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Regulation of innate immune response by enhancer elements and genetic variants within them

  • Full or part time
  • Application Deadline
    Sunday, December 01, 2019
  • Competition Funded PhD Project (Students Worldwide)
    Competition Funded PhD Project (Students Worldwide)

Project Description

Non-coding DNA elements such as gene enhancers play key roles in gene regulation, particularly upon stimulus response and in development. Genetic variation at enhancers is known to underlie both rare and common diseases. And yet, many enhancers are apparently dispensable for healthy gene control, and a lot of enhancer-borne variants are phenotypically neutral.

Our group is interested in how enhancers regulate cellular transcriptional programmes, and how their function is modified by natural genetic variation. We combine experimental and computational approaches in our work, capitalising on our expertise in regulatory and single-cell genomics, chromosomal organisation and blood cell biology.

The proposed project will use single-cell transcriptomics and chromatin profiling (such as 10X Genomics sc-RNA-seq and sc-ATAC-seq), as well as 3D chromosomal architecture analysis (such as Promoter Capture Hi-C), to identify the role of enhancers in driving the transcriptional response of human primary innate immune cells to extrinsic stimuli (from individual cytokines to complex microenvironments). This analysis will be extended to cells isolated from multiple individuals to detect genetically-determined differences in stimulus response linked to variation at enhancers. Findings from this project will improve our basic understanding of gene regulation and help leverage the emerging roles of innate immune cells in tissue regeneration, autoimmune disease and cancer progression.

The candidate will become part of our collaborative, interdisciplinary team (http://functionalgenecontrol.group) and will have ample opportunities to acquire expertise in state-of-the-art experimental and computational techniques irrespectively of prior background.

To Apply: Please visit our website (https://lms.mrc.ac.uk/study-here/phd-studentships/lms-3-5yr-studentships/) to download an application form.

Funding Notes

This project is one of multiple available projects potentially funded by the MRC. If successful the studentship would cover all tuition fee payments and includes a tax-free stipend amounting to £21,000pa (paid in monthly installments directly to the student) for 3.5 years.

Whilst this funding is available to students worldwide, due to the higher tuition fee rate of overseas students competition is higher and so only exceptional OS applicants will be considered.

References

Schoenfelder S, Fraser P. Long-range enhancer-promoter contacts in gene expression control. Nat Rev Genet. 2019. 20(8):437-455.

Guilliams M, Mildner A, Yona S. Developmental and Functional Heterogeneity of Monocytes. Immunity. 2018. 49(4):595-613.

Freire-Pritchett P, Schoenfelder S, Várnai C, Wingett SW, Cairns J, Collier AJ, García-Vílchez R, Furlan-Magaril M, Osborne CS, Fraser P, Rugg-Gunn PJ*, Spivakov M*. (2017). Global reorganisation of cis-regulatory units upon lineage commitment of human embryonic stem cells. eLife. 6, e21926.

Javierre BM, Burren O, Wilder S, Kreuzhuber R, Hill S, Sewitz S, Cairns J, Wingett SWW, Várnai C, Thiecke MJ, Burden F, Farrow S, Cutler AJ, Rehnstrom K, Downes K, Grassi L, Kostadima M, Freire-Pritchett P, Wang F, The BLUEPRINT Consortium, Stunnenberg HG, Todd JA, Zerbino DR, Stegle O, Ouwehand WH, Frontini M*, Wallace C*, Spivakov M*, Fraser P*. 2016. Lineage-specific genome architecture links enhancers and non-coding disease variants to target gene promoters. Cell, 147,1369–1384.

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