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Gene Regulatory Networks in Development and Disease


Weatherall Institute of Molecular Medicine

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Dr T Sauka-Spengler No more applications being accepted Competition Funded PhD Project (Students Worldwide)
Oxford United Kingdom Bioinformatics Cell Biology Data Analysis Genetics Immunology Molecular Biology Other

About the Project

Our laboratory focuses on deciphering gene regulatory networks that govern complex programmes during early vertebrate development. We use systems approaches in specific cell types isolated directly from developing embryos to analyse transcriptional, epigenomic and cis-regulatory landscapes to decode and probe developmental programmes at the population and single-cell level.

One of the intriguing developmental populations studied in our lab is the vertebrate neural crest. Neural crest (NC) is a unique multipotent embryonic cell population that differentiates into a plethora of diverse cell types, giving rise to structures as different as neurons and glia of peripheral nervous system, bone, cartilage and connective tissue elements of craniofacial skeleton and body’s pigmentation. Defects in neural crest patterning are some of the most common causes of birth anomalies, accounting for up to one-third of all congenital disabilities. Due to the unique multipotency, developmental plasticity and vast migratory potential of neural crest cells, there is today broad interest in using their regenerative capacity in stem cell-based therapeutics.

By systematic genome-wide profiling of the neural crest regulatory landscape in two model organisms, zebrafish and chicken, our laboratory has, over the past few years, generated an unprecedented systems-level representation into the complex gene regulatory programmes that underlie early steps of neural crest formation. With the regulatory picture obtained directly from developing embryos, we started to unravel the chromatin dynamics at the regulatory loci, characterising the topological structure of neural crest cell epigenomic landscapes and probing the cis-regulatory elements that coordinate neural crest programme. This unique breadth of information now allows us to explore and utilise gene regulatory interactions uncovered to model minimal neural crest specification programme and develop protocols for the directed specification of neural crest derivatives from stem cells.

We are engaged in multiple lines of investigation of the neural crest gene regulatory network. For example, we offer opportunities to study complex mechanisms such as multiple enhancer convergence in super enhancer-like clusters, to decipher the events of commitment to neural crest fates at a single-cell level, or to target and activate critical neural crest circuits endogenously in human embryonic stem cells using novel epigenome engineering (EGE) approaches (CRISPR/Cas9 effector technology), already existing in the lab. The lab routinely uses single-cell technologies, permitting to perform, define and follow developmental trajectories by employing a combination of transcriptomic and epigenomic profiling at the single-cell level using both 10X and smartseq3 technologies, spatial transcriptomics, as well as massively parallel approaches for genetic lineage tracing. In addition to this combination of cutting-edge technologies that enable an analysis of transcriptional, regulatory and epigenetic landscapes at the single-cell level, we also apply the most advanced computational approaches to obtain the maximal resolution of gene regulatory programmes underlying cell fate definition and trajectories in specific developmental cell types. Majority of our lab members (and all graduate students and postdocs) lead both wet-lab and computational portions of their projects. We also offer an opportunity to extend the network knowledge to the context of human development and provide opportunities to explore the wealth of accumulated data using deep learning approaches to study principles of gene regulation across evolution.

We are looking for an excellent, motivated and creative candidate to become part of our dynamic and ambitious team. The successful candidate will receive first-hand training in cutting-edge, state-of-the-art genome-wide profiling and epigenome engineering technologies at the single-cell level, as well as in developmental genomics and computational biology, to be able to successfully tackle the chromatin changes or activate regulatory elements that prime and drive neural crest programme during embryonic development. The candidate will be allowed to influence and freely shape his/her project, while at the same time being carefully advised on feasibility and potential pitfalls of the approaches. It is our aim to foster creativity, novelty and excellent science, provide multifaceted training while answering questions at the cutting edge of our field. They will be embedded within a dynamic group of researchers that employ genetic and system biology approaches to study gene regulatory circuitry in the various contexts of development and disease and will have ample opportunities to grow in spheres of genomics and quantitative biology, as well as to develop collaborations with modelling and stem cell biology groups.

Information about training can be found on our website.


Funding Notes

Funding for this project is available to scientists through the WIMM Prize and 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 8th January 2020 at 12 noon (midday), UK time.
Please visit our website for more information on how to apply.

References

Weinberger* M, Simões* FC, Patient R, Sauka-Spengler* T, and Riley* PR. (2020). Functional heterogeneity within the developing zebrafish epicardium. Dev Cell 52(5):574-590.e6.

Simões* FC, Cahill* TJ, Kenyon A, Gavriouchkina D, Vieira JM, Sun X, Pezzolla D, Ravaud C, Masmanian E, Weinberger M, Mayes S, Lemieux ME, Barnette DN, Gunadasa-Rohling M, Williams RM, Greaves DR, Trinh LA, Fraser SE, Dallas SL, Choudhury* RP, Sauka-Spengler* T, Riley* PR (2020). Macrophages directly contribute collagen to scar formation during zebrafish heart regeneration and mouse heart repair. Nat Commun 11(1):600.

Ling, ITC and Sauka-Spengler T. (2019) Early chromatin shaping predetermines multipotent vagal neural crest into distinct lineages. Nat Cell Bio 21(12):1504-1517.

Hockman D, Chong-Morrison V, Green S, Gavriouchkina D, Candido-Ferreira I, Ling ITC, Williams RM, Amemiya CT, Smith JJ, Bronner ME, Sauka-Spengler T. (2019) A genome-wide assessment of the ancestral neural crest gene regulatory network. Nat Commun. 10(1):4689. (2019).

Williams RM, Candido-Ferreira I, Repapi E, Gavriouchkina D, Senanayake U, Ling ITC, Telenius J, Taylor S, Hughes J, Sauka-Spengler T. (2019). Reconstruction of the global neural crest gene regulatory network in vivo. Dev Cell 51(2):255-276.e7.

Lukoseviciute* M, Gavriouchkina* D, Williams* RM, Hochgreb-Hagele T, Senanayake U, Chong-Morrison V, Thongjuea S, Repapi E, Mead A, Sauka-Spengler T. (2018) From pioneer to repressor: Bimodal foxd3 activity dynamically remodels neural crest regulatory landscape in vivo. Dev Cell 47, 608-628.

Williams* R.M, Senanayake* U, Artibani M, Taylor O.G, Wells D, Ahmed A.A, Sauka-Spengler T. (2018). Genome and epigenome engineering CRISPR toolkit for in vivo modulation of cis-regulatory interactions and gene expression in the chicken embryo. Development Feb 23;145(4) dev.160333.

Kenyon A, Gavriouchkina D, Zorman J, Chong-Morrison V, Napolitani G, Cerundolo V, Sauka-Spengler T. (2018) Generation of a double binary transgenic zebrafish model to study myeloid gene regulation in response to oncogene activation in melanocytes. Dis Model Mech. 2018 Apr 6;11(4).

Trinh* LA, Chong-Morrison* V, Gavriouchkina D, Hochgreb-Hägele T, Senanayake U, Fraser SE, Sauka-Spengler T (2017). Biotagging of Specific Cell Populations in Zebrafish Reveals Gene Regulatory Logic Encoded in the Nuclear Transcriptome. Cell Rep. 19(2):425-440.
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