Topology regulatory elements: from shaping genome architecture to gene regulation

The importance of 3D genome topology in the control of gene expression is becoming increasingly
apparent, while regulatory mechanisms remain incompletely understood. Several recent studies
have identified architectural elements that influence developmental gene expression by shaping
locus topology. We refer to these elements as topological regulatory elements (TopoREs) to
reflect their dual roles in genome organisation and gene expression. Importantly, these elements
do not harbour autonomous transcriptional activation capacity, and instead appear to facilitate
enhancer-promoter interactions, contributing to robust and precise timing of transcription. We
discuss examples of TopoREs from two classes that are either dependent or independent of
CTCF binding. Importantly, identification and interpretation of TopoRE function may shed light on
multiple aspects of gene regulation, including the relationship between enhancer-promoter
proximity and transcription, and enhancer-promoter specificity. Ultimately, understanding TopoRE
diversity and function will aid interpretation of how human sequence variation can impact
transcription and contribute to disease phenotypes.