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

In this study 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 sub-diffusive populations. One accounts for specific binding to chromatin, while the other represents a confinement state that requires an intrinsically disordered region (IDR), consistent with 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. Overall design: Genome-wide occupancy profiling of GR ChIP-seq from mouse mammary adenocarcinoma cell lines (3617) knock-out of endogenous GR (3617-KOGR) and stably integrated with GFP-tagged GR mutants, in biological duplicates, using Illumina NextSeq 500. GRwt binding data from the 3617-KOGR cells was used as comparison standard for GR (GSE108634).