Mechanisms of Interplay between Transcription Factors and the 3D Genome

Transcription factors (TFs) bind DNA in a sequence-specific manner and thereby serve as the protein anchors and determinants of 3D genome organization. Conversely, chromatin conformation shapes TF activity, for example, by looping TF-bound enhancers to distally located target genes. Despite considerable effort, our understanding of the mechanistic relation between TFs and 3D genome organization remains limited, in large part due to this interdependency. In this review, we summarize the evidence for the diverse mechanisms by which TFs and their activity shape the 3D genome and vice versa. We further highlight outstanding questions and potential approaches for untangling the complex relation between TF activity and the 3D genome. Transcription factors shape 3D genome organization, which in turn affects transcription factor activity. Kim and Shendure review our current understanding of the mechanisms underlying this interdependency, discuss implications for transcriptional regulation, and propose approaches to address the key questions that remain.