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Targeted reversal of epigenetic silencing at specific tumour suppressor genes in lymphoma

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  • Full or part time
    Dr R Jenner
    Dr J Fitzgibbon
  • Application Deadline
    No more applications being accepted
  • Funded PhD Project (European/UK Students Only)
    Funded PhD Project (European/UK Students Only)

Project Description

This 4-year PhD studentship is offered by the Cancer Research UK City of London Centre

This project seeks to develop a novel biological therapy to precisely modulate the epigenetic state of specific tumour suppressor genes in lymphoma.

Cancer cells exhibit epigenetic changes that drive their growth and survival. Deregulation of the epigenetic regulator Polycomb Repressive Complex 2 (PRC2) is particularly common (1). The PRC2 subunit EZH2 modifies chromatin by trimethylating histone H3 lysine 27 (H3K27me3), which leads to gene repression.

Germinal centre B-cell (GCB) diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) occur in both children and adults (2). Current R-CHOP therapy is only successful for 50% of DLBCL patients and FL remains incurable. GCB-DLBCL and FL often exhibit gain-of-function mutation of EZH2, increasing levels of H3K27me3 and causing inappropriate silencing of tumour suppressor genes such as CDKN1A and differentiation genes such as PRDM1 (3). This holds the cancer cells in a proliferative, undifferentiated state. Ectopic silencing of INK4A by PRC2 also drives diffuse intrinsic pontine glioma (DPIG), the second most common type of primary, high grade brain tumour in children.

Inhibition of EZH2 methyltransferase activity blocks DLBCL and DIPG tumour growth, and EZH2 inhibitors (including tazemetostat) are in clinical trials for DLBCL, FL and other cancers. However, because PRC2 represses the expression of many hundreds of genes, EZH2 inhibition leads to widespread gene activation, increasing transcriptional instability and potentially driving tumour heterogeneity. Furthermore, global EZH2 inhibition has potential side effects, including immunosuppression. A method that allows the selective reversal of the specific gene silencing events that contribute to oncogenesis without affecting other genes would therefore be of great benefit and allow the precise targeting of oncogenic gene silencing events.

In addition to interacting with chromatin, PRC2 also interacts with RNA. We have shown that PRC2 directly interacts with nascent pre-mRNA and that this blocks the ability of PRC2 to bind to chromatin (5). Utilising this mechanism, we have developed a method that selectively removes PRC2 from specific genes (Beltran et al., in revision). Thus, this method potentially allows the specific removal of PRC2 from CDKN1A and PRDM1 in DLBCL and FL, and also the identification of other gene silencing events critical for oncogenesis.
Working between epigenetics, structural biology, and haematology research labs, the candidate will develop the means to remove PRC2 from specific genes in DLBCL cells and demonstrate that this blocks cancer cell proliferation in cell culture and mouse models. The student will also create the viral vectors that can be used to specifically deliver the RNA and gene targeting proteins to B cells and test their efficacy in culture and mouse tumour models.

The student will benefit from inter-disciplinary training in cell biology, epigenetics, biophysics, and bioinformatics, and gain expertise working with tumour xenografts.
The project would suit a candidate with a background in molecular biology or biochemistry and with an interest in applying this knowledge to the development of novel and precise forms of cancer therapy.

Potential research placements

1. Training in DLBCL culture and transduction. Supervisor: Professor Jude Fitzgibbon, Barts Cancer Institute, QMUL.
2. Training in the quantitative measurement of protein-RNA binding using biophysical techniques. Supervisor: Dr Jon Wilson, the Crick,
3. Training in mouse xenografts. Supervisor: Dr Marc Mansour, UCL Cancer Institute

Talented and motivated students passionate about doing research are invited to apply for this PhD position. The successful applicant will join the CRUK CoL Centre PhD Programme in September 2019 and will register for their PhD at their primary supervisor’s university.
Applicants should hold or expect to gain a first/upper second-class honours degree or equivalent in a relevant subject and have appropriate research experience as part of, or outside of, a university degree course and/or a Masters degree in a relevant subject.

APPLICATIONS MUST BE MADE ONLINE VIA OUR WEBSITE (ACCESSIBLE VIA THE ‘APPLY NOW’ LINK ABOVE) BY 12:00 (NOON) 19 MARCH 2019. APPLICATIONS WILL NOT BE ACCEPTED IN ANY OTHER FORMAT.

Funding Notes

Successful candidates will receive a £21,000 tax-free student stipend (living allowance) per year for 4 years plus payment of university tuition fees. Non-EU candidates are not eligible to apply.

References

1. Comet I, Riising EM, Leblanc B, Helin K. Maintaining cell identity: PRC2-mediated regulation of transcription and cancer. Nat Rev Cancer, 2016; 16:803-10.
2. Heward JA, Kumar EA, Korfi K, Okosun J, and Fitzgibbon J. Precision medicine and lymphoma. Curr Opin Hematol, 2018; 25:329-334.
3. Beguelin W et al. EZH2 is required for germinal center formation and somatic EZH2 mutations promote lymphoid transformation. Cancer Cell, 2013; 23:677-92.
4. Wang X et al. Targeting of Polycomb Repressive Complex 2 to RNA by Short Repeats of Consecutive Guanines. Mol Cell, 2017; 65:1056-67 e5.
5. Beltran M et al. The interaction of PRC2 with RNA or chromatin is mutually antagonistic. Genome Res, 2016; 26:896-907.



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