The relation between alterations in chromatin structure and changes in gene 
expression during cell differentiation has served as a paradigm to understand 
the link between genome organization and function. Yet, the factors involved and 
the mechanisms by which the 3D organization of the nucleus is established remain 
poorly understood. The use of Chromosome Conformation-Capture (3C)-based 
approaches has resulted in a new appreciation of the role of architectural 
proteins in the establishment of 3D genome organization. Architectural proteins 
orchestrate higher-order chromatin organization through the establishment of 
interactions between regulatory elements across multiple spatial scales. The 
regulation of these proteins, their interaction with DNA, and their 
co-occurrence in the genome, may be responsible for the plasticity of 3D 
chromatin architecture that dictates cell and time-specific blueprints of gene 
expression.