Embryonic stem cells are pluripotent cells derived from early embryos that retain the ability to differentiate into all somatic cells. Pluripotency is dependent on the expression of key pluripotency regulators. On receiving signals to differentiate, gene expression profiles are reshaped to repress pluripotency factors and to express the proteins required of the new cell lineage. We investigate how cellular pathways influence the gene expression machinery during differentiation and pluripotency to determine which proteins are expressed. Our focus is on understanding how cellular pathways regulate the mRNA cap, a structure added to transcripts which is critical for gene expression. The mRNA cap recruits protein complexes which mediate processing and translation initiation. We have recently found that formation of the mRNA cap is regulated during neural differentiation which represses pluripotency genes and upregulates neural genes.
The PhD project would be to investigate the role of the mRNA capping enzymes in embryonic stem cell pluripotency and differentiation. Which genes do the capping enzymes control? What is the impact of the capping enzymes on embryonic stem cell differentiation? Should the capping enzymes be considered as therapeutic targets?
The student will be investigating T cell differentiation and function, and transcription and translation using next generation sequencing and mass spectrometry. The student will work within the laboratories of Victoria Cowling and Greg Findlay, integrated in the Centre for Gene Expression and MRC Protein Phosphorylation Unit, at the University of Dundee.
Recent work from the lab can be found in the following references:
Grasso L, Suska O, Davidson L, T, Williamson R, Wasmus L, S, Peggie M, Stavridis MP and Cowling 2016) mRNA cap methylation in pluripotency and differentiation Cell Rep. 2016 Aug 2;16(5):1352-65. : 10.1016/j.celrep.2016.06.089. 2016 Jul 21 PMID 27452456
Varshney D, Lombardi O, Schweikert G, Dunn S, Suska O and Cowling VH (2018) mRNA cap methyltransferase (RNMT-RAM) is required for RNA pol II-dependent transcription Cell Rep. 2018 May 1;23(5):1530-1542. : 10.1016/j.celrep.2018.04.004 PMID: 29719263
Aregger M, A, Fernandez-Sanchez ME, Simone Weidlich S and Cowling 2016) CDK1-cyclinB activates RNMT mRNA cap methylation with G1 phase transcription Molecular Cell 2016 Mar 3;61(5):734-46. : 10.1016/j.molcel.2016.02.008 PMID: 26942677