Cellular heterogeneity and gene regulatory network coordination during thymic epithelial cell development
Faculty AdvisorRené Maehr
UMass Chan AffiliationsProgram in Molecular Medicine
Document TypeDoctoral Dissertation
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AbstractThymic epithelial cells, derived from the pharyngeal endoderm, perform essential functions for establishing a self-tolerant immune system. Unsurprisingly, dysfunction of thymic epithelial cells resulting from maldevelopment of the pharyngeal endoderm causes immunodeficiency or autoimmunity syndromes, some of which cannot be fully explained according to known genetic errors. Despite the functional significance and disease-relevance of pharyngeal endoderm with respect to thymic epithelial cells, we lack a comprehensive understanding of the gene regulatory networks driving pharyngeal endoderm differentiation. To close this gap, we applied transcriptome and chromatin accessibility single cell profiling to generate a multi-omic developmental resource covering pharyngeal differentiation toward organ-specific epithelia in the mouse embryo. We identified cell-type specific gene regulation of developing organ domains and characterized the role of an immunodeficiency-associated forkhead box transcription factor, Foxn1, during early thymus development. Furthermore, analyses of the pharyngeal endoderm multi-omics atlas led us to discover a novel gene associated with thymus development, namely Grainyhead-like3 (Grhl3). We assessed the expression pattern and the functional importance of Grhl3 in the prenatal and postnatal thymus, uncovering a putative role in a specialized medullary thymic subtype. In conclusion, this dissertation provides insight on the molecular basis of pharyngeal endoderm differentiation and subsequent development of the thymus.
Permanent Link to this Itemhttp://hdl.handle.net/20.500.14038/51133
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