Control of transcriptional networks by reversible phosphorylation

Tight regulation of gene expression is critical for cells to respond normally to physiological and environmental cues and to allow cell specialisation. Reversible phosphorylation of key structural and regulatory proteins, from histones to the transcriptional machinery, is acknowledged to play important roles in coordinating spatial and temporal patterns of gene expression. However, the precise roles of kinases and phosphatases, which add or remove phosphate to proteins, in transcriptional programming are still poorly understood. Protein phosphatase 1 (PP1) is a major class of serine/ threonine protein phosphatase that is found at many sites on eukaryotic chromosomes where it has been implicated in controlling gene expression and chromatin structure. PP1 is targeted to different chromosomal loci through interaction with a variety of different regulatory subunits, which modify PP1’s activity towards specific substrates. The purpose of the project is to: i) determine where precisely on chromosomes PP1 is located using recently established genomic approaches; ii) establish which regulatory subunit targets PP1 to each of these loci; iii) analyse the effect of each holoenzyme on transcription and chromatin modification (both globally and at specific loci); iv) determine the substrates of the holoenzymes; v) determine the effect of (de)phosphorylation, on transcriptional memory and cell identity. Elucidating how transcriptional programmes are coordinated is not only critical for understanding tissue and organism size regulation during normal development, but is also important for understanding the misappropriation or dysfunction of metabolic pathways that underlie numerous disease processes. Importantly, kinases and phosphatases have proven to be effective drug targets and therefore offer the potential to manipulate transcriptional networks pharmaceutically


Training:
The student will be associated with active research groups conducting lab-based molecular genetics and genomics research highly relevant to the student’s project. Within the groups, several lab members are working on related projects, and adjacent collaborating labs have additional expertise, giving the student access to a large set of other workers to gain advice and intellectual input. The student will be expected to regularly interact with all supervisors to enable rapid progress and to ensure a broad training in the relevant inter-disciplinary approaches. The approaches proposed are state-of-the art (including Drosophila genetics, RNAi, RNA-Seq, ChIP-Seq) and infrastructure and support is exceptionally strong; this means that there will be good career development opportunities for the student. Regular PGR meetings will enable regular progress checks, so that we can identify and remedy technical and other problems quickly. Generic skills training will be provided through weekly lab meetings. These will give the student experience of oral presentation of their work, will expose them to other research methods and systems and broaden their scientific outlook. The student will also be expected to attend other seminar series within Liverpool and present their work at a minimum of one international meeting.