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(BBSRC DTP) Functional analysis of the histone tail modifier and longevity regulator RBBP5


Faculty of Biology, Medicine and Health

Manchester United Kingdom Biochemistry Bioinformatics Cancer Biology Cell Biology Genetics Molecular Biology Structural Biology

About the Project

The genome is the blueprint of any living system. However, it is the regulation of gene expression that enables life. For transcription to take place, the molecular machinery involved has to access genomic DNA. Every 150 base pairs of DNA is wrapped around an octamer of core histones forming the nucleosome, the fundamental unit of chromatin. These core histones are heavily modified. It is thought that these modifications form a code that regulates access to DNA. Methylation of histone 3 lysine 4 (H3K4) is an important component of this code and is strongly associated with accessible and transcribed DNA. The project will investigate the structure-function relationship of RBBP5, a core component required for the deposition of methyl marks at H3K4. Recent structural studies have shown that RBBP5 acts as a scaffold stabilising and activating the H3K4 methyltransferase enzymes of the complex. RBBP5 interacts with other components of the complex as well as with the nucleosome. However, the role of these interactions in an animal system remains unknown.

Directed mutagenesis will be used to generate a library of edited RBBP5 proteins. These will be introduced first in the powerful genetic model system C. elegans to address their functions at a molecular level using ChIP-seq and ATAC-seq as well as at the organismal level using stress resistance and lifespan assays, since H3K4 methylation is an important regulator of longevity. Those modified RBBP5 proteins that affect function in the worms will then be investigated in mammalian cell culture and Embryonic Stem Cells (ESCs). The role of RBBP5 will also be investigated in a cancer context. Cancer Stem Cells (CSCs) in glioblastoma, the most common malignant primary brain tumour, are resilient cells hard to eliminate by traditional therapeutic interventions. It was recently shown that CSCs self-renewal capacity relies on RBBP5 activity. The project will identify RBBP5 amino acids with contribute disproportionally towards H3K4 methylation activity and forming so-called ‘hot pockets’, that may be targeted to develop novel small molecule compounds and potentially useful in therapeutic interventions against glioblastoma. During the project, the student will be trained in a range of molecular biology, genomic, genetic and bio-informatic approaches.

https://www.research.manchester.ac.uk/portal/gino.poulin.html
https://www.research.manchester.ac.uk/portal/alan.j.whitmarsh.html
https://www.research.manchester.ac.uk/portal/andrew.d.sharrocks.html

Entry Requirements:
Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equivalent) in a relevant subject.

UK applicants interested in this project should make direct contact with the Principal Supervisor to arrange to discuss the project further as soon as possible. International applicants (including EU nationals) must ensure they meet the academic eligibility criteria (including English Language) as outlined before contacting potential supervisors to express an interest in their project. Eligibility can be checked via the University Country Specific information page (https://www.manchester.ac.uk/study/international/country-specific-information/).

If your country is not listed you must contact the Doctoral Academy Admissions Team providing a detailed CV (to include academic qualifications – stating degree classification(s) and dates awarded) and relevant transcripts.

Following the review of your qualifications and with support from potential supervisor(s), you will be informed whether you can submit a formal online application.

To be considered for this project you MUST submit a formal online application form - full details on how to apply can be found on the BBSRC DTP website http://www.manchester.ac.uk/bbsrcdtpstudentships

Funding Notes

Funding will cover UK tuition fees/stipend only. The University of Manchester aims to support the most outstanding applicants from outside the UK. We are able to offer a limited number of scholarships that will enable full studentships to be awarded to international applicants. These full studentships will only be awarded to exceptional quality candidates, due to the competitive nature of this scheme.

Equality, diversity and inclusion is fundamental to the success of The University of Manchester, and is at the heart of all of our activities. The full Equality, diversity and inclusion statement can be found on the website View Website

References

1.Han S, Schroeder EA, Silva-García CG, Hebestreit K, Mair WB, Brunet A. Mono-unsaturated fatty acids link H3K4me3 modifiers to C. elegans lifespan. Nature. 2017 Apr 13;544(7649):185-190

2.Xue H, Yao T, Cao M, Zhu G, Li Y, Yuan G, Chen Y, Lei M, Huang J. Structural basis of nucleosome recognition and modification by MLL methyltransferases. Nature. 2019 Sep 4.

3.Hsu PL, Li H, Lau HT, Leonen C, Dhall A, Ong SE, Chatterjee C, Zheng N. Crystal Structure of the COMPASS H3K4 Methyltransferase Catalytic Module.Cell. 2018 Aug 23;174(5):1106-1116

4. Alvarado AG, Thiagarajan PS, Mulkearns-Hubert EE, Silver DJ, Hale JS, Alban TJ, Turaga SM, Jarrar A, Reizes O, Longworth MS, Vogelbaum MA, Lathia JD. Glioblastoma Cancer Stem Cells Evade Innate Immune Suppression of Self-Renewal through Reduced TLR4 Expression. Cell Stem Cell. 2017 Apr 6;20(4):450-461

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