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dc.contributor.authorDenisenko, Elena
dc.date.accessioned2018-12-13T22:22:17Z
dc.date.available2018-12-13T22:22:17Z
dc.date.issued2018
dc.identifier.urihttp://hdl.handle.net/10179/14127
dc.descriptionThe results presented in Chapter 3 of this thesis were published as (the Authors retain copyright): Denisenko, E., Guler, R., Mhlanga, M. M., Suzuki, H., Brombacher, F., & Schmeier, S. (2017). Genome-wide profiling of transcribed enhancers during macrophage activation. Epigenetics & Chromatin, 10(1), 50. doi: 10.1186/s13072-017-0158-9en_US
dc.description.abstractMacrophages are sentinel cells essential for tissue homeostasis and host defence. Owing to their plasticity, macrophages acquire a range of functional phenotypes in response to microenvironmental stimuli. Of those, M(IFN-γ) and M(IL-4/IL-13) macrophage activation states are well known for their opposing pro- and anti-inflammatory roles. Imbalance in these populations of macrophages has been implicated in progression of various diseases. Macrophages also comprise the first line of an organism’s defence against Mycobacterium tuberculosis, the causative agent of tuberculosis; interactions between the bacteria and host macrophages define the infection outcome. The area of mammalian transcriptional regulation progressed remarkably with recent advances in high-throughput technologies. Enhancers emerged as crucial regulatory DNA elements capable of activating transcription of target genes at distance in an orientation-independent manner. A recent discovery revealed that enhancers can be transcribed themselves into enhancer RNAs, or eRNAs. Enhancers were shown to be pervasive, yet the associated regulatory patterns remain largely unknown and require further research. In this thesis, we investigated in silico transcribed enhancers in mouse tissues and cell lines, with a particular focus on macrophages. We have performed a large-scale study to identify transcribed enhancers across multiple tissues and to characterise their properties. In macrophages, we have established the most accurate, to our knowledge, genome-wide catalogue of transcribed enhancers and enhancer-gene regulatory interactions. We have inferred enhancers that might drive transcriptional responses of protein-coding genes upon M(IFN-γ) and M(IL-4/IL-13) macrophage activation, and demonstrated stimuli specificity of regulatory associations. We have conducted the first to our knowledge study of the role of transcribed enhancers in macrophage response to Mycobacterium tuberculosis infection. Taken together, the present work provides new insights into genome-wide enhancer-mediated transcriptional control of macrophage protein-coding genes in different conditions. Given the increasing promise for enhancer and chromatin-directed therapy, this work paves the way for further studies towards hostdirected therapies and novel treatments for tuberculosis and immune diseases associated with macrophage dysfunction.en_US
dc.language.isoenen_US
dc.publisherMassey Universityen_US
dc.rightsThe Authoren_US
dc.subjectGenetic transcription|xRegulationen_US
dc.subjectGenetics|xResearchen_US
dc.subjectMacrophagesen_US
dc.subjectMycobacterium tuberculosisen_US
dc.titleTranscriptional regulation in mouse macrophages : the role of enhancers in macrophage activation and infectionen_US
dc.typeThesisen_US
thesis.degree.disciplinePhDen_US
thesis.degree.levelDoctoralen_US
thesis.degree.nameDoctor of Philosophyen_US


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