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Title: The role of histone 3 lysine 27 trimethylation in thymic epithelial cell development and function
Author: Graedel, Annina
ISNI:       0000 0004 7966 1687
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2018
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Thymic epithelial cells (TEC) create the unique environment for the selection of T cells that are tolerant to self but reactive to foreign antigens. For this purpose, TEC express an almost comprehensive repertoire of self-antigens, through a process referred to as promiscuous gene expression (PGE). The precise molecular mechanisms that account for PGE remain incompletely defined although a subset of promiscuously expressed genes rely for their efficient expression on the presence of the Autoimmune Regulator (AIRE). This transcriptional facilitator preferentially controls the expression of genes that display the repressive histone mark H3K27me3 at their transcriptional start sites. To address the question whether alterations in the H3K27me3 landscape influence TEC biology, mice with a TEC-specific loss of the H3K27me3 demethylases UTX and JMJD3 were generated. These mice demonstrated that a deficiency in UTX and JMJD3 reduced the frequency of immature medullary TEC (mTEC), while increasing the frequency of mature mTEC. Although the resulting gene expression changes were limited, AIREregulated genes were strongly enriched within the upregulated genes, supporting the hypothesis that H3K27me3 modifications serve as recognition marks for AIRE-regulated PGE. Placement of H3K27me3 marks is mediated by the polycomb repressive complex 2 (PRC2), which gets recruited to its target genes by cofactor JARID2. Mice with a TECspecific deficiency of JARID2 were also generated and investigated. Despite its seemingly different functional role, a JARID2 deficiency had a similar impact on the mTEC phenotype as a loss of H3K27me3 demethylases UTX and JMJD3. The altered TEC compartment of both experimental animal models further altered the frequency of thymocytes undergoing negative selection in the medulla and mildly decreased the generation of single positive thymocytes. Taken together, this work shows that a TEC-specific loss of epigenetic modifiers of H3K27 methylation impacts on TEC differentiation and function.
Supervisor: Holländer, Georg Sponsor: Swiss National Science Foundation
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available