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dc.contributor.authorPillidge, Zoe
dc.date.accessioned2019-03-25T09:37:42Z
dc.date.available2019-03-25T09:37:42Z
dc.date.issued2019-05-18
dc.date.submitted2018-09-26
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/290796
dc.description.abstractDuring normal development, different genes are expressed in different cell types, often directed by cell signalling pathways and the pre-existing chromatin environment. The highly-conserved Notch signalling pathway is involved in many cell fate decisions during development, activating different target genes in different contexts. Upon ligand binding, the Notch receptor itself is cleaved, allowing the intracellular domain to travel to the nucleus and activate gene expression with the transcription factor known as Suppressor of Hairless (Su(H)) in Drosophila melanogaster. It is remarkable how, with such simplicity, the pathway can have such diverse outcomes while retaining precision, speed and robustness in the transcriptional response. The primary goal of this PhD has been to gain a better understanding of this process of rapid transcriptional activation in the context of the chromatin environment. To learn about the dynamics of the Notch transcriptional response, a live imaging approach was used in Drosophila Kc167 cells to visualise the transcription of a Notch-responsive gene in real time. With this technique, it was found that Notch receptor cleavage and trafficking can take place within 15 minutes to activate target gene expression, but that a ligand-receptor interaction between neighbouring cells may take longer. These experiments provide new data about the dynamics of the Notch response which could not be obtained with static time-point experiments. The chromatin accessibility and nucleosome dynamics at Notch-responsive enhancers were also studied using a variety of molecular techniques. These experiments showed that enhancers occupied by Su(H) were highly accessible with a high level of nucleosome turnover, and that Notch signalling promoted a further increase in accessibility. The BRM complex, a SWI/SNF chromatin remodeller implicated in many cancers, was identified as essential for the high chromatin accessibility at these regions and the Notch response. This new insight into the link between a simple signalling pathway and chromatin remodelling could have implications for understanding the complicated process of development and what goes wrong in diseases like cancer.
dc.language.isoen
dc.rightsAll rights reserved
dc.rightsAll Rights Reserveden
dc.rights.urihttps://www.rioxx.net/licenses/all-rights-reserved/en
dc.subjectNotch
dc.subjectchromatin
dc.subjecttranscription
dc.subjectdevelopment
dc.subjectsignalling
dc.titleTranscription and chromatin dynamics in the Notch signalling response
dc.typeThesis
dc.type.qualificationlevelDoctoral
dc.type.qualificationnameDoctor of Philosophy (PhD)
dc.publisher.institutionUniversity of Cambridge
dc.publisher.departmentDepartment of Physiology, Development and Neuroscience
dc.date.updated2019-03-23T11:14:48Z
dc.identifier.doi10.17863/CAM.37999
dc.publisher.collegeChurchill
dc.type.qualificationtitlePhD in Physiology, Development and Neuroscience
cam.supervisorBray, Sarah
cam.thesis.fundingtrue
rioxxterms.freetoread.startdate2020-03-25


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