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Developmentally regulated expression of the transcription factor PRDM1 in the mouse


Sir William Dunn School of Pathology

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Prof E Robertson No more applications being accepted Funded PhD Project (Students Worldwide)

About the Project

The master transcriptional regulator Blimp-1/PRDM1 contains an N-terminal PR/SET domain and five C2H2 zinc fingers located near its C-terminus that mediate DNA binding, nuclear import, and recruitment of histone modifying enzymes. These activities account for its ability to control cell-fate decisions and govern tissue homeostasis in multiple cell types in the developing embryo and adult organism (reviewed Bikoff et al., 2009).
In the early embryo Blimp-1/PRDM1 silences the default somatic pathway and causes a few epiblast cells to become exclusively allocated to the germ cell lineage. Blimp-1/PRDM1 also regulates placental and forelimb development, pharyngeal and heart morphogenesis, adult skin homeostasis, and governs postnatal re-programming of intestinal enterocytes (Robertson et al, 2007; Morgan et al., 2009; Harper et al., 2010, Mould et al., 2012, 2015). Blimp-1/PRDM1 associations with numerous epigenetic partners potentially mediate gene silencing and re-organize chromatin structure at cell type-specific target sites (reviewed Bikoff et al., 2009).
The aim of the project is to identify the cis-regulatory regions acting upstream as information “hubs” to coordinately regulate dose-dependent Blimp1/PRDM1 expression patterns during embryogenesis. Cell marking, chromatin conformation, transgenic analysis and the generation of germ line targeted deletions will be exploited to characterize enhancer elements controlling Blimp1/Prdm1 transcriptional outputs during stem cell maintenance, cell lineage allocation and terminal differentation of specialized cell types.

Funding Notes

4 Year DPhil Prize Studentships cover University fees, a tax free stipend of ~£17,009 pa, and up to £5,300 pa for research costs and travel. The competition is open to applicants from all countries. See https://www.path.ox.ac.uk/content/prospective-graduate-students for full details and to apply.

References

Senft, A., Bikoff, E.K., Robertson, E.J., and Costello, I. (2019). Genetic dissection of Nodal and Bmp signalling requirements during primordial germ cell development in mouse. Nature Comms. 10, 1089. doi: 10.1038/s41467-019-09052-w

Mould, A., Morgan, M.A., Nelson, A., Bikoff, E.K., and Robertson, E.J. (2015). Blimp1/Prdm1 functions in opposition to Irf1 to maintain neonatal tolerance during postnatal intestinal maturation. PLoS Genet. 2015 Jul 9;11(7):e1005375

Mould, A., Morgan M.A.J., Li, L., Bikoff, E. K., and Robertson, E. J. (2012). Blimp1/Prdm1 governs terminal differentiation of endovascular trophoblast giant cells and defines multipotent progenitors in the developing placenta. Genes & Dev 26, 2063-74.

Harper, J., Mould, A., Andrews, R. Bikoff, E., and Robertson E.J. (2011) The transcriptional repressor Blimp1/Prdm1 regulates post-natal reprogramming of intestinal enterocytes. Proc Natl Acad Sci U S A. 108, 10585-90

Bikoff, E.K, Morgan, M.A., and Robertson, E.J. (2009). An expanding job description for Blimp1/PRDM1. Current Opinion Genet. Dev. 19, 379-85.
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