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Title: Studies of the regulation of the Fv1 gene : implications for retroviral restriction
Author: Felton, V.
Awarding Body: University College London (University of London)
Current Institution: University College London (University of London)
Date of Award: 2013
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A study of the sequence immediately upstream of the Fv1 ORF predicted several transcription factor binding motifs and multiple transcription start sites, suggesting the presence of a core promoter. This was confirmed using in vitro assays with a Luciferase reporter, which demonstrated that this sequence could drive transcription. Promoter activity could also be detected in the antisense direction, prompting the hypothesis that Fv1, which is derived from an endogenous retrovirus, was formed by insertion of an open reading frame into the mouse genome, ‘hijacking’ the promoter of the upstream gene, Miip, to form a novel bidirectional gene pair. The SC-1 and 3T3-FL cell lines were described in the 1970s as being dually sensitive to both N- and B-tropic MLV. An analysis of these cell lines revealed that they both encode a functional Fv1n protein but that transcription of Fv1 was repressed. It was hypothesized that this was due to inhibitory epigenetic marks on the Fv1 promoter. It was also shown that Fv1 is constitutively expressed at very low levels, not requiring up-regulation by viral infection or interferon in order to display antiretroviral restriction. To study the relationship between Fv1 expression levels and virus restriction, a number of constructs were developed that expressed Fv1 under the control of the natural promoter. In addition, a tetracycline-inducible Fv1 system was also developed. With these systems the low concentration requirements for Fv1 were confirmed. Moreover, an interesting difference between the n and b alleles was revealed. Whereas Fv1n appears only to repress B-tropic MLV, Fv1b restricts a broader range of viruses when expressed at higher concentrations.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available