Twists and Turns of Transcription: Dynamic interplay between RNA Polymerase II and the nucleosome
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Transcription regulation underlies basic processes essential to life, including differentiation and development, cell-to-cell communication, and response to environmental stimuli. How the cell achieves a precise gene expression system to maintain cellular identity while allowing for plasticity remains an important biological question. As the interface between DNA and DNA-binding factors, chromatin exerts substantial influence on transcriptional regulation through its fundamental unit, the nucleosome. The following thesis addresses the questions of how nucleosomes influence transcriptional regulation, how RNA Polymerase II (Pol II) affects nucleosome stability and dynamics, and how Pol II overcomes the nucleosomal barrier. Using the heat shock response as a model for transcriptional regulation, we found that nucleosomes of activated genes increased in turnover, while those of repressed genes exhibited decreased turnover, suggesting that the act of transcription causes nucleosome turnover. This causality challenges the role of histone modifications in regulating gene expression, as modifications must be re-established after each turnover event. Furthermore, we discovered that the transcription-driven nucleosome turnover is partly mediated by the torsional stress on the DNA generated during Pol II translocation. Nucleosomes were destabilized as Pol II generates positive torsion ahead, and stabilized by the negative torsion behind, providing a mechanism for efficient Pol II progression while maintaining chromatin structure and organization.