Four-dimensional nuclear speckle phase separation dynamics regulate proteostasis

Abstract

Phase separation and biorhythms control biological processes in the spatial and temporal dimensions, respectively, but mechanisms of four-dimensional integration remain elusive. Here, we identified an evolutionarily conserved XBP1s-SON axis that establishes a cell-autonomous mammalian 12-hour ultradian rhythm of nuclear speckle liquid-liquid phase separation (LLPS) dynamics, separate from both the 24-hour circadian clock and the cell cycle. Higher expression of nuclear speckle scaffolding protein SON, observed at early morning/early afternoon, generates diffuse and fluid nuclear speckles, increases their interactions with chromatin proactively, transcriptionally amplifies the unfolded protein response, and protects against proteome stress, whereas the opposites are observed following reduced SON level at early evening/late morning. Correlative Son and proteostasis gene expression dynamics are further observed across the entire mouse life span. Our results suggest that by modulating the temporal dynamics of proteostasis, the nuclear speckle LLPS may represent a previously unidentified (chrono)therapeutic target for pathologies associated with dysregulated proteostasis.

The ultradian transcriptome of the human prefrontal cortex and abnormalities in schizophrenia

“…These findings indicate that 12 h rhythms in the brain are associated with processes necessary for essential cellular functions – and may be fundamental for timing processes to maximize resources and reserve energy when not needed. This is consistent with previous analyses in mouse liver, which uncovered 12 h rhythms in metabolism-related transcripts and processes fundamental to transcription, RNA splicing, translation and proteostasis [23,24]. The timing of these processes coincided with sleep/wake transition times, leading to the proposal of a vehicle-cargo hypothesis for 12 h rhythms, in which 12 h rhythmicity accommodates increased demand for gene expression/processing at biological ‘rush hours’ (i.e.…”

Biological 12-hour rhythm facilitates re-entrainment from circadian desynchrony and promotes psychological resilience during long-duration spaceflight

“…A 12-h oscillator independent from the 24-h circadian clock is thought to be regulated by the unfolded protein response (UPR) transcription factor spliced form of X-Box Binding Protein 1 (XBP1s) [27,28,29,30,31,32,34,35]. The 12-h rhythm provides an evolutionary advantage in mammals, including humans [25,28,30,33,63,64]. Previously, we reported that the 12-h component can be important for the rapid adaptation to microgravity in space [19].…”

“…1), and fostering psychological resilience in space (Table 5). It should come to no surprise since an XBP1s-SON axis implies a cellautonomous 12-h rhythm of nuclear speckle liquid-liquid phase separation (LLPS) dynamics [33,65]. A large protein called Son is essential for appropriate subnuclear organization of pre-mRNA splicing factors and for promoting normal cell cycle progression [66,67].…”

“…An evolutionarily conserved XBP1s-SON axis coordinates a rapidly functioning feedforward loop connecting nuclear speckle LLPS and proteostasis, resulting in a highly e cient genetic information transfer functioning at multiple temporal scales,. At the molecular level, it modulates the rates of chemical reactions; at the mesoscale, it organizes large structures within cells; and at the cellular level, it facilitates the localization of cellular materials and homeostatic responses [33,64,65].…”

“…An altered 12-h component related to cardiovascular dysfunction [26] may imply that it is potentially important for human health and adaptation to a novel environment, including space. Following the pioneering study by Hughes et al [27], a series of studies of Pittsburgh's group [28,29,30,31,32,33] identi ed a cellautonomous 12-h oscillator of nuclear speckle liquid-liquid phase separation dynamics in mammals, including humans, which regulates 12-h rhythms of systemic gene expression and metabolism independently from the 24-h circadian clock. The 12-h oscillation was found to be regulated by the unfolded protein response (UPR) transcription factor spliced form of X-Box Binding Protein 1 (XBP1s) [31,32,33,34,35].…”