Non-coding RNAs could fine-tune transcription of proximal genes by modulating dynamics of transcriptional condensates

Bio-molecular factories called transcriptional condensates transcribe several genes associated with cell identity and cancer. They are dense assemblies of transcriptional proteins that form at genomic regions with a high density of protein-binding DNA called super-enhancers (SE). Some of these proteins have positively charged disordered domains that can interact via screened electrostatic interactions with the negatively charged phosphate backbone of RNAs. Using a free energy functional that takes into account the interactions between the different molecular species, we modeled the dynamics of concentration fields using Model B dynamics for the stable protein and non-coding RNA coupled to a reaction-diffusion equation for the transcribed mRNA that pushes the system far away from equilibrium. In the absence of active mRNA transcription, we predict that non-coding RNAs localized near SEs can aid the recruitment of transcriptional proteins by (i) serving as an attractive well to nucleate the condensate and (ii) by jumping over to the condensate after its formation to help it recruit more protein. When there is active mRNA transcription, we predict that non-coding RNAs localized nearby can initially “accelerate” protein recruitment and mRNA transcription at the SE. As more mRNA is produced, the unfavorable electrostatic repulsion between the RNA species “slows down” protein recruitment and mRNA transcription. The tussle between these two effects determines the total amount of mRNA transcribed over time. The consequences of this mechanism could explain some puzzles related to gene regulation by non-coding RNAs such as the sequence-independent effect of certain non-coding RNAs on gene expression and why non-coding RNAs promote gene expression in certain cases and repress gene expression in others.