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dc.contributor.authorSadiyah, Mohammed Firas
dc.date.accessioned2021-12-23T02:52:57Z
dc.date.available2021-12-23T02:52:57Z
dc.date.submitted2021-06-30
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/331749
dc.description.abstractT cells coordinate immune functions by differentiating into highly specialised cellular lineages that either promote or suppress immune reactions. Whereas effector T (Teff) cells drive immune activation and promote clearance of infections and cancer, regulatory T (Treg) cells suppress their function to prevent excessive immune reactions that would otherwise result in autoimmune and allergic disease. During cell fate decisions, access to lineage-specific regulatory elements in the genome, which is tightly controlled by chromatin structure, is required to acquire a specific gene expression profile and a new cell identity. The dynamic changes of the chromatin landscape during Treg differentiation are largely unknown. To study this, I measured chromatin accessibility during the activation of naïve CD4 + T cells in the presence of TGF β (iTreg) or no cytokine (Th0) at different time points and integrated them with known gene expression and histone modification datasets to further characterise these changes. This shows that the chromatin landscape in iTreg cells undergoes dynamic remodelling in response to TCR stimulation and cytokine signalling with convergent effects of the two signals at many regulated loci. BACH2 is a transcriptional repressor whose expression is predominantly restricted to lymphocytes. Whether the suppression role of BACH2 is mainly through steric competition with the AP-1 family or involves other mechanisms is currently unclear. To test this, I measured gene-wide accessibility, DNA binding, and gene expression in Bach2-deficient and Bach2-sufficient Treg cells. While BACH2 is a critical regulator of T cell differentiation, its effect on accessible chromatin was minimal supporting a model whereby it functions principally as a steric repressor of AP-1-driven gene expression. Prior to Treg lineage commitment, BACH2 expression is required for induction of Foxp3, but its role after Treg lineage commitment has been unclear. To test this, I examined gene expression and genome-wide chromatin accessibility in natural Treg (nTreg) cells. This shows that BACH2 is repurposed following Treg lineage commitment, and represses the induction of activated Treg genes to promote the quiescence of resting Treg cells.
dc.rightsAll Rights Reserved
dc.rights.urihttps://www.rioxx.net/licenses/all-rights-reserved/
dc.subjectT-cell
dc.subjectImmunology
dc.subjectGenomics
dc.subjectEpigenetics
dc.titleControl of chromatin accessibility during CD4+ T cell development and activation
dc.typeThesis
dc.type.qualificationlevelDoctoral
dc.type.qualificationnameDoctor of Philosophy (PhD)
dc.publisher.institutionUniversity of Cambridge
dc.date.updated2021-12-16T11:14:53Z
dc.identifier.doi10.17863/CAM.79198
rioxxterms.licenseref.urihttps://www.rioxx.net/licenses/all-rights-reserved/
rioxxterms.typeThesis
cam.supervisorRoychoudhuri, Rahul
cam.depositDate2021-12-16
pubs.licence-identifierapollo-deposit-licence-2-1
pubs.licence-display-nameApollo Repository Deposit Licence Agreement
rioxxterms.freetoread.startdate2022-12-23


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