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dc.contributor.authorFisher, Jasmin
dc.contributor.authorKöksal, AS
dc.contributor.authorPiterman, N
dc.contributor.authorWoodhouse, S
dc.date.accessioned2017-11-15T16:06:17Z
dc.date.available2017-11-15T16:06:17Z
dc.date.issued2015
dc.identifier.isbn9783319216898
dc.identifier.issn0302-9743
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/269317
dc.description.abstractA fundamental challenge in biology is to understand the complex gene regulatory networks which control tissue development in the mammalian embryo, and maintain homoeostasis in the adult. The cell fate decisions underlying these processes are ultimately made at the level of individual cells. Recent experimental advances in biology allow researchers to obtain gene expression profiles at single-cell resolution over thousands of cells at once. These single-cell measurements provide snapshots of the states of the cells that make up a tissue, instead of the population-level averages provided by conventional high-throughput experiments. The aim of this PhD was to investigate the possibility of using this new high resolution data to reconstruct mechanistic computational models of gene regulatory networks. In this thesis I introduce the idea of viewing single-cell gene expression profiles as states of an asynchronous Boolean network, and frame model inference as the problem of reconstructing a Boolean network from its state space. I then give a scalable algorithm to solve this synthesis problem. In order to achieve scalability, this algorithm works in a modular way, treating different aspects of a graph data structure separately before encoding the search for logical rules as Boolean satisfiability problems to be dispatched to a SAT solver. Together with experimental collaborators, I applied this method to understanding the process of early blood development in the embryo, which is poorly understood due to the small number of cells present at this stage. The emergence of blood from Flk1+ mesoderm was studied by single cell expression analysis of 3934 cells at four sequential developmental time points. A mechanistic model recapitulating blood development was reconstructed from this data set, which was consistent with known biology and the bifurcation of blood and endothelium. Several model predictions were validated experimentally, demonstrating that HoxB4 and Sox17 directly regulate the haematopoietic factor Erg, and that Sox7 blocks primitive erythroid development. A general-purpose graphical tool was then developed based on this algorithm, which can be used by biological researchers as new single-cell data sets become available. This tool can deploy computations to the cloud in order to scale up larger high-throughput data sets. The results in this thesis demonstrate that single-cell analysis of a developing organ coupled with computational approaches can reveal the gene regulatory networks that underpin organogenesis. Rapid technological advances in our ability to perform single-cell profiling suggest that my tool will be applicable to other organ systems and may inform the development of improved cellular programming strategies.
dc.description.sponsorshipMicrosoft Research PhD Scholarship
dc.language.isoen
dc.publisherSpringer International Publishing
dc.rightsNo Creative Commons licence (All rights reserved)
dc.rightsAll Rights Reserved
dc.rights.urihttps://www.rioxx.net/licenses/all-rights-reserved/
dc.subjectsingle cell genomics
dc.subjectgene regulatory networks
dc.subjectcomputational biology
dc.titleSynthesising executable gene regulatory networks from single-cell gene expression data
dc.typeThesis
dc.type.qualificationlevelDoctoral
dc.type.qualificationnameDoctor of Philosophy (PhD)
dc.publisher.institutionUniversity of Cambridge
dc.publisher.departmentDepartment of Haematology
dc.date.updated2017-11-15T14:50:10Z
prism.publicationNameLecture Notes in Computer Science (including subseries Lecture Notes in Artificial Intelligence and Lecture Notes in Bioinformatics)
dc.identifier.doi10.17863/CAM.15516
rioxxterms.versionofrecord10.1007/978-3-319-21690-4_38
dc.contributor.orcidFisher, Jasmin [0000-0003-4477-9047]
dc.identifier.eissn1611-3349
dc.publisher.collegeDarwin
dc.type.qualificationtitlePhD in Haematology
cam.issuedOnline2015-07-16
cam.supervisorGottgens, Berthold
cam.supervisorFisher, Jasmin
rioxxterms.freetoread.startdate2017-11-15


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