University of Leeds Featured PhD Programmes
University of Edinburgh Featured PhD Programmes
King’s College London Featured PhD Programmes

Investigating Chromatin Organization and Dynamics in Gene Regulation

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  • Full or part time
    Prof B Hill
    Prof N Gilbert
  • Application Deadline
    No more applications being accepted
  • Competition Funded PhD Project (European/UK Students Only)
    Competition Funded PhD Project (European/UK Students Only)

About This PhD Project

Project Description

A 3 year PhD position is available with Professor Bob Hill and Professor Nick Gilbert at the MRC Human Genetics Unit, Institute for Genetics and Molecular Medicine at the University of Edinburgh.

Every mammalian cell is faced with the task of packaging two meters of DNA into its nucleus, but in a manner in which the chromatin is organised and primed for gene expression. To achieve this both local and large-scale chromatin architecture plays a key role in regulating gene expression. During embryonic development many genes controlling organogenesis are regulated by large genomic domains containing multiple cis-regulatory elements including enhancers, insulators and boundary elements. Regulatory domains can occupy up to several 100’s of kilobases; control of gene expression must overcome the problems of how to organise chromatin in nuclear space enabling access to crucial regulatory factors, and how to promote communication between cis-regulators and promoters separated by long genomic distances. The Shh gene is a fundamental model for investigating gene regulation by a complex regulatory domain[1]. The Shh gene encodes a developmental signalling factor that requires multiple regulatory elements spread over a genomic distance of a million base pairs to regulate its expression in the early embryo. Mutations that reside in Shh regulatory elements cause mis-regulation of the gene resulting in common congenital abnormalities which include skeletal and craniofacial defects.


Exciting new technologies are being developed to facilitate visualisation of chromatin domains within the nucleus and enable us to investigate complex gene regulation. In this project the successful applicant will refine and use cutting-edge approaches to visualize large-scale chromatin organisation of the Shh locus using super-resolution microscopy and analyse structural changes upon gene activation/regulation [2]. Using new approaches utilising a modified CRISPR/Cas9 system, the student will also visualise conformational changes that occur in live cells during early mammalian development [3]. To investigate the underlying molecular mechanisms the student will use chromosomal deletions and inversions, which we have already made, to dissect the crucial processes important for supporting long range regulation of gene expression and revealing new fundamental molecular mechanisms.

Students should have, or expect to obtain a good Upper Second or First Class degree. Applicants should send a covering letter, stating why they are interested in the project, along with an up-to-date CV which includes contact details of two academic referees to [Email Address Removed] by 31 March 2017.

Academic and informal enquiries can also be sent to Professor Bob Hill – [Email Address Removed]

References

[1] Anderson E, Peluso S, Lettice LA, Hill RE. (2012) Human limb abnormalities caused by disruption of hedgehog signaling. Trends Genet. 28: 364-373.

[2] Wang S, Su JH, Beliveau BJ, Bintu B, Moffitt JR, Wu CT, Zhuang X. (2016) Spatial organization of chromatin domains and compartments in single chromosomes. Science. 353: 598-602.

[3] Chen B, Gilbert LA, Cimini BA, Schnitzbauer J, Zhang W, Li GW, Park J, Blackburn EH, Weissman JS, Qi LS, Huang B. (2013) Dynamic imaging of genomic loci in living human cells by an optimized CRISPR/Cas system. Cell 155: 1479-1491.



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