Stopping transcription at the end of mammalian protein coding genes: How is this achieved and why does this matter
This research project will focus on my lab’s recent development of genomic methodology for nascent transcription analysis (1). This can now be employed to characterise the extent of nascent transcription generated by RNA polymerase II (Pol II) that reads past gene 3’ end poly(A) signals, up to the positions of final transcript cessation. This defines the termination site of a gene (2). In particular, single molecule sequencing of this highly unstable 3’ end transcript, captured while still engaged in transcriptional elongation can be achieved by a combination of mNET-seq and Oxford Nanopore sequencing. This technology has recently been developed in my lab. The project will involve manipulating cells by selectively removing known termination protein factors such as PCF1, Xrn2, Drosha and Integrator complex (2-5) using either CRISPR-cas9 or gene degron tagging strategies. Nanopore sequence libraries will be bioinformatically analysed to better establish the molecular mechanism of Pol II termination. Furthermore, loss of termination will be monitored to investigate the effects of readthrough transcription on downstream gene expression (4). These studies will provide the basis for better understanding why either viral infection or cancer can result in loss of normal gene termination.
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 View Website for full details and to apply.
1) Nojima et al. Cell. 121, 526-540 (2015). doi: 10.1016/j.cell.2015.03.027
2) Proudfoot. Science. 532, aad9926 (2016). doi: 10.1126/science.aad9926
3) Kamieniarz-Gdula et al. Mol. Cell 74, 158-172 (2019). doi: 10.1016/j.molcel.2019.01.027
4) Dhir et al. NSMB. 22, 319-327 (2015). doi: 10.1038/nsmb.2982
5) Nojima et al. Mol. Cell. 72, 970-984 (2018). doi: 10.1016/j.molcel.2018.10.011.
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