G-Quadruplexes at the ‘Interface’ of Transcription and Alternative Splicing

DNA and RNA G-quadruplexes (G4s and rG4s, respectively) are well-known modulators of transcription and splicing. G4s are enriched in transcriptionally active chromatin domains that produce transcripts susceptible to alternative splicing (AS), at least in higher vertebrates. These domains are arranged close to nuclear speckles (NSs), where key AS regulators are stored. Recent findings have revealed new aspects of cotranscriptional AS, emphasizing the advantages of transient rG4s and revealing the connection between excessive rG4s and disease. Here, we discuss how (r)G4s’ presumed ability to promote liquid–liquid phase separation at active chromatin and their affinity for dual regulators of transcription and splicing has brought them to the forefront of communication between NSs and their associated chromatin domains. We also discuss how NS components may contribute to maintaining balanced (r)G4 folding, provide examples of imbalance, and analyze the prospects of G4-based AS reprogramming.