CTCF knockout in zebrafish induces alterations in regulatory landscapes and developmental gene expression

CTCF is as an architectural protein involved in 3D genome folding; however its contribution to animal development has not been well characterized. Here the authors show that CTCF is not only pivotal for 3D chromatin structure and enhancer-promoter interactions in zebrafish, but it is also essential for controlling the expression of thousands of genes during development. Coordinated chromatin interactions between enhancers and promoters are critical for gene regulation. The architectural protein CTCF mediates chromatin looping and is enriched at the boundaries of topologically associating domains (TADs), which are sub-megabase chromatin structures. In vitro CTCF depletion leads to a loss of TADs but has only limited effects over gene expression, challenging the concept that CTCF-mediated chromatin structures are a fundamental requirement for gene regulation. However, how CTCF and a perturbed chromatin structure impacts gene expression during development remains poorly understood. Here we link the loss of CTCF and gene regulation during patterning and organogenesis in a ctcf knockout zebrafish model. CTCF absence leads to loss of chromatin structure and affects the expression of thousands of genes, including many developmental regulators. Our results demonstrate the essential role of CTCF in providing the structural context for enhancer-promoter interactions, thus regulating developmental genes.