Studying blood stem cell development through single cell and lineage tracing analyses
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 blood (haematopoietic) stem cells (HSCs) are specified during embryonic development.
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. There is now increasing evidence that the earliest events underlying lineage specification arise before mesoderm patterning, i.e. before gastrulation. The PhD student will join our team to dissect the very first molecular events controlling haemopoietic specification during embryonic development at the epiblast stage. Single cell analyses and lineage tracing studies will be developed to track the earliest cells programmed to give rise to the HSC lineage, using in vivo mouse models as well as human and mouse embryonic stem (ES) cell systems. Transcriptomics, functional and biochemical 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. This study will provide general principles in the control of cell fate decisions and guide the design of protocols supporting HSC differentiation in vitro from pluripotent stem cells.
The host laboratory is based in the MRC Molecular Haematology Unit (Weatherall Institute of Molecular Medicine). Initial discussions with the supervisor will define the details of the PhD project. Over the course of this project, the student will be trained by senior post-doctoral fellows in specialised and state-of-the-art technologies (such as ES cell differentiation cultures, single cell genomics, genome editing (CRISPR/Cas9), lineage tracing techniques, protein biochemistry, chromatin immunoprecipitation (ChIP), next generation sequencing, flow cytometry). Our Institute holds regular seminar series and organises formal training in many essential skills (such as bioinformatics and grant writing) as well as a methods and techniques course for all first year PhD students. The student will develop their oral skills when presenting to our laboratory and departmental meetings and their written skills when writing their thesis and papers for publication. As part of the MHU student mentoring scheme, students have a Thesis Committee to advise them on their academic work. Finally, students are strongly encouraged to attend national and international meetings and present their work.
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.
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.
|1||Porcher C, Swat W, Rockwell K, Fujiwara Y, Alt FW, Orkin SH. 1996. The T cell leukemia oncoprotein SCL/tal-1 is essential for development of all hematopoietic lineages. Cell, 86 (1), pp. 47-57. - http://www.ncbi.nlm.nih.gov/pubmed/8689686|
|2||D'Souza SL, Elefanty AG, Keller G. 2005. SCL/Tal-1 is essential for hematopoietic commitment of the hemangioblast but not for its development.Blood, 105 (10), pp. 3862-70. - http://www.ncbi.nlm.nih.gov/pubmed/15677567|
|3||Mohammed H, Hernando-Herraez I, Savino A, Scialdone A, Macaulay I, Mulas C, Chandra T, Voet T, Dean W, Nichols J, Marioni JC, Reik W. 2017. Single-cell landscape of transcriptional heterogeneity and cell fate decisions during mouse early gastrulation. Cell Reports, 20 (5), pp. 1215-1228|
|4||El Omari K, Hoosdally SJ, Tuladhar K, Karia D, Hall-Ponselé E, Platonova O, Vyas P, Patient R, Porcher C, Mancini EJ. 2013. Structural basis for LMO2-driven recruitment of the SCL:E47bHLH heterodimer to hematopoietic-specific transcriptional targets. Cell Rep, 4 (1), pp. 135-47. - http://www.ncbi.nlm.nih.gov/pubmed/23831025|
|5||Porcher C, Chagraoui H, Kristiansen MS. 2017. SCL/TAL1: a multifaceted regulator from blood development to disease. Blood. 129 (15), pp. 2051-2060|
|6||Padrón-Barthe L, Temiño S, Villa del Campo C, Carramolino L, Isern J, Torres M. 2014. Clonal analysis identifies hemogenic endothelium as the source of the blood-endothelial common lineage in the mouse embryo. Blood. 124 (16), pp. 2523-2532|