Insights into gene regulation: From regulatory genomic elements to DNA-protein and protein-protein interactions.

Transcription is orchestrated by non-coding regulatory elements embedded in chromatin, which exist within the larger context of chromosome topology. Here, we review recent insights into the functions of non-coding regulatory elements and their protein interactors during transcription control. A picture emerges in which the topological environment constraints enhancer-promoter interactions and specific enhancer-bound proteins with distinct promoter-compatibilities refine target promoter choice. Such compatibilities are encoded within the sequences of enhancers and promoters and realized by diverse transcription factors and cofactors with distinct biochemical activities. An emerging property of transcription factors and cofactors is the formation of nuclear microenvironments or membraneless compartments that can have properties of phase-separated liquids. These environments are able to selectively enrich certain proteins and small molecules over others. Further investigation into the interaction of transcriptional regulators with themselves and regulatory DNA elements will help reveal the complexities of gene regulation within the context of the nucleus.