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Chromatin remodelling in health and disease

  • Full or part time

    Prof D Higgs
  • Application Deadline
    Friday, January 10, 2020
  • Competition Funded PhD Project (Students Worldwide)
    Competition Funded PhD Project (Students Worldwide)

Project Description

It has become apparent that the regulation of chromatin structure is of paramount importance in a wide variety of fundamental nuclear processes including gene expression, DNA replication, repair and recombination. The ATP-dependent chromatin remodelling factor ATRX has emerged as a key player in each of these processes. Recent developments have demonstrated that ATRX is involved in the deposition of the histone variant H3.3 in chromatin and through this helps maintain epigenetic marks and gene expression, prevent stalling of the replication fork particularly in tandem repetitive DNA such as the telomeres, and facilitates the repair of double strand breaks.

Germline mutations in ATRX give rise a complex genetic disease, X-linked α thalassaemia /intellectual disability syndrome, characterised by severe learning difficulties, a characteristic facial appearance, abnormal sexual development and a form of anaemia, α thalassaemia. The latter arises because of reduced expression of α globin, a component of adult haemoglobin. Whole genome sequencing in cancer has revealed that somatic mutations in ATRX are a hallmark of tumours that maintain their telomeres using a telomerase- independent mechanism - the alternative lengthening of telomere pathway.

The purpose of our work is to determine the role of ATRX in the maintenance of chromatin and how mutations perturb disparate nuclear nuclear processes and lead to human disease. Of particular interest to us is the role ATRX plays in gene expression. We have found that perturbation in gene expression seen when ATRX is mutated is related to the size of adjacent G-rich tandem repeats and that ATRX can bind to the G quadruplex structures that form at these sequences in vitro. Our hypothesis is that a central role of ATRX is to suppress the formation of DNA secondary structures in repetitive DNA. The persistence of secondary structures is known to lead to stalling in DNA replication and secondarily to the loss of epigenetic memory and perturbation of gene expression. The three main areas of research in the lab are: the role of ATRX in DNA replication; how mutations in ATRX leads to abnormal gene expression and to determine how ATRX and its partner protein DAXX interact with chromatin through solving their protein structure.

The molecular biology projects offer an opportunity to learn how to induce lineage specific differentiation of CD34+ cells and iPS cells, FACS analysis and sorting, CRISP/Cas9 gene editing, epigenetic profiling including mapping G4 and R-loops in the genome, next generation sequencing, optical mapping and assaying replicative stress and DNA damage. Students will be trained in bioinformatics to facilitate the analysis of their genome-wide data.

Additional supervision may be provided by Dr David Clynes and Dr Denis Ptchelkine (Dept of Oncology).

In the structural studies, carried out in collaboration with Dr Denis Ptchelkine, the students will learn how to produce high quality protein samples for biophysical and structural work using eukaryotic expression systems and to characterize proteins by biophysical techniques. Structural studies will involve protein crystallography and cryo-electron microscopy; the student will also learn how to analyse their data.

Students will be enrolled on the MRC WIMM DPhil Course, which takes place in the autumn of their first year. Running over several days, this course helps students to develop basic research and presentation skills, as well as introducing them to a wide-range of scientific techniques and principles, ensuring that students have the opportunity to build a broad-based understanding of differing research methodologies.

Generic skills training is offered through the Medical Sciences Division’s Skills Training Programme. This programme offers a comprehensive range of courses covering many important areas of researcher development: knowledge and intellectual abilities, personal effectiveness, research governance and organisation, and engagement, influence and impact. Students are actively encouraged to take advantage of the training opportunities available to them.

As well as the specific training detailed above, students will have access to a wide-range of seminars and training opportunities through the many research institutes and centres based in Oxford.

All WIMM graduate students are encouraged to participate in the successful mentoring scheme of the Radcliffe Department of Medicine, which is the host department of the WIMM. This mentoring scheme provides an additional possible channel for personal and professional development outside the regular supervisory framework. The RDM also holds an Athena SWAN Silver Award in recognition of our efforts to build a happy and rewarding environment where all staff and students are supported to achieve their full potential.

Funding Notes

Funding for this project is available to scientists through the RDM Scholars Programme, which offers funding to outstanding candidates from any country. Successful candidates will have all tuition and college fees paid and will receive a stipend of £18,000 per annum.
For October 2020 entry, the application deadline is 10th January 2020 at 12 noon (midday).
Please visit our website for more information on how to apply.

References

Law MJ, Lower KM, Voon HP, Hughes JR, Garrick D, Viprakasit V, Mitson M, De Gobbi M, Marra M, Morris A, Abbott A, Wilder SP, Taylor S, Santos GM, Cross J, Ayyub H, Jones S, Ragoussis J, Rhodes D, Dunham I, Higgs DR, Gibbons RJ. (2010). ATR-X syndrome protein targets tandem repeats and influences allele-specific expression in a size-dependent manner.Cell, 143 (3), pp. 367-78. http://www.ncbi.nlm.nih.gov/pubmed/21029860

Sarkies P, Reams C, Simpson LJ, Sale JE. (2010). Epigenetic instability due to defective replication of structured DNA. Mol. Cell, 40 (5), pp. 703-13. http://www.ncbi.nlm.nih.gov/pubmed/21145480

Clynes D, Jelinska C, Xella B, Ayyub H, Taylor S, Mitson M, Bachrati CZ, Higgs DR, Gibbons RJ. (2014). ATRX dysfunction induces replication defects in primary mouse cells. PLoS ONE, 9 (3), pp. e92915. http://www.ncbi.nlm.nih.gov/pubmed/24651726

Voon HP, Hughes JR, Rode C, De La Rosa-Velázquez IA, Jenuwein T, Feil R, Higgs DR, Gibbons RJ. (2015) ATRX Plays a Key Role in Maintaining Silencing at Interstitial Heterochromatic Loci and Imprinted Genes. Cell Reports. 11:405-418 https://www.ncbi.nlm.nih.gov/pubmed/25865896

Clynes D, Jelinska C, Xella B, Ayyub H, Scott C, Mitson M, Taylor S, Higgs DR, Gibbons RG (2015) Suppression of the alternative lengthening of telomere pathway by the chromatin remodelling factor ATRX. Nature Communications 6:7538. doi: 10.1038/ncomms8538.
https://www.ncbi.nlm.nih.gov/pubmed/26143912

Nguyen DT, Voon HPJ, Xella B, Scott C, Clynes D, Babbs C, Ayyub H, Kerry J, Sharpe JA, Sloane-Stanley JA, Butler S, Fisher CA, Gray NE, Jenuwein T, Higgs DR, Gibbons RJ. (2017) The chromatin remodelling factor ATRX suppresses R-loops in transcribed telomeric repeats. EMBO Rep. 2017 Jun;18(6):914-928. https://www.ncbi.nlm.nih.gov/pubmed/28487353

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