Glucocorticoid regulation of microRNA expression modulates lymphocyte apoptosis

Smith, Lindsay Kay

Glucocorticoid regulation of microRNA expression modulates lymphocyte apoptosis Public Deposited

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March 20, 2019

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Smith, Lindsay Kay
- Affiliation: School of Medicine, Curriculum in Toxicology

Abstract

Apoptosis of immature thymocytes is a carefully coordinated process that is controlled by the actions of pro-apoptotic and anti-apoptotic effectors. Endogenous glucocorticoids modulate immune development and function through the induction of lymphocyte apoptosis via mechanisms requiring alterations in gene expression. Recently, short, non-coding microRNAs have been identified as key regulators of lymphocyte function, however, it is unknown whether glucocorticoids regulate non-coding microRNAs and whether this regulation contributes to lymphocyte apoptosis. This dissertation seeks to evaluate the expression and delineate the potential regulatory role of microRNAs in glucocorticoid-induced apoptosis of lymphocytes. First, this dissertation establishes a glucocorticoid-induced apoptotic signature of microRNA expression through the demonstration of prevalent repression of microRNAs and microRNA bioprocessing machinery. Furthermore, the work presented herein delineates the regulatory role of microRNAs in glucocorticoid-induced apoptosis. Global reduction of microRNA expression via Dicer depletion significantly enhanced glucocorticoid-induced apoptosis while the overexpression of specific glucocorticoid-repressed microRNAs blunted glucocorticoid induced apoptosis, suggesting a role for microRNA processors and specific microRNAs in cell life/death decisions. Finally, studies of primary thymocyte sub-populations exhibiting the distinct morphological characteristics of apoptosis identified microRNAs uniquely regulated during glucocorticoid-induced and spontaneous apoptosis. This analysis also identified the novel induction of microRNAs 223 and 451 during both apoptotic pathways. This induction occurs under conditions of ongoing Dicer depletion. The inhibition of miR-223 activity significantly enhanced glucocorticoid-induced apoptosis, suggesting an anti-apoptotic role for this microRNA. These studies elucidate the dysregulation of microRNA expression and processing during glucocorticoid-induced apoptosis and the Dicer-independent induction of apoptotic effector microRNAs in glucocorticoid-induced and spontaneously apoptotic thymocyte sub-populations.

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