The molecular basis of transcription initiation by RNA polymerase II

Transcription initiation in eukaryotes is a major regulatory checkpoint for ensuring that genes are precisely activated. Although the basic components of the transcription machinery were identified decades ago, recent breakthroughs in high-resolution cryo-electron microscopy have transformed our understanding of how these massive complexes function as dynamic assemblies rather than as static entities. In this Review, we focus on transcription by RNA polymerase II (Pol II) and discuss the integrated roles of the universal promoter scaffold factor TFIID, the transcription co-activator Mediator and the epigenetic status of the +1 nucleosome. We first discuss the structural basis of TFIID-mediated recognition of the core promoter and the modular assembly of the pre-initiation complex and pre-initiation complex-Mediator, which involves phosphorylation of the Pol II C-terminal domain. We then discuss how the chromatin environment regulates selection of the transcription start site and transcription directionality, before turning to the progression from transcription initiation to elongation, including promoter opening and promoter escape. Finally, we discuss transcription initiation as a programmed process, in which inhibitory factors are released and regulatory factors are progressively exchanged through competition for binding surfaces.