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bioRxiv · 10.1101/2023.01.04.522753

A model for cis-regulation of transcriptional condensates and gene expression by proximal lncRNAs

Natarajan, P.·Shrinivas, K.·Chakraborty, A. K.
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Abstract

Long non-coding RNAs (lncRNAs) perform several important functions in cells including cis-regulation of transcription. Barring a few specific cases, the mechanisms underlying transcriptional regulation by lncRNAs remain poorly understood. Transcriptional proteins can form condensates via phase separation at protein-binding loci (BL) on the genome (e.g., enhancers and promoters). lncRNA-coding genes are present at loci in close genomic proximity of these BL and these RNAs can interact with transcriptional proteins via attractive heterotypic interactions mediated by their net charge. Motivated by these observations, we propose that lncRNAs can dynamically regulate transcription in cis via charge-based heterotypic interactions with transcriptional proteins in condensates. To study the consequences of this mechanism, we developed and studied a dynamical phase-field model. We find that proximal lncRNAs can promote condensate formation at the BL. Vicinally localized lncRNA can migrate to the BL to attract more protein because of favorable interaction free energies. However, increasing the distance beyond a threshold leads to a sharp decrease in protein recruitment to the BL. This finding could potentially explain why genomic distances between lncRNA-coding genes and protein-coding genes are conserved across metazoans. Finally, our model predicts that lncRNA transcription can fine-tune transcription from neighboring condensate-controlled genes, repressing transcription from highly expressed genes and enhancing transcription of genes expressed at a low level. This non-equilibrium effect can reconcile conflicting reports that lncRNAs can enhance or repress transcription from proximal genes. SIGNIFICANCELong non-coding RNAs (lncRNAs) form a significant part of the human genome but do not code for any proteins. They have many hypothesized functions in the cell, including the regulation of transcription. Transcriptional condensates are assemblies of transcriptional proteins that concentrate at specific genomic sites through phase separation and can regulate transcription. In this study, we propose that lncRNAs can regulate transcription by interacting with proteins in transcriptional condensates to modulate condensate formation. We find that this model can explain some puzzling observations such as conflicting reports of gene activation and repression by lncRNAs, and conservation of genomic distances between lncRNA-coding genes relative to protein-coding genes in metazoans. Experimentally testable predictions that can further explore our model are discussed.

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Natarajan, P., Shrinivas, K., Chakraborty, A. K.. 2023-01-04. A model for cis-regulation of transcriptional condensates and gene expression by proximal lncRNAs. https://doi.org/10.1101/2023.01.04.522753

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