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Molecular dissection of blood cell fate determination: identifying key principles in the control of cell fate decisions

  • Full or part time
    Dr C Porcher
    Prof M DeBruijn
    Prof T Milne
  • Application Deadline
    Friday, January 11, 2019
  • Competition Funded PhD Project (Students Worldwide)
    Competition Funded PhD Project (Students Worldwide)

Project Description

Molecular dissection of blood cell fate determination.

Understanding the molecular mechanisms underlying cell fate decisions during embryonic development is a key biological question, not only from a fundamental scientific point of view but also to inform attempts at producing tissue stem cells in vitro for regenerative medicine purposes. The Porcher lab investigates how haematopoietic stem cells (HSCs, the cells with self-renewal and multilineage potentialities that give rise to the entire blood system) are specified during embryonic development. This is achieved by studying the differentiation trajectory of the blood lineage from mesoderm and the transcriptional and epigenetic control of blood cell production throughout this developmental progression. These studies rely on cutting edge technologies, such as in vivo lineage tracing; single cell transcriptomics and imaging; chromatin immunoprecipitation (ChIP), chromatin accessibility (ATAC) and next generation sequencing; genome editing (CRISPR/Cas9); multi-colour flow cytometry; mouse and human ES cell differentiation cultures.

We have recently shown that multilineage-primed mesodermal cells acquire a blood fate at the expense of other mesodermal-derived lineages (heart, bones or muscles) through tight transcriptional and epigenetic control of gene expression. This has revealed the establishment of a repressive environment by the key transcription factor also driving haematopoietic specification, SCL/TAL1. We are currently further investigating these repressive transcriptional activities and their functional link to chromatin remodelling complexes, such as Polycomb, both in vivo and in vitro using ES cell differentiation cultures. Transcriptomics, functional and structural approaches will further characterise the networks of genetic and protein/protein interactions required to establish a haematopoietic-specific gene expression programme and drive HSC development. These studies will identify key principles in the control of cell fate decisions.

Another important aspect of our research is the design of protocols that carefully recapitulate development of the HSC lineage in serum-free mouse and human pluripotent stem cell (PSC) differentiation cultures, as it happens during embryonic development. Indeed, over the past decade, numerous efforts have been deployed to produce HSCs in vitro from PSCs for mechanistic and therapeutic purposes. However, none of the differentiation cultures developed so far have been able to produce long-term repopulating HSCs. This is likely to reflect the lack of critical signalling molecules supporting HSC development in the current differentiation cultures. We are designing new protocols supporting this stepwise cellular differentiation, based on our knowledge of blood development during embryogenesis. Cell fate replating studies combined with single cell transcriptomics, epigenetics and chromatin accessibility approaches will inform on the cellular potential and the evolution of the molecular landscape as the cells transit through the stages leading to production of HSCs. Ultimately, our goal is to translate our findings to the clinical setting.

PhD students will join our team and contribute to the development of some of the areas of investigation detailed above. Potential PhD projects include the molecular and functional study of the relationship between transcriptional and epigenetic regulatory mechanisms during blood specification and the modelling of HSC differentiation from human pluripotent stem cells. Prospective PhD students are strongly encouraged to discuss possible PhD projects directly with the PI.


Training Opportunities

The students will learn how to design their PhD project under the guidance of the PI and collaborators. This will help them frame their project both conceptually and experimentally and will be an excellent way to learn about the field. Once a thesis plan is in place, weekly one-to-one meetings with the thesis supervisor, as well as regular lab meetings, thesis committee meetings and opportunities to present to a wider audience will further the intellectual training.

Initially, students will work closely with senior students or post-docs in the lab who will provide training at the bench on a daily basis. This will ensure that they rapidly master the molecular and cellular technologies required for their project. Training in computing science is available in the Institute as well as externally, and strongly recommended to anyone whose project requires bio-informatics analyses.
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

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

Chagraoui H, Kristiansen MS, Ruiz JP, Serra-Barros A, Richter J, Hall-Ponselé E, Gray N, Waithe D, Clark K, Hublitz P, Repapi E, Otto G, Kerry J, Sopp P, Taylor S, Vyas P and Porcher C. SCL establishes a global repressive environment and co-operates with RYBP-PRC1 to repress alternative lineages in blood-fated cells. In revision.

Karamitros D et al. Heterogenetiy of human lympho-myeloid progenitors at the single cell level. Nature Immunology 19:85-97 (2018)

Porcher C, Chagraoui H, Kristiansen MS. SCL/TAL1, a multifaceted regulator from blood development to disease. Blood, 129:2051- 60 (2017).

Chen II, Caprioli A, Ohnuki H, Kwak H, Porcher C, Tosato G. EphrinB2 regulates the emergence of a hemogenic endothelium from the aorta. Scientific Reports 6:27195 (2016)

Leung A, Ciau-Uitz A, Pinheiro P, Monteiro R, Zuo J, Vyas P, Patient R & Porcher C. Uncoupling VEGFA functions in arteriogenesis and hematopoietic stem cell specification. Developmental Cell, 24, 144-158 (2013).

El Omari K, Hoosdally SJ, Tuladhar K, Karia D, Hall-Ponsele E, Platonova O, Vyas P, Patient R, Porcher C*, Mancini EJ*. Structural Basis for LMO2-Driven Recruitment of the SCL: E47bHLH Heterodimer to Hematopoietic-Specific Transcriptional Targets. Cell Reports 4:135 (2013).

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

FTE Category A staff submitted: 238.51

Research output data provided by the Research Excellence Framework (REF)

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