Engineering three-dimensional genome folding

Recent technologies allow experimental manipulation of chromatin conformation. This Perspective discusses the insights obtained from gain-of-function studies that engineer the three-dimensional genome. Animal genomes are partitioned and folded at various scales that contribute distinctly to nuclear processes. While structural features have been disrupted either globally or at select loci in loss-of-function studies, gain-of-function studies that probe the role of genome architecture have lagged behind. Here we examine recent advances in experimentally creating chromatin loops, contact domains, boundaries and compartments. Furthermore, we explore parallels between this emerging theme and natural evolution of mammalian genomes with increasing architectural complexity. Finally, we provide a perspective on how insights arising from recent gain-of-function studies may inform future endeavors toward engineering the three-dimensional genome.