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Genome function depends on its 3D organization. In the nucleus of eukaryotic cells, interphase chromosomes occupy distinct territories with respect to each other (1) (Fig. 1), and the spatial positioning of genomic segments affects ongoing DNA transactions. In recent years, the combination of advanced imaging techniques and new molecular approaches revealed the occurrence of previously underestimated long-range intrachromosomal and even interchromosomal interactions that have been linked to fundamental biological processes such as genomic imprinting (2), X-chromosome inactivation (3), and developmentally regulated programs (4). Therefore, considerable interest is growing around the study of 3D models of gene expression, focused on describing the fine-grain organization of chromatin architecture and the key players mediating and controlling long-range contacts. The development of Hi-C (high-throughput detection of chromosomal interactions) technology has markedly advanced the field and has revealed that chromosome territories are further arranged into large megabase-sized topological domains (5) that are highly conserved and stable across the cell type (6). In contrast, subregions within each domain are dynamic and may be responsible for cells' type-specific regulatory events (Fig. 1). As the boundaries between different domains dictate their spatial organization and function, understanding the contribution of factors that demarcate domain boundaries is of compelling importance. The work of Zuin et al. in PNAS explores the 3D architecture of the genome by studying the contributions of two leading players in loop organization: the CCCTC-binding factor (CTCF) and the cohesin complex (7). CTCF is a highly conserved protein with a unique structure that confers a versatile role in genome function (8). Through the 11 zinc fingers of its DNA-binding domain, …

CTCF and cohesin cooperate to organize the 3D structure of the mammalian genome