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Foundational models of transcriptional regulation involve the assembly of protein complexes at DNA elements associated with specific genes. These assemblies, which can include transcription factors, cofactors, RNA polymerase, and various chromatin regulators, form dynamic spatial compartments that contribute to both gene regulation and local genome architecture. This DNA-protein-centric view has been modified with recent evidence that RNA molecules have important roles to play in gene regulation and genome structure. Here, we discuss evidence that gene regulation by RNA occurs at multiple levels that include assembly of transcriptional complexes and genome compartments, feedback regulation of active genes, silencing of genes, and control of protein kinases. We thus provide an RNA-centric view of transcriptional regulation that must reside alongside the more traditional DNA-protein-centric perspectives on gene regulation and genome architecture. 

Macroscopic membraneless organelles containing RNA such as the nucleoli, germ granules, and the Cajal body have been known for decades. These biomolecular condensates are liquid-like bodies that can be formed by a phase transition. Recent evidence has revealed the presence of similar microscopic condensates associated with the transcription of genes. This brief article summarizes thoughts about the importance of condensates in the regulation of transcription and how RNA molecules, as components of such condensates, control the synthesis of RNA. Models and experimental data suggest that RNAs from enhancers facilitate the formation of a condensate that stabilizes the binding of transcription factors and accounts for a burst of transcription at the promoter. Termination of this burst is pictured as a nonequilibrium feedback loop where additional RNA destabilizes the condensate. 

Abstract Insulin receptor (IR) signaling is central to normal metabolic control and is dysregulated in metabolic diseases such as type 2 diabetes. We report here that IR is incorporated into dynamic clusters at the plasma membrane, in the cytoplasm and in the nucleus of human hepatocytes and adipocytes. Insulin stimulation promotes further incorporation of IR into these dynamic clusters in insulin-sensitive cells but not in insulin-resistant cells, where both IR accumulation and dynamic behavior are reduced. Treatment of insulin-resistant cells with metformin, a first-line drug used to treat type 2 diabetes, can rescue IR accumulation and the dynamic behavior of these clusters. This rescue is associated with metformin’s role in reducing reactive oxygen species that interfere with normal dynamics. These results indicate that changes in the physico-mechanical features of IR clusters contribute to insulin resistance and have implications for improved therapeutic approaches. 

The nucleus contains diverse phase-separated condensates that compartmentalize and concentrate biomolecules with distinct physicochemical properties. Here, we investigated whether condensates concentrate small-molecule cancer therapeutics such that their pharmacodynamic properties are altered. We found that antineoplastic drugs become concentrated in specific protein condensates in vitro and that this occurs through physicochemical properties independent of the drug target. This behavior was also observed in tumor cells, where drug partitioning influenced drug activity. Altering the properties of the condensate was found to affect the concentration and activity of drugs. These results suggest that selective partitioning and concentration of small molecules within condensates contributes to drug pharmacodynamics and that further understanding of this phenomenon may facilitate advances in disease therapy.