An Intrinsic Disordered Region Mediated Confinement State Contributes to Dynamics and Function of Transcription Factors

DIEGO M PRESMAN; LORENZO RINALDI; RIKKE A.M. JENSEN; GORDON L. HAGER; THOMAS A. JOHNSON; KAUSTUBH WAGH; VILLE PAAKINAHO; ARPITA UPADHYAYA; DAVID A. GARCIA; GREGORY FETTWEIS; STAVREVA, DIANA A.; SUSANNE MANDRUP

Virtual

Congreso; CELL BIO VIRTUAL 2020; 2020

ASCB EMBO

Transcription factors (TFs) regulate gene expression by binding to specific consensus motifs within the local chromatin context. The mechanisms by which TFs navigate the nuclear environment as they search for binding sites remains unclear. Here, we used single-molecule tracking and machine-learning based classification to directly measure the nuclear mobility of the glucocorticoid receptor (GR) in live cells. We revealed two distinct and dynamic low-mobility populations. One accounts for specific binding to chromatin, while the other represents a confinement state that requires an intrinsically disordered region (IDR), implicated in liquid-liquid condensate subdomains. Further analysis showed that the dwell times of both subpopulations follow a power-law distribution, consistent with a broad distribution of affinities on the GR cistrome and interactome. Altogether, our data link IDRs with a confinement state that is functionally distinct from specific chromatin binding and modulates the transcriptional output by increasing the local concentration of TFs at specific sites.