Department of Molecular Biology, University of Texas Southwestern Medical Center, TX 75390, USA.
Neurobiol Dis. 2010 Jul;39(1):73-84. doi: 10.1016/j.nbd.2010.01.008. Epub 2010 Jan 28.
In mature, differentiated neurons in the central nervous system (CNS), epigenetic mechanisms--including DNA methylation, histone modification, and regulatory noncoding RNAs--play critical roles in encoding experience and environmental stimuli into stable, behaviorally meaningful changes in gene expression. For example, epigenetic changes in mature hippocampal neurons have been implicated in learning and memory and in a variety of neuropsychiatric disorders, including depression. With all the recent (and warranted) attention given to epigenetic modifications in mature neurons, it is easy to forget that epigenetic mechanisms were initially described for their ability to promote differentiation and drive cell fate in embryonic and early postnatal development, including neurogenesis. Given the discovery of ongoing neurogenesis in the adult brain and the intriguing links among adult hippocampal neurogenesis, hippocampal function, and neuropsychiatric disorders, it is timely to complement the ongoing discussions on the role of epigenetics in mature neurons with a review on what is currently known about the role of epigenetics in adult hippocampal neurogenesis. The process of adult hippocampal neurogenesis is complex, with neural stem cells (NSCs) giving rise to fate-restricted progenitors and eventually mature dentate gyrus granule cells. Notably, neurogenesis occurs within an increasingly well-defined "neurogenic niche", where mature cellular elements like vasculature, astrocytes, and neurons release signals that can dynamically regulate neurogenesis. Here we review the evidence that key stages and aspects of adult neurogenesis are driven by epigenetic mechanisms. We discuss the intrinsic changes occurring within NSCs and their progeny that are critical for neurogenesis. We also discuss how extrinsic changes occurring in cellular components in the niche can result in altered neurogenesis. Finally we describe the potential relevance of epigenetics for understanding the relationship between hippocampal neurogenesis in neuropsychiatric disorders. We propose that a more thorough understanding of the molecular and genetic mechanisms that control the complex process of neurogenesis, including the proliferation and differentiation of NSCs, will lead to novel therapeutics for the treatment of neuropsychiatric disorders.
在中枢神经系统（CNS）中成熟的分化神经元中，表观遗传机制（包括 DNA 甲基化、组蛋白修饰和调节性非编码 RNA）在将经验和环境刺激编码为基因表达的稳定、具有行为意义的变化方面发挥着关键作用。例如，成熟海马神经元中的表观遗传变化与学习和记忆以及多种神经精神疾病有关，包括抑郁症。由于最近（并且有充分理由）关注成熟神经元中的表观遗传修饰，很容易忘记表观遗传机制最初是因其在胚胎和早期产后发育（包括神经发生）中促进分化和驱动细胞命运的能力而被描述的。鉴于成年大脑中持续存在神经发生以及成年海马神经发生、海马功能和神经精神疾病之间的有趣联系，及时补充关于表观遗传学在成熟神经元中的作用的讨论，以审查目前已知的表观遗传学在成年海马神经发生中的作用是适时的。成年海马神经发生的过程很复杂，神经干细胞（NSC）产生命运受限的祖细胞，最终成熟为齿状回颗粒细胞。值得注意的是，神经发生发生在一个日益明确的“神经发生龛”内，其中成熟的细胞成分，如血管、星形胶质细胞和神经元，释放可以动态调节神经发生的信号。在这里，我们回顾了证据表明，成年神经发生的关键阶段和方面受表观遗传机制的驱动。我们讨论了对神经发生至关重要的 NSCs 及其后代中发生的内在变化。我们还讨论了龛内细胞成分中发生的外在变化如何导致神经发生改变。最后，我们描述了表观遗传学对于理解神经精神疾病中海马神经发生的潜在相关性。我们提出，更深入地了解控制 NSCs 的增殖和分化等复杂神经发生过程的分子和遗传机制，将为神经精神疾病的治疗带来新的治疗方法。
