Transcription factors as drivers of 3D enhancer-promoter interactions

The molecular basis for specific pairing between transcriptional enhancers and promoters remains a highly active area of investigation, even over four decades after enhancers were first discovered. Numerous studies have explored general mechanisms such as those involving the cohesin/CTCF system and the core transcriptional machinery, including RNA polymerase 2, but these fail to account for the specificity of gene expression across cell types, maturation stages, and cell cycle intervals. Genetic loss of tissue-specific transcription factors provided early insights, but the findings were fraught with potentially confounding secondary effects. The advent of tools permitting rapid protein degradation has changed that. Here we discuss recent studies of illustrative mammalian transcription (co-) factors with architectural roles that contribute to enhancer-promoter communication, and contextualize their functions within generic chromatin-organizing principles.