Nuclear Biology: What’s Been Most Surprising?

The regulatory potential of the human genome is much richer than some had anticipated. With greatly refined annotations, we now realize that each gene finds itself surrounded by a huge number of potentially regulatory elements in a very crowded nucleus. Given that many regulatory elements control genes through direct physical interaction, one can imagine that this could create a potentially risky situation in which genes get misregulated by chance encounters with inappropriate elements. So, a major question in the field of nuclear organization is how do cells ensure that genes only respond to the right regulatory elements while ignoring the hundreds of thousands of others? Recent work has revealed a surprisingly simple strategy for matching genes to only some regulatory elements, which involves the spatial organization and folding of chromosomes inside the nucleus. In Drosophila, mouse, and human nuclei, chromosomes are spatially compartmentalized. Using 5C and Hi-C technologies, it has been shown that chromosomes form strings of topologically associating domains (TADs) that are each hundreds of Kb in size but are spatially insulated fromneighboring TADs. As a result, a given gene lives in a relatively small neighborhood where it encounters only a small section of the genome and thus can partner with only a small number of regulatory elements. Future studies will no doubt unveil how TADs are established and how they insulate genes from the wrong crowd. Plasticity of Interpretation