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Gene Regulatory Networks in Development and Disease: Focusing on systems level “big picture” approaches to understand gene regulation and build gene regulatory networks during development and disease in zebrafish, chick, lamprey and human models.


Project Description

Focusing on systems level “big picture” approaches to understand gene regulation and build gene regulatory networks during development and disease in zebrafish, chick, lamprey and human models.

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 with an aim 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 birth defects. 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, gained an unprecedented systems level insight 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 events at the regulatory loci, characterising the structure of the topologically associating domains of neural crest regulators and probe 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 directed specification of neural crest derivatives from stem cells.

At this point, we are engaging 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 from the chromatin/gene regulatory interaction standpoint, 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. We are looking for an excellent, motivated and creative candidate to become a 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, 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. The candidate 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.

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

Funding for this project is available through the RDM Scholars Programme or the WIMM Prize Studentship. Both programmes offer 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.

Applications must be received, including all relevant supporting materials, by Friday 11th January 2019 at 12 noon (midday).

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

References

Lukoseviciute* M, Gavriouchkina* D, Williams* R, Hochgreb-Hagele T, Senanayake U, Chong-Morrison V, Thongjuea S, Repapi E, Mead A, Sauka-Spengler T. From pioneer to repressor: Bimodal foxd3 activity dynamically remodels neural crest regulatory landscape in vivo. (Accepted Dev Cell, bioRxiv bioRxiv 213611; doi: https://doi.org/10.1101/213611).

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.

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

Hockman D, Chong-Morrison V, Gavriouchkina D, Green S, Amemiya CT, Smith JJ, Bronner ME, Sauka-Spengler T. A genome-wide assessment of the ancestral neural crest gene regulatory network. (bioRxiv 275875 doi: https://doi.org/10.1101/275875)

Kenyon A, Gavriouchkina D, Zorman J, Napolitani G, Cerundolo V, Sauka-Spengler T. Active nuclear transcriptome analysis reveals inflammasome-dependent mechanism for early neutrophil response to Mycobacterium marinum. Sci Rep. 2017 Jul 26;7(1):6505.

Sauka-Spengler T, Bronner-Fraser M. A gene regulatory network orchestrates neural crest formation. Nat Rev Mol Cell Biol. 2008 Jul;9(7):557-68

How good is research at University of Oxford in Clinical Medicine?

FTE Category A staff submitted: 238.51

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