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Functional dissection of disease associated genetic loci in rheumatoid arthritis


Project Description

Rheumatoid arthritis (RA) is a common chronic disease characterized by inflammation of the joints with a high socioeconomic burden.
Genome wide association studies (GWAS) have identified over 100 genetic variants associated with RA risk. 90% of them lie outside protein coding genes and, therefore, their potential role in pathological mechanisms is not obvious, but there is now strong evidence that disease associated non-coding variants are involved in transcriptional regulation.
The aim of the project is to characterize regulatory elements harbouring RA-associated variants, in order to determine the genes, biological pathways and mechanisms by which these variants act in specific cell subtypes to increase the risk of disease, with the following specific objectives:
1. To identify the genes that cause RA: we will map cis-regulatory chromatin contacts in immune cells from RA patients, as well as in healthy individuals. Active regulatory elements (enhancers) will also be characterized. These experiments will allow us to identify disease-specific enhancer-promoter interactions that will define relevant genes in the pathology of RA. By overlaying the GWAS data, active enhancers affected by disease-associated variants will also be defined.
2. To investigate the effect of RA associated variants on the regulation of transcription: Transcriptomic profiling can also help us identify the genes that are important in disease. We will detect differentially expressed genes between patients and healthy individuals. We will also explore whether RA-associated SNP genotypes are correlated with differential gene expression in both RA patients and healthy individuals.
3. Validation of function of disease SNPs on gene expression: We will use genome editing to verify target genes and the functional importance of identified elements containing RA associated variants.

This project will contribute to the identification of genes and biological pathways that mediate RA pathology, which will in turn inform novel therapeutic targets discovery and drug repurposing.

Training/techniques to be provided:
Hi-C
ChIP-Seq
RNA-Seq
SNP genotyping
Bioinformatics
Statistics
CRISPR-Cas9 genome editing

Entry Requirements:
Candidates are expected to hold (or be about to obtain) a minimum upper second class honours degree (or equivalent) in a related area / subject.

For international students we also offer a unique 4 year PhD programme that gives you the opportunity to undertake an accredited Teaching Certificate whilst carrying out an independent research project across a range of biological, medical and health sciences. For more information please visit http://www.internationalphd.manchester.ac.uk

Funding Notes

Applications are invited from self-funded students. This project has a Band 2 fee. Details of our different fee bands can be found on our website (View Website). For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy 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

Chromatin interactions reveal novel gene targets for drug repositioning in rheumatic diseases. Martin P, Ding J, Duffus K, Gaddi VP, McGovern A, Ray-Jones H, Yarwood A, Worthington J, Barton A, Orozco G. Annals of the Rheumatic Diseases. 2019;78:1127-1134.

The genetics revolution in rheumatology: large scale genomic arrays and genetic mapping. Eyre S, Orozco G, Worthington J. Nature Reviews Rheumatology. 2017. 13:421-432.

Capture Hi-C identifies a novel causal gene, IL20RA, in the pan-autoimmune genetic susceptibility region 6q23. McGovern A, Schoenfelder S, Martin P, Massey J, Duffus K, Plant D, Yarwood A, Pratt AG, Anderson AE, Isaacs JD, Diboll J, Thalayasingam N, Ospelt C, Barton A, Worthington J, Fraser P, Eyre S, Orozco G. Genome Biol. 2016. 1;17:212.
Capture Hi-C reveals novel candidate genes and complex long-range interactions with related autoimmune risk loci.
Martin, P., Mcgovern, A., Orozco, G., Duffus, K., Yarwood, A., Schoenfelder, S., Cooper, N., Barton, A., Wallace, C., Fraser, P., Worthington, J. & Eyre, S 2015, Nature Communications. 6, 10069.

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