Phase separation of NELFE modulates chromatin accessibility to promote dichotomous signaling pathways in hepatocellular carcinoma.

Biomolecular condensates partition various cellular processes including transcription, DNA repair, and RNA metabolism. We report NELFE, a member of the Negative Elongation Factor complex required for Polymerase II (Pol II) pausing, forms distinct foci mediated by two low complexity sequences. We show NELFE is oncogenic in hepatocellular carcinoma (HCC) by undergoing liquid-liquid phase separation (LLPS) with SMARCB1 to modulate chromatin accessibility to downregulate pro-apoptotic genes through Pol II pausing while activating pro-growth signals to promote HCC progression. Our work highlights the importance of NELFE LLPS as a mechanism of chromatin accessibility to regulate both paused and non-paused genes to drive tumorigenesis in hepatocellular carcinoma.