HSF1-dependent, long-range directional <i>HSPA1</i> gene motion to nuclear speckles is coupled to DDX39B condensate dynamics

Approximately 5-10% of the genome, enriched ∼10-fold in the most highly active genes, positions near deterministically within several hundred nm of nuclear speckles (NS). This includes the <i>HSPA1</i> locus, among the most strongly NS-associated genes. Here we address how <i>HSPA1</i> endogenous genes and transgenes stably position adjacent to the nuclear speckle periphery, facilitating their gene expression amplification. Live-cell imaging demonstrates a transcription-dependent speckle-anchoring of <i>HSPA1</i> genes. Removal of this anchoring reveals sustained, long-range, curvilinear oscillations of the HSPA1 genes away from and back to nuclear speckles or between nuclear speckles. Curvilinear transgene movements are dependent on the transcription factor HSF1, largely independent of nuclear actin or cohesin, but unexpectedly spatially and temporally correlated with DDX39B condensate dynamics and dependent on DDX39B protein levels. We propose that stable nuclear speckle association of <i>HSPA1</i> results from combining metastable speckle anchoring with constitutive, restorative long-range chromosome movements driven by DDX39B condensate dynamics.