Toward 3-D genome visualization with in situ cryo-electron tomography

This review focuses on how cryo-electron tomography (cryo-ET) is contributing to the structural cell biology of eukaryotic chromatin in situ (inside cells) and on the technologies needed to unite the structural cell biology and 3-D genomics fields. Cryo-ET is a form of cryo-EM in which a frozen-hydrated sample is imaged from multiple views; these 2-D images are then computationally processed into a 3-D image called a cryotomogram. Cryo-ET is applicable to purified/constituted nucleosome arrays, isolated chromosomes, isolated nuclei, cells, and tissues. The imaging of cells and tissues makes in situ cryo-ET a powerful approach to study chromatin structure inside cells in a life-like state. This field is in its infancy and lacks the throughput and scalability of genomics. Once several key labeling and image-analysis technologies mature, "structural genomics" will provide both nanometer 3D spatial resolution and base-pair sequence-space resolution to address fundamental mechanisms of gene regulation inside cells.