Ng, Kevin W;
(2022)
Diversification of gene function by endogenous retroelements.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Endogenous retroelements (EREs) comprise nearly 50% of the human genome and are a major source of genetic and transcriptomic diversity. Here, we catalogue the contribution of EREs to novel transcript isoforms of immune-related genes using a de novo transcriptomics approach. As an exemplar gene, we studied PD-L1, an inhibitory molecule encoded by the CD274 gene critical for immune tolerance. We identified a novel truncated CD274 variant resulting from exonization of an intronic L2A retroelement and lacking a transmembrane domain, which we term CD274-L2A. Expression of CD274- L2A produced a soluble form of PD-L1 that displayed no immunosuppressive activity in isolation, but acted as a receptor antagonist in the presence of transmembrane PD-L1. Expression of CD274-L2A in murine tumour models delayed tumour growth, phenocopying the effect of exogenous checkpoint blockade. Human CD4+ T cells selectively upregulated soluble PD-L1 upon T cell receptor (TCR) stimulation, and CD274-L2A was upregulated in CD4+ T cells in patients with systemic lupus erythematous (SLE). We also studied ACE2, the cellular receptor for SARS-CoV-2. ACE2 has been proposed to be an interferon-stimulated gene, calling into question the efficacy and safety of therapeutic recombinant interferon. We identified a novel truncated ACE2 transcript generated from an intronic MIRb retroelement, which we term MIRb- ACE2. Importantly, interferon stimulation upregulated MIRb-ACE2 but not ACE2 in cell lines, and MIRb-ACE2 could be detected in the lungs of COVID-19 patients. Importantly, the protein product of MIRb-ACE2 is unstable and does not permit SARS-CoV-2 entry and infection. These two genes exemplify the co-evolutionary battle between retroelements and mammalian genomes, and how such evolutionary forces can diversity immune responses to cancer, infection, and autoimmunity.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Diversification of gene function by endogenous retroelements |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2022. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. - Some third party copyright material has been removed from this e-thesis. |
| UCL classification: | UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10150185 |
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