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Molecular dissection of blood cell fate determination


Weatherall Institute of Molecular Medicine

Assoc Prof C Porcher Friday, January 08, 2021 Competition Funded PhD Project (Students Worldwide)

About the Project

The Porcher lab investigates how Haematopoietic Stem Cells (HSCs, the cells with self-renewal and multilineage potentialities that give rise to the entire blood system) are produced during embryonic development. To do this, we study the developmental pathway of the blood lineage from mesoderm through to production of HSCs (see Figure) at mechanistic and functional levels. In addition to increasing our understanding of this fundamental biological process, better knowledge of how the first HSCs are generated during embryogenesis is critical to inform experiments aiming at producing HSCs in vitro for regenerative medicine purposes and to help explain how these processes, when corrupted, can lead to haematological malignancies (leukaemia) that manifest in early life.

How the blood lineage develops during embryogenesis is not fully understood and many questions remain unanswered or controversial (see Figure): what is the micro-environment (or cellular niche) of the mesoderm at the origin of HSCs? what are the signals inducing a blood fate? how are alternative fates repressed? what are the cellular intermediates? To answer these questions, we have developed two strategies relying on cutting edge technologies.

• We have engineered an in vivo lineage tracing model in mice, based on a system originally established in zebrafish (McKenna et al. Science, 353:aaf7907, 2016). This allows to track the development of lineages through progressive editing of a barcode by a spatio-temporally inducible CRISPR/Cas9 system during a chosen time window. Single cell transcriptomics retrieves the scarred barcodes and assigns cell identity, thus allowing lineage tree reconstruction and branching point identification. We are currently using this approach to reconstruct the developmental trajectory of the blood lineage in order to characterise its mesodermal origin and developmental relationship with other mesodermal tissues, and identify cellular intermediates in an unbiased manner. This is combined with in situ single molecule RNA FISH and high-throughput single cell transcriptomic and epigenetic analyses to characterise the cellular niches supporting the specification of the HSC lineage and the molecular determinants of cell fate at key developmental stages.

• We have recently shown that multilineage-primed mesodermal cells acquiring a blood fate do so at the expense of alternative mesodermal-derived lineages (heart, bones, muscles) through epigenetic control of gene expression (Chagraoui et al. Nature Communications, 2018). This results from the co-operation between a key blood-specific transcription factor (SCL) and the chromatin remodelling repressive complex Polycomb, and the establishment of a global repressive environment. This suggests a profoud remodelling of the genome at the time of lineage specification. We are currently investigating the molecular mechanisms underlying this process (role of Polycomb, functional relationship with SCL) using loss-of-function, proteomics, high-throughput genomics (ChIP-seq), epigenetics (ATAC-seq) and 3D genomics (Hi-C/Capture-C) assays.

Prospective PhD students with interests in cell fate decisions and transcriptional/epigenetic regulation of gene expession are strongly encouraged to discuss possible PhD projects with Prof. Catherine Porcher. These include the use of our mouse lineage tracing system to investigate specific aspects of blood development in normal, perturbed or pathological conditions. Other projects involve mechanistic investigations of the regulatory processes controlling cell fate decisions (such as Polycomb-mediated repression) at key developmental stages, using the technologies mentioned above. Altogether, these studies will provide invaluable information for a better understanding of blood development and how to model it in vitro from pluripotent stem cells. More globally, this will unveil some of the key principles and mechanisms governing cell fate decisions that are likely to apply to most tissues, in the embryo and in the adult.

The students will plan their PhD project conceptually and experimentally under the guidance of the PI and collaborators. This will be an excellent way to learn about the field and ensure the biological question integral to the project is appropriately formulated and addressed. Once a thesis plan is in place, weekly one-to-one meetings with the thesis supervisor, quarterly meetings with the co-supervisor, yearly thesis committee meetings as well as regular lab meetings and opportunities to present to a wider audience will further the intellectual training.
Initially, students will work closely with senior students or post-docs in the lab who will provide training at the bench on a daily basis. This will ensure that they rapidly master the molecular and cellular technologies required for their project. Training in computing science is available in the Institute as well as externally, and strongly recommended to anyone whose project requires bio-informatics analyses.

More information about training opportunities can be found on our website

Funding Notes

Funding for this project is available to scientists through the WIMM Prize Studentship and the RDM Scholars Programme, which offers funding to outstanding candidates from any country. Successful candidates will have all tuition and college fees paid and will receive a stipend of £18,000 per annum.

For October 2021 entry, the application deadline is 8th January 2021 at 12 noon midday, UK time.

Please visit our website for more information on how to apply.



References

Juban G, Sakakini N, Chagraoui H, Cheng Q … Porcher C*, Vyas P*. Oncogenic Gata1 causes stage-specific megakaryocyte differentiation delay. Haematologica. Online ahead of print (2020).

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).

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)

Karamitros D et al. Heterogenetiy of human lympho-myeloid progenitors at the single cell level. Nature Immunology 19:85-97 (2018)

Porcher C, Chagraoui H, Kristiansen MS. SCL/TAL1, a multifaceted regulator from blood development to disease. Blood, 129:2051- 60 (2017).

Chen II, Caprioli A, Ohnuki H, Kwak H, Porcher C, Tosato G. EphrinB2 regulates the emergence of a hemogenic endothelium from the aorta. Scientific Reports 6:27195 (2016)

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