At any time in the human body, in approximately 30 trillion cells, DNA is being "read" into messenger RNA (mRNA) molecules, an intermediate step between DNA and protein, a process called transcription. Scientists have a good understanding of how transcription begins: proteins called RNA polymerase are recruited to specific regions of DNA molecules and begin to move along the DNA strand, synthesizing mRNA molecules as they go. But part of the process is unclear: how do cells know when to stop transcription?
Now, in a new study, researchers from the Whitehead Institute for Biomedical Research and the Massachusetts Institute of Technology have found that RNA molecules regulate their own formation through a feedback loop. When there are too few RNA molecules, the cell initiates transcription to produce more RNA molecules. However, at a certain threshold, too many RNA molecules cause transcription to stop. The results of the study were published online in the journal Cell with the title of "RNA-Mediated Feedback Control of Transcriptional Condensates".
Figure 1. A Model for RNA-Mediated Feedback Control of Transcriptional Condensates. (Henninger J E, et al., 2020)
Previous research work has focused on transcriptional condensates, which are small transcriptional droplets that aggregate molecules needed for DNA transcription into RNA. Transcriptional condensates can compartmentalize and concentrate a large number of transcription factors, cofactors, and RNA Pol II at super-enhancers, clusters of enhancers that regulate genes with important roles in cell identity. The component enhancer elements of these genes promote transcriptional condensate formation by aggregating transcription factors and Mediator at densities above sharply defined thresholds for condensate formation. Transcriptional condensates are highly dynamic and can be observed in live cells to form and dissolve over a time range from seconds to minutes. The periodic formation and dissolution of dynamic transcriptional condensates, together with evidence that different species and levels of RNAs are produced at different stages of transcription, makes researchers doubt whether transcriptional condensates are regulated by a non-equilibrium feedback mechanism mediated by its RNA product.
RNA molecules are components of and play regulatory roles in multiple biomolecular condensates. Condensates are considered to be formed by an ensemble of low-affinity molecular interactions, including electrostatic interactions, and RNA can be a powerful regulator of condensates formed and maintained by electrostatic forces. The study suggests that transcription is a nonequilibrium process, which provides dynamic feedback through its RNA product. The results support a model where RNA provides positive and negative feedback on transcription by regulating electrostatic interactions in transcriptional condensates. The formation of transcriptional condensates involves the crowding of transcription factors by enhancer DNA and electrostatic and other interactions between the IDRs of transcription factors and coactivators, engage RNA to both promote and dissolve the condensates. In this RNA feedback model, low levels of short RNAs produced during transcription initiation promote the formation of transcriptional condensates, whereas high levels of the longer RNAs produced during elongation can lead to the dissolution of condensate.
Researchers believe that understanding this new role of RNA in cells may provide information for the treatment of a variety of diseases. A deeper understanding of RNA behavior may provide information for broader treatment. In the past 10 years, a variety of drugs have been developed that have successfully targeted RNA directly. Understanding how RNA molecules regulate gene expression provides a bridge between gene disorders in diseases and new therapies targeting RNA.