The exciting life of giants: single cell molecular and functional studies of megakaryocytes

WOJTOWICZ_E23DTP

Clotting at the site of an injury is a lifesaving mechanism mediated by platelets. It is estimated that a healthy individual produces 1 million platelets every second for this purpose. However, in older people, cancer patients, and those suffering from autoimmune diseases, there can be a life-threatening shortage of platelets. Understanding why could help us develop new treatments.

Platelets originate from megakaryocytes, one of the largest and most mysterious mammalian cells. These giant cells can have up to 32 copies of the genome and fragment their cytoplasm to give rise to platelets. However, it is unknown if all megakaryocytes contribute equally or if there is a correlation between genome ploidy and platelet output.

Using RNA lineage tracing, we have recently shown that not all megakaryocyte progenitors produce platelets. Although the main function of megakaryocytes is to produce platelets, growing evidence suggests they have a role in immune defence. This distinct function is assumed to be executed by a subset of megakaryocytes.
We are offering a collaborative multi-disciplinary PhD project between the Wojtowicz, Macaulay and Haerty groups. The aim of the project is to apply single cell RNA lineage tracing, combined with long- and short-read sequencing, to determine the origins – and molecular and functional consequences – of increased ploidy in megakaryocytes.

The student will work in a rapidly developing field and gain unique expertise in experimental single cell functional and molecular biology, technology development, and computational biology. The project will be conducted at the Earlham Institute, a BBSRC-supported, world-leading research centre for single cell technology development, genomics, and bioinformatics. The student will have access to training, peer support, and career development opportunities.

References

1. Wojtowicz, E. E. et al. Parallel clonal and molecular profiling of hematopoietic stem cells using RNA barcoding. bioRxiv 2022.05.16.491933 (2022) doi:10.1101/2022.05.16.491933.

2. Wojtowicz, E. E. et al. Ectopic miR-125a Expression Induces Long-Term Repopulating Stem Cell Capacity in Mouse and Human Hematopoietic Progenitors. Cell Stem Cell 19, 383–396 (2016).

3. Macaulay, I. C. et al. G&T-seq: parallel sequencing of single-cell genomes and transcriptomes. Nat. Methods 12, 519–522 (2015).

4. Shultz, Gan, Dick & Lechman. Functional profiling of single CRISPR/Cas9-edited human long-term hematopoietic stem cells. Nature.