Unfolding neural diversity: how dynamic three-dimensional genome architecture regulates brain function and disease

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.