Pharmacological Inhibition of Core Regulatory Circuitry Liquid-liquid Phase Separation Suppresses Metastasis and Chemoresistance in Osteosarcoma.

ABSTRACT: Liquid-liquid phase-separated (LLPS) transcriptional factor assemblies at super-enhancers (SEs) provide a conceptual framework for underlying transcriptional control in mammal cells. However, the mechanistic understanding of LLPS in aberrant transcription driven by dysregulation of SEs in human malignancies is still elusive. By integrating SE profiling and core regulatory circuitry (CRC) calling algorithm, the CRC of metastatic and chemo-resistant osteosarcoma is delineated. CRC components, HOXB8 and FOSL1, produce dense and dynamic phase-separated droplets in vitro and liquid-like puncta in cell nuclei. Disruption of CRC phase separation decreases the chromatin accessibility in SE regions and inhibits the release of RNA polymerase II from the promoter of SE-driven genes. Importantly, abse

SUBMITTER: Lu B 

PROVIDER: S-EPMC8529446 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature