Eukaryotic transcriptional dynamics: from single molecules to cell populations

• Published in: Nature reviews. Genetics Vol. 14; no. 8; pp. 572 - 584
• Main Authors: Coulon, Antoine, Chow, Carson C., Singer, Robert H., Larson, Daniel R.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.08.2013; Nature Publishing Group
• Subjects: Agriculture; Animal Genetics and Genomics; Biology; Biomedicine; Cancer Research; DNA-Directed RNA Polymerases - genetics; DNA-Directed RNA Polymerases - metabolism; Gene expression; Gene Expression Regulation; Gene Function; Genetic regulation; Genetic transcription; Genome, Human; Genomes; Human Genetics; Humans; Kinases; Medical research; Microscopy; Molecular genetics; review-article; RNA polymerase; RNA sequencing; Transcription Factors - genetics; Transcription Factors - metabolism; Transcription, Genetic; United States; United States > US; Maryland
• ISSN: 1471-0056; 1471-0064
• DOI: 10.1038/nrg3484

Key Points Single-molecule and genome-wide studies of transcription reveal the importance of dynamics for understanding the mechanisms of gene regulation. A single gene can be regulated by dozens of factors interacting in a combinatorial manner. Observing all such interactions experimentally is still a daunting task, but computational models of transcription dynamics can provide insight into the underlying mechanisms. Molecular models of transcription often emphasize sequential, ordered recruitment, for example in the formation of a pre-initiation complex at a promoter. These sequential processes are best-described by non-equilibrium thermodynamics, in which kinetics and energy dependence are treated explicitly. Models based on non-equilibrium thermodynamics provide insight into a range of transcription phenomena, including nucleosome positioning, transcriptional bursting, and refractory periods during transcription. Our understanding of transcription is being improved through single-molecule and genome-wide approaches. Quantitative models are also required to provide insights into the underlying mechanisms of transcription, and the authors discuss how experimental results and models can be brought together. Transcriptional regulation is achieved through combinatorial interactions between regulatory elements in the human genome and a vast range of factors that modulate the recruitment and activity of RNA polymerase. Experimental approaches for studying transcription in vivo now extend from single-molecule techniques to genome-wide measurements. Parallel to these developments is the need for testable quantitative and predictive models for understanding gene regulation. These conceptual models must also provide insight into the dynamics of transcription and the variability that is observed at the single-cell level. In this Review, we discuss recent results on transcriptional regulation and also the models those results engender. We show how a non-equilibrium description informs our view of transcription by explicitly considering time- and energy-dependence at the molecular level.