From genesis to destruction: how does transcription initiation base selection regulate mRNA fate in development and tumorigenesis (360G-Wellcome-317502_Z_24_Z)

The core promoter integrates regulatory information conveyed by cis-regulatory elements such as enhancers to control the start of mRNA synthesis. A little understood function of promoters is the precise definition of transcription start sites (TSS). Accumulating evidence suggests that the position and nucleobase composition of TSS dictate post-transcriptional mRNA stability and protein translation control in distinct physiological contexts. However, the regulation of transcription initiation and its interplay with post- transcriptional RNA regulation is largely unexplored. We hypothesize that: \- TSS control is a global regulator of mRNA stability and translation; \- TSS- choice coordinates mRNA diversification in response to growth signals and metabolic shifts during development and tumorigenesis. We will determine both the transcriptional and post-transcriptional regulator factors and sequences, which control diversification of mRNA 5’ ends. We will dissect how TSS- variation diversifies mRNAs with distinct 5’ end features and how these distinct mRNAs coordinate translation rates and mRNA stability upon growth and metabolic signaling. Finally, we will uncover the roles and mechanisms of TSS variation during embryonic development and in tumourigenesis. We combine the expertise of transcriptional / developmental genetics (Mueller) with posttranscriptional, translation regulation expertise (Bushell) to understand the little studied causative relationship between transcription initiation and translation.