Development of the hematopoietic/ immune system in the embryo
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 [email protected]
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.
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.
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