Pitfalls and missing links in current understanding of 4D genomes

Abstract The spatial and temporal organization of the genome—collectively termed the 4D genome—is pivotal for regulating gene expression, maintaining genome stability, and guiding development. The convergence of chromosome conformation capture technologies, super‐resolution microscopy, and single‐cell epigenomics has transformed our understanding of chromatin structure and function. Despite these advances, critical gaps remain, particularly, in integrating multi‐scale data, interpreting dynamic cellular states, and bridging evolutionary and developmental processes. This critical review synthesizes recent findings and identifies three key conceptual pitfalls: scale transformation, temporal causality, and plasticity in evolutionary‐developmental dynamics. I also outline emerging methodologies and theoretical frameworks aimed at overcoming these challenges and propose directions for future research to achieve a unified and predictive model of a functional genome.