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(BBSRC DTP) Functional and structural analysis of RBBP5: a histone tail modifier essential for development, disease and healthy ageing


Project Description

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 the DNA. Methylation of histone 3 lysine 4 (H3K4) is an important component of this code and is strongly associated with accessible and transcribed DNA. This methylation mark is deposited by the COMPASS complex. A critical component of this complex is RBBP5 which acts as a structural scaffold to stabilise and activate the H3K4 methyltransferase enzyme component. RBBP5 also interacts with other components of the complex as well as with the nucleosome. However, the functional importance these interactions is poorly understood and has not been explored in an animal system. To address this, a library of RBBP5 mutants will be generated in the powerful genetic model system C. elegans and molecular readouts of changes in genome architecture analysed using ChIP-seq and ATAC-seq. At the organismal level, the effects of the RBBP5 mutations on developmental and behavioural phenotypes will be assessed, with a particular focus on stress resistance and lifespan, as H3K4 methylation is an important regulator of longevity. The mammalian orthologues of promising RBBP5 mutants will then be investigated in cell culture and Embryonic Stem Cells (ESCs). Cancer Stem Cells (CSCs) in glioblastoma 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. The identification of such hot pockets would be useful to develop novel small molecules compounds directed against RBBP5. Overall, altering RBBP5 activity by mutagenesis or in the longer term with small molecule compouds could have broad implications on ESCs, response to stress, and healthy ageing.

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:
Applications are invited from UK/EU nationals only. Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equivalent) in a relevant subject.

Funding Notes

This project is to be funded under the BBSRC Doctoral Training Partnership. If you are interested in this project, please make direct contact with the Principal Supervisor to arrange to discuss the project further as soon as possible. You MUST also submit an online application form - full details on how to apply can be found on the BBSRC DTP website View Website

As an equal opportunities institution we welcome applicants from all sections of the community regardless of gender, ethnicity, disability, sexual orientation and transgender status. All appointments are made on merit.

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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