Nuclear RNA forms an interconnected network of transcription-dependent and tunable microgels

The human cell nucleus is comprised of proteins, chromatin and RNA, yet how they interact to form supramolecular structures and drive key biological processes remains unknown. Conflicting models have proposed either a fluid-like or solid-like nature for the intranuclear microenvironment. To reconcile this discrepancy, we investigated the 3D structure and properties of the nuclear interior using experiments and computer simulations. We reveal a novel mechanism where newly synthesized RNA interacts with SAF-A (scaffold attachment factor A, or HNRNPU), forming interconnected microgels degraded by the exonuclease XRN2, leading to dynamic cycles of gelation and fluidization. This emergent microgel network depends on transcription, and is disrupted by SAF-A depletion. It also decreases protein mobility and regulates chromatin compaction by modulating microphase separation, thereby opening transcriptionally active regions. This tunable intranuclear network exhibits scale-dependent fluid- and solid-like features, that we suggest may regulate transcription by controlling access to regulatory proteins and polymerases.

Highlights

RNA and SAF-A interact to form clusters that form a nuclear-spanning network of microgels

Emergent microgel network requires transcription and XRN2 activity to undergo gelation and fluidization

Microgel network impacts nuclear protein mobility

Molecular dynamics modelling shows RNA/SAF-A microgels regulate chromatin decompaction by steric hinderance

Graphical Abstract