Otto Warburg Medal (sponsored by Elsevier) :
Principles of mRNA synthesis and its regulation

Patrick Cramer

Max Planck Institute for Biophysical Chemistry, Göttingen, Germany,

In eukaryotic cells, mRNA is synthesized by RNA polymerase II (Pol II) in a reaction that involves over one hundred accessory proteins. Pol II regulation underlies organism development, cell differentiation, and responses of cells to environmental changes, and its dysregulation can cause cancer and other diseases. Our laboratory combines integrated structural biology with functional genomics and computational biology to study the mechanisms of gene transcription and its regulation in eukaryotic cells. In a long-term effort, we have now arrived at a molecular-mechanistic understanding of many aspects of transcription by RNA polymerase II, including several regulatory strategies. We recently elucidated how chromatin is first opened at the promoter to enable transcription initiation (Wang et al., Nature 2020; Wagner et al., Nature, in press). We also reported mechanisms of transcription initiation at promoters (Plaschka et al. Nature 2015, 2016; Nozawa et al. Nature 2017; Schilbach et al. Nature 2017). We further revealed the molecular basis for transcription regulation during early elongation of the mRNA chain in the promoter-proximal region (Vos and Farnung Nature 2018; Vos et al. Nature 2018). We have begun to study the next step, transcription elongation through chromatin (Farnung Nature 2017; Wang, NSMB 2019). Transcription depends on multiple phosphorylation events, and such phosphorylation may control the partitioning of RNA polymerase II between different nuclear condensates by differential liquid-liquid phase separation (Cramer, Nature 2019; Boehning et al., NSMB 2018). To complement our structural studies, we also developed transient transcriptome sequencing (TT-seq), which monitors RNA synthesis and regulatory enhancer landscapes at high temporal resolution (Schwalb Science 2016;Demel Mol. Syst. Biol. 2017). In recent work, we have combined functional genomics and kinetic modeling to derive kinetic insights into transcriptonal regulation, and found that impaired elongation can limit initiation (Gressel,Schwalb et al. Leonhardt, Eick, and Cramer, eLife 2017). In my lecture I will concentrate on the most recent findings and suggest future directions for the investigation of the molecular and cellular mechanisms of genome regulation.

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