Three-dimensional genome architecture: players and mechanisms

Contacts between distant genomic regions in the same or in different chromosomes are important in the regulation of gene expression, as highlighted by the activation of genes by chromatin contacts between promoters and enhancers that can lie hundreds of kb away.Chromatin contacts are currently measured by two main approaches: chromosome conformation capture (3C)-based techniques and nuclear imaging methods such as fluorescence in situ hybridization (FISH). Both approaches have caveats, and the field is ripe for further technical development.The formation of chromatin contacts is promoted by chromatin-binding proteins that can bind two or more genomic regions simultaneously. Such proteins include transcription factors, RNA and DNA polymerases, Polycomb repressive complexes and chromosomal scaffold proteins such as cohesin.Topologically associating domains (TADs) are genomic regions enriched with contacts within them. TADs have specific sizes and positions in the genome and are found in a wide range of metazoans. The factors and mechanisms that promote TAD formation are a matter of considerable debate.The three-dimensional organization of the genome also depends on the formation of chromatin contacts with nuclear domains and compartments such as the nuclear lamina and the nucleolus. Specific sets of chromatin contacts are formed within each chromosome, and between them and nuclear domains. The mechanisms that govern chromosome localization, volume and shape remain poorly understood.Many cellular processes such as division, differentiation and senescence, present challenges to the maintenance of nuclear organization, gene expression programs and cell identity. At the same time, they can also offer opportunities for chromatin remodelling and the reinforcement of gene expression patterns.