3C-based technologies to study the shape of the genome.

Ever since microscopes enabled visualization of the organization of eukaryotic cells, scientists have been fascinated by the function and structure of their largest organelle, the cell nucleus [1,2]. The realization that this is the compartment where the cell stores its genetic material further intensified research on nuclear organization. Studying the in vivo folding of chromosomes long relied predominantly on microscopy. Fluorescence in situ hybridization (FISH) in particular has been, and still is, instrumental for localizing the positions of whole chromosomes, individual loci and actively transcribed genes in nuclei of single cells. Sophisticated FISH strategies revealed that that the nucleus may be structurally and functionally compartmentalized with active and inactive genes adopting different sub-nuclear positions [3]. They also highlighted the probabilistic nature of genome folding, by showing cell-to-cell differences in the positioning of chromosomes and genes [4]. Classical FISH studies however are limited in throughput and resolution. Although resolution continues to improve, FISH cannot provide the fine-structure of chromosomal sub-regions where regulatory sequences communicate with target genes. The technique can be applied to interrogate contacts between more distal chromosomal sites, but only between those selected by the investigator.

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