Epigenetic programming of hematopoietic stem cells and their progeny

The blood system produces more than ten mature cellular lineages all of which are derived from a small (1:10,000) pool of multi-potent, self-renewing hematopoietic stem cells (HSCs). Until recently, HSCs were thought to be a uniform cell population, and that the lineage commitment and differentiation of their progeny was determined by the stochastic action of lineage instructive transcription factors. However, it is now clear that distinct HSC populations exist which preferentially produce one subset of hematopoietic progenitors and differentiated cell types, but contribute little, or not at all, to other lineages. We recently identified a HSC subpopulation with a strong platelet bias (Sanjuan-Pla et al., Nature 2013), and showed that these platelet-biased HSCs can give rise to HSCs with either myeloid or lymphoid lineage bias, but not vice-versa , suggesting that HSC populations are hierarchically organized, as are downstream, lineage-restricted progenitors.

We now wish to determine how these HSC subtypes are specified, and how their lineage bias is maintained. In particular, we want to understand how one type of lineage bias can replace another, and whether the epigenetic programme in biased HSC subtypes differ from those in the downstream lineage committed progenitors and their differentiating progeny. To gain insight into these processes we will develop highly sensitive global profiling of the chromatin state of all cis-acting elements (e.g. enhancers, promoters and boundary elements) associated with platelet, myeloid and lymphoid lineage programs in pre-programmed HSCs and in the corresponding fully committed progenitors. This will allow the epigenetic profiles associated with bias and commitment to be directly compared. These studies will be combined with global RNA sequencing to identify putative mediators of the observed differences between chromatin states, including lincRNAs, transcription factors and chromatin modifications.

TRAINING OPPORTUNITIES

This project will be based in the MRC Molecular Hematology Unit at the MRC Weatherall Institute of Molecular Medicine, with access to state-of-the-art facilities. The project provides an opportunity for training in a broad range of different techniques, including stem cell biology as a research subject, as well as the use of transgenic mice, combining chromatin analysis with high throughput sequencing, bioinformatics, and the opportunity to translate findings to the human hematopoietic system, and human HSCs in particular.

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. Students are also able to attend the Methods and Techniques course run by the MRC Weatherall Institute of Molecular Medicine. This course runs through the year, ensuring that students have the opportunity to build a broad-based understanding of differing research techniques. There are also courses on Immunology and Bioinformatics and others may be added. Institute Seminars are held on a weekly basis and regularly attract world-class scientists in haematopoiesis research. Informal exchange of ideas in the coffee area is encouraged and is an attractive feature of the MRC WIMM.

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.

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 support the careers of female students and staff.