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Functional investigation of genetic variants associated with rheumatoid arthritis using CRISPR-Cas9


Project Description

The aim of this PhD project is to characterise gene regulatory elements (enhancers) harbouring rheumatoid arthritis (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. Specifically, you will use cutting edge technologies such as CRISPR-Cas9, single cell RNA-Seq, ChIP, HiChIP and Hi-C to explore the effect of disease associated variants on the expression of genes that may have a key role in the development of RA. The PhD will also include the characterisation of genetically engineered cells using CyTOF.

RA is a chronic, disabling autoimmune disease characterized by inflammation of the peripheral joints, which causes swelling, stiffness, pain and progressive joint destruction. There is no cure for RA and although some therapies are available, many patients do not respond appropriately. Finding novel and more effective therapies is challenging because the biological mechanisms involved in disease are not completely understood.
Genome-wide association studies (GWAS) have been used to great effect to identify over 100 genetic variants that increase the risk of RA. However, 90% of them lie outside traditional protein coding regions of the genome, often at considerable genomic distances from annotated genes and, therefore, their potential role in pathological mechanisms is not obvious.
Previous work by our group1 and others has shown that these disease variants accumulate in enhancers and can be involved in transcriptional regulation of their target genes through chromosomal interactions. We have generated, for the first time, a vast amount of functional genomics datasets (RNA-Seq, Hi-C, CHi-C, ATAC-Seq) in different tissues from RA patients. These can help us formulate hypothesis as to what are the genes affected by disease predisposing variants, but they need functional validation. This PhD will build on these exciting findings, developing the genetic knowledge into translation to the clinic.

Applications are invited from UK/EU nationals only. Candidates are expected to hold (or be due to obtain) a minimum upper-second (or equivalent) class undergraduate degree in genetics, bioinformatics or a relevant subject. A Masters degree in a related subject and/or relevant research experience is desirable.
For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website (https://www.bmh.manchester.ac.uk/study/research/apply/). Informal enquiries may be made directly to the primary supervisor.

Funding Notes

This project is funded by Arthritis Research UK Centre for Genetics and Genomics with RCUK stipend. Starting Sept 2019 for 3 years. If you are interested please make direct contact with the Supervisor to discuss the project . You MUST also submit an online application form - choose PhD Genetics.

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. Martin,P. et al. Capture Hi-C reveals novel candidate genes and complex long-range interactions with related autoimmune risk loci. Nat. Commun. 6, 10069 (2015).

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