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Molecular dissection of blood cell fate determination.

Porcher

About the Research

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.

 

Students will be enrolled on the MRC WIMM DPhil Course, which takes place in the autumn of their first year. Running over several days, this course helps students to develop basic research and presentation skills, as well as introducing them to a wide-range of scientific techniques and principles, ensuring that students have the opportunity to build a broad-based understanding of differing research methodologies.

Generic skills training is offered through the Medical Sciences Division's Skills Training Programme. This programme offers a comprehensive range of courses covering many important areas of researcher development: knowledge and intellectual abilities, personal effectiveness, research governance and organisation, and engagement, influence and impact. Students are actively encouraged to take advantage of the training opportunities available to them.

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

All MRC WIMM graduate students are encouraged to participate in the successful mentoring scheme of the Radcliffe Department of Medicine, which is the host department of the MRC WIMM. This mentoring scheme provides an additional possible channel for personal and professional development outside the regular supervisory framework. The RDM also holds 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.

 

Publications

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).

Supervisors

Other potential supervisors

Dr Denis Ptchelkine
MRC Weatherall Institute of Molecular Medicine