from patient-derived tissue, have also begun to reveal alterations of epigenetic mechanisms in the pathophysiology and treatment of mood disorders. We summarize growing evidence supporting the notion that selectively targeting chromatin-modifying complexes, including those containing histone deacetylases (HDACs), provides a means to reversibly alter the acetylation state of neuronal chromatin and benefically impact neuronal activity-regulated gene transcription and mood-related behaviors. Looking beyond current knowledge, we discuss how high-resolution, whole-genome methodologies, such as RNA-sequencing (RNA-Seq) for transcriptome analysis and chromatin immunoprecipitation-sequencng (ChIP-Seq) for analyzing genome-wide occupancy of chromatin-associated factors, are beginning to provide an unprecedented view of both specific genomic loci as well as global properties of chromatin in the nervous system. These methodologies when applied to the characterization of model systems, including those of patient-derived induced pluripotent (iPS) cell and induced neurons (iNs), will greatly shape our understanding of epigenetic mechanisms and the impact of genetic variation on the regulatory regions of the human genome that can affect neuroplasticty. Finally, we point out critical unanswered questions and areas where additional data are needed in order to better understand the potential to target mechanisms of chromatin-mediated neuroplasticity for novel treatments of mood and other psychiatric disorders.
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影响因子：
3.7
作者：
Beconi M;Aziz O;Matthews K;Moumné L;O'Connell C;Yates D;Clifton S;Pett H;Vann J;Crowley L;Haughan AF;Smith DL;Woodman B;Bates GP;Brookfield F;Bürli RW;McAllister G;Dominguez C;Munoz-Sanjuan I;Beaumont V
通讯作者：
Beaumont V
DOI：
10.1523/jneurosci.1758-09.2009
发表时间：
2009-09-16
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Covington HE 3rd;Maze I;LaPlant QC;Vialou VF;Ohnishi YN;Berton O;Fass DM;Renthal W;Rush AJ 3rd;Wu EY;Ghose S;Krishnan V;Russo SJ;Tamminga C;Haggarty SJ;Nestler EJ
通讯作者：
Nestler EJ
影响因子：
14.8
作者：
Bradner, James E.;West, Nathan;Grachan, Melissa L.;Greenberg, Edward F.;Haggarty, Stephen J.;Warnow, Tandy;Mazitschek, Ralph
通讯作者：
Mazitschek, Ralph
影响因子：
56.9
作者：
Choudhary, Chunaram;Kumar, Chanchal;Mann, Matthias
通讯作者：
Mann, Matthias
影响因子：
4.7
作者：
Cheung AY;Horvath LM;Carrel L;Ellis J
通讯作者：
Ellis J