Logeman Brandon L, Grieco Steven F, Holmes Todd C, Xu Xiangmin
Department of Molecular and Cellular Biology, Howard Hughes Medical Institute, Center for Brain Science, Harvard University, Cambridge, MA, USA.
Department of Anatomy and Neurobiology, School of Medicine, University of California, Irvine, CA, 92697, USA.
Mol Psychiatry. 2025 May 23. doi: 10.1038/s41380-025-03056-3.
The advent of single cell multi-omic technologies has ushered in a revolution in how we study the impact of three-dimensional genome organization on brain cellular composition and function. Transcriptomic and epigenomic studies reveal enormous cellular diversity that is present in mammalian nervous systems, raising the question, "how does this diversity arise and for what is its use?" Advances in the field of three-dimensional nuclear architecture have illuminated our understanding of how genome folding gives rise to dynamic gene expression programs important in healthy brain function and in disease. In this review we highlight recent work defining how neuronal identity, maturation, and plasticity are shaped by genome architecture. We discuss how newly identified genetic variations influence genome architecture and contribute to the evolution of species-unique neuronal and behavioral functional traits. We include examples for both humans and model organisms in which maladaptive genomic architecture is a causal agent in disease. Finally, we make conclusions and address future perspectives of dynamic three-dimensional genome (4D nucelome) research.
单细胞多组学技术的出现，为我们研究三维基因组组织对大脑细胞组成和功能的影响带来了一场革命。转录组学和表观基因组学研究揭示了哺乳动物神经系统中存在的巨大细胞多样性，这就引出了一个问题：“这种多样性是如何产生的，有什么作用？”三维核结构领域的进展，让我们对基因组折叠如何产生对健康大脑功能和疾病至关重要的动态基因表达程序有了更深入的理解。在这篇综述中，我们重点介绍了最近关于基因组结构如何塑造神经元身份、成熟和可塑性的研究工作。我们讨论了新发现的基因变异如何影响基因组结构，并促进物种独特的神经元和行为功能特征的进化。我们列举了人类和模式生物的例子，其中适应不良的基因组结构是疾病的致病因素。最后，我们得出结论并探讨动态三维基因组（4D核基因组）研究的未来前景。
