An RNA-centric view of transcription and genome organization

Abstract

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.

Keywords: RNA; RNA-binding proteins; biomolecular condensates; feedback; gene expression; genome organization; transcription; transcription factors.

Figure 1. Active regulatory elements are transcribed.

(A) Depiction of the types of gene regulatory elements that exist within gene neighborhoods and are bidirectionally transcribed (RNA Pol II: RNA polymerase II; pre-mRNA: pre-messenger RNA; lncRNA: long non-coding RNA). (B) Table of types of RNAs transcribed from gene regulatory elements, including their features and half-lives^,–. Note that there are many additional types of RNAs, such as short stable miRNAs derived from processed RNA precursors, that are not presented here (uaRNA: upstream antisense RNA; paRNA: promoter-associated RNA; PROMPT: promoter upstream transcripts).

Figure 2. RNA molecules are bound by transcription factors and cofactors.

Many of the protein factors involved in transcription bind RNA at active genes. Boxes include examples of RNA-binding proteins, derived from a study by Oksuz et al. and corroborated by previous studies cited throughout the review.

Figure 3. Actively transcribed loci nucleate assembly of proteins into compartments.

(A) Types of spatial compartments formed by interactions between protein, DNA, and RNA molecules at active genes. (B) Principles underlying the formation, dissolution, and dynamics of spatial compartments, mediated by condensates.

Figure 4. RNA is a general regulator of condensate physicochemistry and dynamics.

(A) RNA can act as a scaffolding molecule to stimulate formation of condensates (B) RNA modifies condensate composition and material properties, such as surface tension depicted as wetting against a surface. (C) Increasing RNA levels at constant protein levels can lead to reentrant phase transitions, where RNA initially stimulates condensate formation near charge balance, but then stimulates condensate dissolution through like-like repulsive interactions.