Transcriptional condensates and the nuclear pore complex regulate gene expression and 3D genome architecture in...

Cells respond to thermal, chemical, and oxidative stress by activating an evolutionarily conserved adaptive mechanism known as the heat shock response (HSR) that maintains protein homeostasis and ensures cell survival. Central to the HSR is Heat Shock Factor 1 (HSF1), a highly conserved master transcription factor that up-regulates genes encoding molecular chaperones and other homeostasis factors in response to proteotoxic stress. In both yeast and mammals, the HSR is accompanied by the inducible formation of phase-separated condensates that concentrate components of the transcriptional machinery into discrete intranuclear foci. The assembly of these condensates may be driven by a combination of liquid-liquid phase separation and low-valency Interactions with spatially Clustered Binding Sites (ICBS). In budding yeast, these condensates - which contain HSF1, Mediator, and RNA polymerase II - drive concerted intraand interchromosomal interactions between HSF1 target genes, creating extensive DNA loops between regulatory and transcribed sequences. In this and other ways, yeast HSR genes resemble mammalian super-enhancers. Emerging evidence suggests that the nuclear pore complex (NPC) - a macromolecular assembly at the nuclear periphery that regulates protein and RNA transport across the nuclear membrane - serves as a scaffold for the formation of transcriptional condensates and maintains chromatin architecture. In yeast, nuclear basket proteins - which dynamically exchange between the NPC and nucleoplasm - contribute to the heat shock-induced intergenic clustering of HSF1 target loci, whereas essential NPC scaffold-associated proteins do not. Such gene clustering is accompanied by the formation of multiplexed HSR mRNAs that could potentially co-ordinate both mRNA export and translation. Here we review evidence that links genome architecture, transcriptional condensates, the NPC, and nuclear basket proteins and discuss potential implications for the treatment of disease.