Immunology and Microbiology
Molecular, Cell and Cancer Biology Department
First Thesis Advisor
Eric Baehrecke, PhD
Ecdysone, Peptidoglycan, Carrier Proteins, Drosophila, Drosophila Proteins, Gene Expression Regulation, Transcription Factors, Innate Immunity
Theses, UMMS; Ecdysone; Peptidoglycan; Carrier Proteins; Drosophila; Drosophila Proteins; Gene Expression Regulation; Transcription Factors; Immunity, Innate
Drosophila is host to the steroid hormone ecdysone, which regulates development and immune functions using a common group of transcription factors. Developmentally-induced ecdysone pulses activate the expression of the EcR, BR-C, HR46, Eip74EF, Eip75B, Eip78C, and Eip93F, which assume control of hundreds of other genes involved in the transition from larva to pupa stage. Many of the transcription factors are related to mammalian nuclear hormone receptors by homology. In addition to these transcription factors, the ecdysoneregulated GATA factors SRP and PNR are required for the proper expression of the peptidoglycan sensor PGRP-LC, which belongs to a conserved class of proteins in innate immunity. Although the transcriptional network has been elucidated in development, it is unclear why ecdysone control of PGRP-LC gene activity involves these nine transcription factors and how ecdysone is regulated in the context of an infection in vivo.
An ecdysone-activated enhancer was located upstream of the PGRP-LC locus using a reporter plasmid. Female flies that lacked the enhancer had reduced PGRP-LC expression, but survived infection. Male flies did not experience these changes. Therefore, PGRP-LC enhancer appears to be a female-specific cis-regulatory element. The lack of survival phenotype could be caused by using an improper injection site. Bioinformatics software was used to identify putative individual and overlapping binding sites for some transcription factors. Site-directed mutations of the motifs reduced PGRP-LC promoter activity without abolishing the signal. These results suggest that the transcription factors assemble at multiple locations on the PGRP-LC enhancer and form strong protein-protein bonds. Septic injury led to elevated ecdysone in whole flies, which could be a neuroendocrine response to stress similar to the mammalian system. Steroid hormone regulation of immune receptors is a common theme in humans and flies, and these results could advance our understanding of the transcriptional regulation of related genes and gender differences observed in innate immune responses at the transcriptional level.
Tong, M. Transcriptional Regulation of the Drosophila Peptidoglycan Sensor PGRP-LC by the Steroid Hormone Ecdysone: A Masters Thesis. (2015). University of Massachusetts Medical School. GSBS Dissertations and Theses. Paper 800. DOI: 10.13028/M29W2N. https://escholarship.umassmed.edu/gsbs_diss/800
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