Deciphering the regulatory network of microRNAs in tuberculosis infected macrophages : a thesis presented in partial fulfilment of the requirements for the degree of Master of Science in Genetics at Massey University, Albany, New Zealand
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Date
2017
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Massey University
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Abstract
Tuberculosis is an infectious disease that is caused by Mycobacterium tuberculosis (Mtb),
an intracellular pathogen that uses macrophages as a host for replication. The outcome of
the disease depends highly on Mtb’s strategies to circumvent the immune responses of
macrophages. MicroRNAs (miRNAs) are small regulatory RNAs that influence gene
functions post-transcriptionally. Recent studies indicate that miRNAs have prominent
roles in cellular host-pathogen interactions. The aim of this study is to advance our
understanding of the regulatory mechanisms that control key miRNAs in mouse M1
macrophages during Mtb infection using network analysis.
The study began with a construction of a mouse miRNA-centric regulatory network
model by combining a network of miRNA-controlling transcription factors (TFs) with a
miRNA target network. The final network places miRNAs at the center of a
comprehensive regulatory network of TFs, miRNAs and their targets. This network
represents a useful resource for investigating miRNA functions and their control.
Subsequently, we populated the network with CAGE-derived expression data for either
Mtb-infected mouse M1 macrophages or non-infected controls. We used network analysis
to determine key regulatory elements during the infection process. As a result, we
identified a core set of TFs and miRNAs, which are likely critical regulatory elements
during M1 macrophage host and Mtb interactions. Our results also demonstrate that
among the core set of regulatory elements three highly activated miRNAs, mmu-mir-149,
mmu-mir-449a, and mmu-mir-449b, work in unison with mmu-mir-155, the top-ranked
miRNA. They co-regulate a set of downstream tuberculosis immune response related
genes. Four top-ranked TFs, Fosl1, Bhlhe40, Egr1, and Egr2, were identified that they
transcriptionally control this group of miRNAs. The TFs and miRNAs, together with their
targets constitute a mmu-mir-155 regulatory sub-network. Our results also imply that
Bhlhe40 is likely an important TF that modulates the activities of the mmu-mir-155 regulatory sub-network. Bhlhe40 and the mmu-mir-155 regulatory sub-network may be exploited by Mtb to manipulate the host immune defense for advancing survival interests. The findings of this study provide new insights into the host immune regulatory mechanisms of activated macrophages that are essential to control tuberculosis.
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Keywords
Small interfering RNA, Macrophages, Mycobacterium tuberculosis, Research Subject Categories::NATURAL SCIENCES::Biology::Cell and molecular biology::Genetics