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Prof D Higgs , , , Friday, January 08, 2021 Competition Funded PhD Project (Students Worldwide)

About the Project

Our laboratory is interested in the general question of how mammalian genes are switched on and off during lineage commitment and differentiation. We use the most recent genomics technologies and computational approaches to study both the entire genome and individual genes in detail. We study all aspects of gene expression including the key cis-regulatory elements (enhancers, promoters and insulators), the transcription factors and co-factors that bind them, the epigenetic modifications of chromatin and DNA, and the role of associated phenomena such as chromosome conformation and nuclear sub-compartmentalisation using state-of-the-art imaging techniques. These studies are performed both in cell systems and in model organisms as well as in material from human patients with various inherited and acquired, genetic and epigenetic abnormalities. The translational goal of our work is to develop new ways to modify gene expression during blood formation with the aim of manipulating gene expression and ameliorating the clinical phenotypes of patients with a variety of blood disorders.

We study gene regulation using the human and mouse globin loci as haematopoietic cells undergo lineage fate decisions and differentiation. Our aim is to understand the principles by which all mammalian genes are switched on and off during cell fate decisions. Globin gene expression is controlled by a group of conserved, long-range regulatory elements some of which lie within the introns of an adjacent widely expressed gene (Nprl3) and another lies in intergenic DNA. All of these elements have the chromatin signature of enhancers. Using Chromosome Conformation Capture, we have shown that these enhancers physically interact with each other and with the globin gene promoters, and together are essential for normal globin gene expression. From genome-wide studies, this configuration appears to be a common feature of highly expressed, lineage-specific genes and such groups of regulatory elements are referred to as “super-enhancers”. We continue to study such enhancers to understand how they interact with the globin promoters and their effect on the transcription cycle. More recently we have developed analyses to examine gene regulation in single cells including imaging approaches that allow us to visualise chromatin movements and transcription of these genes in real time.

We have recently performed Hi-C experiments and have defined the Topologically Associated chromatin Domain (TAD) containing the globin gene cluster in erythroid and non-erythroid cells. We have also characterised the formation of this domain and of the enhancer promoter contacts during normal in vivo differentiation. We are currently investigating how activation, deletion and re-orientation of the globin regulatory elements (enhancers, promoters and boundary elements) affect expression of other genes within the same TAD and in neighbouring TADs. We also study chromatin structure and movement in real time using super-resolution imaging. Importantly, using globin as our model, we are addressing the general question of the relationship between higher order, long-range chromosomal structure and function.

In addition to understanding how genes are activated we are also interested in how they are silenced. One of the globin genes, lying within the TAD, is only expressed in early developmental life and then remains silenced during adult life. Reactivation of this gene may represent a novel therapeutic option for patients with severe alpha-thalassemia. We are studying the transcriptional and epigenetic pathway by which this gene is silenced and kept so even though it lies adjacent to active erythroid enhancers. Again this is a general question in mammalian genetics and the globin system provides a unique opportunity to establish the biological principles by which gene silencing occurs.
An important aim of our work is to develop new ways of treating blood disorders by genome editing of the regulatory elements we are studying. We currently have clinical projects underway in Sri Lanka and Thailand to develop such techniques to treat patients with thalassaemia, a common form of inherited anaemia.

Students joining our laboratory will have a choice of projects which address current topics in the regulation of gene expression, and their application to human genetic disease, using state-of-the-art approaches to these questions.

For more information about training opportunities please see our website.


Funding Notes

Funding for this project is available to scientists through the WIMM Prize Studentship and 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 2021 entry, the application deadline is 8th January 2021 at 12 noon midday, UK time.

Please visit our website for more information on how to apply.


References

Single-Cell Proteomics Reveal that Quantitative Changes in Co-expressed Lineage-Specific Transcription Factors Determine Cell Fate. Palii CG, Cheng Q, Gillespie MA, Shannon P, Mazurczyk M, Napolitani G, Price ND, Ranish JA, Morrissey E, Higgs DR, Brand M. Cell Stem Cell. 2019
A tissue-specific self-interacting chromatin domain forms independently of enhancer- promoter interactions. Brown JM, Roberts NA, Graham B, Waithe D, Lagerholm C, Telenius JM, De Ornellas S, Oudelaar AM, Scott C, Szczerbal I, Babbs C, Kassouf MT, Hughes JR, Higgs DR, Buckle VJ. 2017 Nat Commun.

Tissue-specific CTCF-cohesin-mediated chromatin architecture delimits enhancer interactions and function in vivo. Hanssen LLP, Kassouf MT, Oudelaar AM, Biggs D, Preece C, Downes DJ, Gosden M, Sharpe JA, Sloane-Stanley JA, Hughes JR ...Higgs DR and Buckle V. 2017. Nat Cell Biol 19: 952-961.

Testing the super-enhancer concept by in-vivo dissection. Hay D, Hughes JR, Babbs C, Davies JOJ, Graham BJ, Hanssen L, Kassouf MT, Oudelaar AM, Sharpe ja, Suciu M, Telenius J, Williams R, Rode C, Li P-S, Pennacchio LA, Sauka-Spengler T, Sloane-Stanley JA, Ayyub H, Butler S, Gibbons RJ, Smith AJH, Wood WG & Higgs DR (2016) Nature genetics, 48, 895-903.

Analysis of hundreds of cis-regulatory landscapes at high resolution in a single, high-throughput experiment. Hughes, J.R., Roberts, N., McGowan, S., Haay, D., Giannoulatou, E., Lynch, M., de Gobbi, M., Taylor, S., Gibbons, R. & Higgs, D.R. (2014) Nat Genet, 46: 205-212.

Single-allele chromatin interactions identify regulatory hubs in dynamic compartmentalized domains. Oudelaar AM, Davies JOJ, Hanssen LLP, Telenius JM, Schwessinger R, Liu Y, Brown JM, Downes DJ, Chiariello AM, Bianco S, Nicodemi M, Buckle VJ, Dekker J, Higgs DR, Hughes JR. Nat Genet. 2018

Dynamics of the 4D genome during in vivo lineage specification and differentiation. Oudelaar AM, Beagrie RA, Gosden M, de Ornellas S, Georgiades E, Kerry J, Hidalgo D, Carrelha J, Shivalingam A, El-Sagheer AH, Telenius JM, Brown T, Buckle VJ, Socolovsky M, Higgs DR, Hughes JR . Nat Commun. 2020




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