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Abstract

The causal relationship between 3D chromatin domains and gene regulation has been of considerable debate in recent years. Initial Hi-C studies profiling the 3D chromatin structure of the genome described evolutionarily conserved Topologically Associating Domains (TADs) that correlated with gene expression. Subsequent evidence from mouse models and human disease directly linked TADs to gene regulation. However, a number of focused genetic and genome-wide studies questioned the relevance of 3D chromatin domains for orchestrating gene expression, ultimately yielding a more multi-layered view of 3D chromatin structure and gene regulation. We review the evidence for and against the importance of 3D chromatin structure for gene regulation and argue for a more comprehensive classification of regulatory chromatin domains that integrates 3D chromatin structure with genomic, functional, and evolutionary conservation.