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Mapping the Transcriptional Landscape of Haematopoietic Stem and Progenitor Cells

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Mapping the Transcriptional Landscape of Haematopoietic Stem and Progenitor Cells Mapping the transcriptional landscape of haematopoietic stem and progenitor cells Sonia Shaw (née Nestorowa) Department of Haematology University of Cambridge This dissertation is submitted for the degree of Doctor of Philosophy Pembroke College January 2019 Declaration I hereby declare that this dissertation is the result of my own work and includes nothing which is the outcome of work done in collaboration except where specifically indicated in the text. Specific details of work done in collaboration are given at the start of relevant chapters. The contents of this dissertation are not substantially the same as any that I have submitted, or, is being concurrently submitted for a degree or diploma or other qualification at the University of Cambridge or any other University or similar institution. I further state that no substantial part of my dissertation has already been submitted, or, is being concurrently submitted for any such degree, diploma or other qualification at the University of Cambridge or any other University or similar institution. The total length of the main body of this dissertation including figure legends is 50,345 words and therefore does not exceed the limit of 60,000 words for such a dissertation. Sonia Shaw January 2019 i Mapping the transcriptional landscape of haematopoietic stem and progenitor cells Sonia Shaw Maintenance of the blood system requires balanced cell-fate decisions of haematopoietic stem and progenitor cells (HSPCs). Individual haematopoietic stem cells (HSCs) decide between self- renewal and differentiation and can generate all mature cell types. Cell-fate decisions are made at the single-cell level and are governed by regulatory networks. Dysregulation in this balanced process could lead to serious blood disorders such as leukaemia; therefore, it is important to understand how individual cells make these cell-fate decisions. To investigate HSPC populations, 1,654 cells were profiled by single-cell RNA-sequencing. Index sorting made it possible to sort HSPCs using broad sorting gates and retrospectively assign them to common HSPC populations, retaining all information about specific functionally pure populations while also capturing any intermediate cells normally excluded by conventional gating. Reconstruction of differentiation trajectories revealed dynamic expression changes associated with early lineage differentiation from HSCs. This transcriptional atlas of HSPC differentiation was further used to identify candidate genes for a CRISPR screen investigating genes implicated in HSC biology. These candidate gene perturbations were interrogated for changes in the expression of the HSC marker EPCR, as well as changes in apoptosis and lineage output. Transcription factors play a key role in regulating cell-fate decisions and operate within organized regulatory programs. To study relationships between transcription factors in HSPC populations, qRT-PCR was used to profile the expression of 41 genes, including 31 transcription factors, in HSPCs at the single-cell level. This approach confirmed known aspects of haematopoiesis and made deeper investigation of HSPC heterogeneity possible. Regulatory networks were reconstructed using Boolean network inference models and recapitulated differentiation of HSCs towards megakaryocyte–erythrocyte progenitors and lymphoid-primed multipotent progenitors. By comparing these two models, a rule specific to the megakaryocyte-erythrocyte progenitor network was identified, in which GATA2 positively regulated Nfe2 and Cbfa2t3h. This was subsequently validated using transcription factor binding profiles and in vitro luciferase assays using a model cell line. ii Overall, the work presented in this thesis confirmed known aspects of HSPC biology using single- cell gene expression analysis and demonstrated how in silico approaches can be used to guide in vitro and in vivo investigations. In addition, the single-cell RNA-sequencing data was developed into an intuitive web interface that can be used to visualise the gene expression for any gene of choice at single-cell resolution across the HSPC atlas, providing a powerful resource for the haematopoietic community. iii iv Acknowledgements First and foremost, I would like to thank my supervisor, Berthold Göttgens, for his mentorship and support over the last four years, as well as Nicola Wilson, who has been a great source of support, both academically and otherwise. I am very grateful to Fiona Hamey for our collaborative work, her patience with my endless questions, and for being a joy to know and work with. I would also like to thank Iwo Kucinski and Joakim Dahlin, for always being available to advise me, support me, and for generally making the lab brighter. I am greatly indebted to everyone in the Göttgens lab for always being willing to help and for being great people to work with throughout my time in the lab. I would also like to thank David Rubinsztein and Scottie Robinson for accepting me onto the CIMR PhD programme, as well as the Medical Research Council for funding my PhD. A huge thank you also goes to Martin Dawes, who always had the answers to all my questions, and has always gone above and beyond to help. Thank you to the Flow Cytometry Team at the CIMR for being a huge support during my PhD and making me look forward to otherwise very long sorting days! I would like to thank my parents, who have been an endless source of love and fierce support and have been invaluable in the toughest times. My wonderful dogs, Trixie and Huxley, are two of the greatest treasures in my life and have provided endless distraction when most needed, as well as unwavering love and emotional support in the form of licks and big, breath-taking cuddles (literally). Finally, I would like to thank my husband Ben Shaw, without whom this PhD and the last four years may have looked very different. He has supported me in every way imaginable and I will be eternally grateful to him for making me a better, stronger, happier person, and for helping me achieve all my goals and more. v vi Table of Contents Declaration........................................................................................................................................ i Abstract ........................................................................................................................................... ii Acknowledgements ......................................................................................................................... v Table of Contents ......................................................................................................................... vii List of Figures .................................................................................................................................. x List of Tables ............................................................................................................................... xiii Abbreviations ............................................................................................................................... xiv Papers arising from this PhD ........................................................................................................ xvi Chapter 1: Introduction .................................................................................................................... 1 1.1. The adult haematopoietic system ...................................................................................... 1 1.2. Cell fate decision making ................................................................................................. 5 1.3. Dysregulation of transcriptional control in haematopoiesis ............................................. 8 1.4. Mammalian genome editing ............................................................................................. 9 1.5. Single cell biology .......................................................................................................... 11 1.6. Aims ................................................................................................................................ 25 Chapter 2: Materials & Methods ................................................................................................... 26 2.1. Cell culture ......................................................................................................................... 26 2.2. Cell Biology ........................................................................................................................ 27 2.3. Molecular Biology .............................................................................................................. 39 2.4. HSC retroviral transduction analysis: genotyping .............................................................. 45 2.5. Single Cell Gene Expression Analysis ............................................................................... 48 2.6. Computational Analysis ..................................................................................................... 53 Chapter 3: A single-cell atlas of adult murine haematopoiesis ..................................................... 57 3.1. Background ......................................................................................................................... 57 3.2. Isolation of haematopoietic stem and progenitor cells for single-cell analysis .................. 59 vii 3.3. Single-cell gene expression analysis reveals distinct HSPC clusters ................................
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