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Development of the hematopoietic/ immune system in the embryo

De bruijn group developmental haematopoiesis

 

About the Research

Our aim is to obtain a mechanistic insight into the birth of hematopoietic stem and progenitor cells in embryonic development and determine the contribution of these cells to the emerging hematopoietic and immune systems of the embryo.

Hematopoietic stem cells (HSCs) are responsible for the lifelong production of blood and adaptive immune cells. They are generated de novo early in development from a specialized subset of endothelial cells, the so-called hemogenic endothelium (HE). Prior to HSC generation, the embryo produces hematopoietic progenitor cells that support its growth and development and contribute to tissue-resident innate immune cells. Taking advantage of unique Runx1 enhancer-reporter mouse models generated in our laboratory we set out to dissect the cellular and molecular events that underlie the birth of blood stem and progenitor cells. Using one of these models we previously analysed HE at the single cell level, showing its dynamic nature during mouse development and rewriting the time line for HE specification to the hematopoietic lineage (Swiers et al., Nature Communications 2013). More recently, we have performed extensive expression (RNA-seq) and chromatin (ATAC-seq) profiling of Runx1 enhancer-reporter-marked cells throughout early mouse development to construct gene interacting networks and identify new players critical to the formation of HE and hematopoietic stem and progenitor cell lineages that will be tested experimentally. Another line of work in the laboratory aims to elucidate the cis-regulatory organization of the transcription factor Runx1 in the developing hematopoietic and immune cell lineages, and identify the trans-acting factors and signals that converge on the enhancers to control cell type specific expression. Runx1 cis-regulation is highly complex and dynamic, and is regulated through cis-regulatory elements distal to its promoters (Nottingham et al., Blood 2007, Bee et al., Blood 2009, Schutte et al., eLife 2016). Our ongoing studies in this area apply state-of-the art chromatin analysis and molecular technologies. Finally, we have begun to trace the early mesodermal origin(s) of hematopoietic stem cells and specific progenitors in the mammalian embryo to map their trajectories through the embryo and the signals they receive that affect their fate decisions. Altogether, insights obtained from these studies will contribute to a better understanding of the cell types that build and maintain the adult hematopoietic and immune systems. In addition, the signals and gene interacting networks underlying the formation of these cells will inform the directed differentiation of ESC/iPSC into clinically relevant hematopoietic and/or immune cells.

Our laboratory is now looking for enthusiastic and motivated students to join our team. The successful candidate will be part of the Developmental Hematopoiesis group in the MRC Molecular Haematology Unit of the MRC Weatherall Institute of Molecular Medicine (WIMM) at the Radcliffe Department of Medicine. In pursuing her/his project, the candidate will have ample opportunities for collaboration with other groups in the WIMM and the Radcliffe Department of Medicine working on gene regulation and epigenetics, gene editing, blood stem and progenitor cell biology, and computational biology. There is an active student association in the WIMM, which organises several events throughout the year.

For further information on potential project areas, please contact:

Prof Marella de Bruijn

Marella.debruijn@imm.ox.ac.uk

 

Training Opportunities

The successful candidate will be expected to have significant input in developing and leading their project in one of our areas of research, with the advice and guidance of the supervisor.

Students will also have a thesis committee to advise them on their academic work and progress. Tailored to the specific project requirements, the successful candidate will receive training in several of the following techniques: embryo dissections, in vitro and in vivo hematopoietic assays, mouse/human ES/iPS cell culture, immunofluorescence, flow cytometry, confocal microscopy and live imaging, molecular biology, genome editing (CRISPR/Cas9), chromatin assays/gene regulation, expression profiling on single cells/small cell numbers, computational biology, and other relevant technologies.

Students are also encouraged to take up a diverse array of technical and transferable skills training in the Medical Sciences Division, Oxford, or relevant courses wider afield. Attendance at (international) meetings to present and discuss data is encouraged. 

 

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

Nottingham et al., Blood 2007

Bee et al., Blood 2009

Swiers et al., Nature Communications 2013

Schutte et al., eLife 2016

Azzoni et al., EMBO Reports 2018




Supervisor