Marina Corral Spence/Nature Publishing Group
Chromosomes interact in cis and trans.
The real estate mantra that emphasizes location over all else is also applicable to mammalian genomes. Gene regulation depends on the organization of chromatin and its regulatory elements in three dimensions within the nucleus. Classical methods that capture chromatin conformation (3C) either at select loci or genome-wide have provided a glimpse into the intricate architecture of the genome. But to really understand this 3D organization, how it evolves over time and how it contributes to disease, researchers need new methods. 3C-derived techniques depend on cross-linking of interacting chromatin loci and on the ligation of these loci prior to amplification and sequencing. These steps limit the throughput of the method and favor interactions in cis rather than in trans. Recent improvements in multiplexing cis interactions that involve two sequential capture steps have increased throughput and resolution and allow the relative quantitation of weak and strong interactions, as well as the elucidation of their respective biological roles (Nat. Methods 13, 74–80, 2016).
For scientists to fully appreciate the dynamics of nuclear organization, it will be important to combine population-based models with data on individual cells at high resolution. This will require a multidisciplinary approach bringing together genomics, biophysics and imaging. The 4D Nucleome Program, recently funded by the US National Institutes of Health, is one initiative that seeks to combine such expertise and includes consortia to map genomic structure, apply high-resolution imaging and study the properties of subnuclear compartments. The goals for tool improvement include improved experimental and computational methods for single-cell nucleome resolution and for the visualization of genome folding.
Once the mapping of nuclear architecture becomes a more routine, quantitative procedure, we will be better able to determine and predict the effects of mutations—whether linked to disease or introduced during genome editing—on gene regulation and the mechanisms by which they act. We may even be able to specifically alter genome architecture to bring about desired changes in a cell.