The saying that one only truly understands what one can build also holds for deciphering the biological impact of genome structure. Many methods have been developed to profile a genome’s arrangement in 3D. A collection of articles on the 3D genome attests to the richness of methodological development in chromosome conformation capture methods, as well as advances in microscopy techniques for imaging genome structure.

Engineering in 3D. Credit: Marina Corral Spence/Springer Nature

Last year we highlighted the importance of both approaches in our call for a dynamic 3D genome. As important as this basic understanding is, it was encouraging to see that in recent years the ability to decipher how chromatin folds in a cell has been augmented by approaches that engineer such folding. Methods that build chromatin interactions then allow the assessment of the interaction’s effects on transcription.

A group led by Gerd Blobel at the University of Pennsylvania saw increased transcriptional bursts when they forced contacts between a β-globin gene enhancer and the gene’s promoter by tethering to the enhancer a self-associating protein domain that interacted with a zinc finger at the promoter (Mol. Cell 62, 237–247; 2016). A year later Kevin Wang and colleagues developed chromatin loop reorganization using CRISPR–dCas9 (CLOuD9). They also targeted the β-globin gene locus and its enhancers with orthogonal Cas9 species fused to dimerization domains that came together once the dimerization trigger was added. The forced interaction resulted in β-globin expression in a cell line where the gene was silent (Nat. Commun. 8, 15993; 2017). In a conceptually similar approach, a group from the University of Adelaide induced the heterodimerization of two orthogonal dCas9 species and showed looping in bacterial genomes (Nat. Commun. 8, 1628; 2017). Recently, a group of scientists from Stanford introduced CRISPR-GO, a system that allows the inducible repositioning of genomic loci toward the nuclear periphery (Cell 175, 1405–1417; 2018). This allowed the researchers to look at the connection between the expression of a gene and its 3D position in the nucleus.

More efforts are under way to direct chromatin movement in precise and controllable ways. These include faster inducers of interactions, techniques that can bring together domains spanning long ranges in linear distance, and engineering of multisite contacts. Methods like these will not only shed light on spatial organization’s role in and importance to the integrity of a cell, but also show how one can design genome architecture to regulate biological processes and influence cell behavior.