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Chromatin remodelling in health and disease: determining the role of ATRX in the maintenance of chromatin and how mutations perturb disparate nuclear nuclear processes and lead to human disease

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  • Full or part time
    Dr R Gibbons
    Prof D Higgs
  • Application Deadline
    No more applications being accepted
  • Self-Funded PhD Students Only
    Self-Funded PhD Students Only

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.

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

The Department has a successful mentoring scheme, open to graduate students, which provides an additional possible channel for personal and professional development outside the regular supervisory framework. We hold 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

Our main deadline for applications for funded places has now passed. Supervisors may still be able to consider applications from students who have alternative means of funding (for example, charitable funding, clinical fellows or applicants with funding from a foreign government or equivalent). Prospective applicants are strongly advised to contact their prospective supervisor in advance of making an application.

Please note that any applications received after the main funding deadline will not be assessed until all applications that were received by the deadline have been processed. This may affect supervisor availability.

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.


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.


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.


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


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.


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.

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