Chromatin sequesters pioneer transcription factor Sox2 from exerting force on DNA (Nguyen et al., Nat Commun 2022)
Sox2 condensates exert differential mechanical tensions within nucleosome-occupied genomic regions versus nucleosome-free regions. Nucleosomes thus serve as mechanical sinks to regulate the force generated by TF:DNA co-condensation.
Formation of biomolecular condensates constitutes an emerging mechanism for transcriptional regulation. Recent studies suggest that protein-DNA co-condensation can generate forces driving genome rearrangement. However, the extent of mechano-regulation mediated by biomolecular condensates within the context of chromatin is not well understood. In this study, we use single-molecule TIRF microscopy and smCFFM to demonstrate that Sox2, a model pioneer factor, forms stable co-condensates with DNA and generates forces up to 7 piconewtons, an order of magnitude higher than the values previously reported for other TFs. We find that the disordered domains of Sox2 are required for maximum force generation but not for condensate formation. Furthermore, we show that nucleosomes drastically attenuate the mechanical stress exerted by Sox2 by sequestering them from bare DNA. Our data thus suggest that protein:DNA co-condensation can cause significant mechanical tension within the genome, which is buffered by the chromatin architecture.