Epigenetic principles and mechanisms underlying nervous system functions in health and disease.
Epigenetic principles and mechanisms underlying nervous system functions in health and disease.
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DOI：
10.1016/j.pneurobio.2008.10.001
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发表时间：
2008-12-11
影响因子：
6.7
通讯作者：
Mehler, Mark F.
中科院分区：
文献类型：
--
作者：
Mehler, Mark F.
关键词：
EpigeneticsChromatin remodelingNon-coding RNAsRNA and DNA editingRNA regulatory networksNuclear architectureStem cell biologyLearning and memoryNeuropsychiatric diseasesNeurodevelopmental disordersNeurodegenerative diseasesNeurooncologyNeuroimmunologyCerebrovascular disordersEnvironmental epigenomicsPharmacoepigenomics
表观遗传学和表观基因组医学涵盖了大脑和行为的新科学，已经为大脑发育，进化，神经元和网络可塑性和稳态，衰老，各种神经系统疾病和神经再生过程的病因学机制提供了独特的见解。表观遗传机制包括DNA甲基化、组蛋白修饰、核小体重新定位、高阶染色质重塑、非编码RNA以及RNA和DNA编辑。RNA是参与指导这些过程的中心，这意味着细胞的转录状态是表观遗传记忆的主要决定因素。这种转录状态可以通过影响基因表达和转录后加工的内部和外部线索进行修饰，也可以通过RNA和DNA编辑，通过活性依赖性细胞内转运和调节RNA和RNA调控超复合物，以及通过功能RNA亚类的跨神经元和系统运输。这些整合过程促进了核结构和基因组景观的动态重组，以调节具有复杂时空轨迹的功能基因和神经网络。表观遗传学代表了在整个生命周期的关键时期介导基因-环境相互作用的分子界面。环境表观基因组学的学科已经开始确定环境应激源的组合概况，其调节特定神经系统疾病的潜伏期、起始和进展，以及对新兴治疗干预的更有选择性的疾病生物标志物和分级的分子反应。药物表观基因组疗法将通过内源性区域神经干细胞命运决定的表观遗传重编程、靶向组织重塑和神经网络完整性、可塑性和连接性的恢复，促进受损和似乎可恢复的认知、行为、感觉运动功能的加速恢复。
Epigenetics and epigenomic medicine encompass a new science of brain and behavior that are already providing unique insights into the mechanisms underlying brain development, evolution, neuronal and network plasticity and homeostasis, senescence, the etiology of diverse neurological diseases and neural regenerative processes. Epigenetic mechanisms include DNA methylation, histone modifications, nucleosome repositioning, higher-order chromatin remodeling, non-coding RNAs, and RNA and DNA editing. RNA is centrally involved in directing these processes, implying that the transcriptional state of the cell is the primary determinant of epigenetic memory. This transcriptional state can be modified by internal and external cues affecting gene expression and post-transcriptional processing, but also by RNA and DNA editing through activity-dependent intracellular transport and modulation of RNAs and RNA regulatory supercomplexes, and through trans-neuronal and systemic trafficking of functional RNA subclasses. These integrated processes promote dynamic reorganization of nuclear architecture and the genomic landscape to modulate functional gene and neural networks with complex temporal and spatial trajectories. Epigenetics represents the long sought after molecular interface mediating gene-environmental interactions during critical periods throughout the lifecycle. The discipline of environmental epigenomics has begun to identify combinatorial profiles of environmental stressors modulating the latency, initiation and progression of specific neurological disorders, and more selective disease biomarkers and graded molecular responses to emerging therapeutic interventions. Pharmacoepigenomic therapies will promote accelerated recovery of impaired and seemingly irrevocably lost cognitive, behavioral, sensorimotor functions through epigenetic reprogramming of endogenous regional neural stem cell fate decisions, targeted tissue remodeling and restoration of neural network integrity, plasticity and connectivity.
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