Evolving methodologies and concepts in 4D nucleome research

Abstract

The genome requires tight regulation in space and time to maintain viable cell functions. Advances in our understanding of the 3D genome show a complex hierarchical network of structures, involving compartments, membraneless bodies, topologically associating domains, lamina associated domains, protein- or RNA-mediated loops, enhancer-promoter contacts, and accessible chromatin regions, with chromatin state regulation through epigenetic and transcriptional mechanisms. Further technology developments are poised to increase genomic resolution, dissect single-cell behaviors, including in vivo dynamics of genome folding, and provide mechanistic perspectives that identify further 3D genome players by integrating multiomics information. We highlight recent key developments in 4D nucleome methodologies and give a perspective on their future directions.

Keywords: 3D topology; Genome; Imaging; Long-range chromatin contacts; Single-cell biology.

Figure 1. Challenges in 4D genome research.

Schematic representation of major features of the interphase genome organization that have been described so far. These include genomic features such as compartments, topologically associating domains (TADs), complex regulatory interactions, and how the genome is organized around nuclear bodies and the lamina. Further technological developments will potentially solve major challenges that remain the 4D genome (highlighted in pink boxes).