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The Porcher group investigates the transcriptional, epigenetic and environmental signals specifying the blood stem cell lineage during embryonic development.

Research

The Porcher group investigates the transcriptional, epigenetic and environmental signals specifying the blood stem cell lineage during embryonic development.

Blood cell fate determination initiates in mesodermal endothelial cell progenitors (angioblasts) at gastrulation, long before production of the first blood cells. The early mechanisms instructing a blood fate in mesodermal cells remain poorly understood. We study how the haematopoietic stem cell (HSC) lineage is specified in a subset of angioblasts and how blood-fated cells further develop into blood cells. This knowledge will reveal the molecular basis of cell fate decisions, inform experiments aiming at producing HSCs in vitro from pluripotent stem cells for regenerative medicine purposes, and help explain how these processes, when corrupted, can lead to haematological malignancies (leukaemia) that manifest in early life.

We study angioblasts in vivo in their native environment. We have developed in situ advanced imaging (single molecule RNA FISH) to characterise the anatomical niches supporting the development of blood-fated angioblasts in developing mouse embryos. We use single cell transcriptomic, epigenetic and chromatin organisation assays to identify and functionally define the signals produced by the niche cells, as well as the intrinsic regulators of blood-fated cells and their epigenetic and chromatin landscape. We study the co-operation between transcription factors and chromatin remodelling complexes specifying a blood fate at a mechanistic level (Chagraoui et al. 2018 Nature Communications) and define gene regulatory networks required in niches cells (Li et al. 2019, Nature Communications). We have recently engineered a CRISPR-Cas9 based in vivo dynamic lineage tracing model in mice, based on a system originally established in zebrafish (McKenna et al. Science, 353:aaf7907, 2016). We are using this approach to reconstruct the developmental trajectory of the blood lineage and its developmental relationship with other specialised vascular endothelial lineages.

Prospective PhD students with interests in cell fate decisions, transcriptional mechanisms, epigenetic imprinting and chromatin organisation are strongly encouraged to discuss possible PhD projects with Professor Catherine Porcher. These include:

  • Spatio-temporal characterisation of angioblasts and their niches; identification and mechanistic analyses of intrinsic and extrinsic regulators of haematopoietic specification.
  • Investigating the haemato-endothelial developmental trajectory in normal, perturbed or pathological conditions using our mouse lineage tracing system.

Training Opportunities

These interdisciplinary projects provide opportunities to be trained in advanced cellular and molecular biology technologies. Training will be provided by our group and through collaboration with other teams at the WIMM in areas such as single cell transcriptomics (RNA-seq), epigenetics (ATAC-seq), genomics (ChIP-seq) and 3D genomics (Hi-C/Capture-C) assays. Our group also uses advanced imaging on whole tissues or sections, in vivo and in vitro experimental models (transgenic mouse lines and embryonic stem cells). Training in computing science is available in the Institute as well as externally, and strongly recommended to anyone whose project requires bio-informatics analyses. Regular meetings with the thesis supervisor, co-supervisor and thesis committee, together with opportunities to present at lab meetings and to a wider audience (such as at conferences) will further the intellectual training.

Students are encouraged to attend the MRC Weatherall Institute of Molecular Medicine 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.

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.

 Publications

1

Harland LTG, Simon CS, Senft AD, Costello I, Greder L, Imaz-Rosshandler I, Göttgens B, Marioni JC, Bikoff EK, Porcher C, de Bruijn MFTR, Robertson EJ. The T-box transcriptional factor Eomesodermin governs haemogenic competence of yolk sac mesodermal progenitors. Nat Cell Biol. 2021, 23:61-74.

2

Li L, Rispoli R, Patient R, Ciau-Uitz A, Porcher C. Etv6 activates vegfa expression through positive and negative transcriptional regulatory networks in Xenopus embryos. Nature Communications, 10:1083 (2019

3

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. Nature Communications, 9:5375 (2018)

4

Juban G, Sakakini N, Chagraoui H, Cheng Q… Porcher C*, Vyas P*. Oncogenic Gata1 causes stage-specific megakaryocyte differentiation delay. Haematologica 2020, 106:1106-25.