Abstract
The mammalian genome is hierarchically packaged into distinct functional units, including chromatin loops, topologically associating domains, compartments and chromosome territories. This structural organization is fundamentally important because it orchestrates essential nuclear functions that underpin normal cellular identity and organismal development. In this review, we synthesize current understanding of the intricate relationship between genome architecture and its critical biological roles. We discuss how hierarchical structures are dynamically established and maintained by architectural proteins, transcription factors, epigenetic regulators and non-coding RNAs via distinct mechanisms. Importantly, we focus on the functional consequences of three-dimensional (3D) genome organization and discuss how it modulates fundamental biological processes such as transcription, gene co-expression, epigenetic modification, DNA replication and repair. We also examine the dynamics of 3D genome organization during cellular differentiation, early embryonic development and organogenesis, followed by discussing how structural disruptions are mechanistically linked to various human diseases. Understanding the biological function of 3D genome organization is thus not only essential for deciphering fundamental nuclear processes but also holds significant promise for elucidating disease etiologies and developing effective therapeutics.