Loyola, L. et al. (2019) Disrupting MLV integrase:BET protein interaction biases integration into quiescent chromatin and delays but does not eliminate tumor activation in a MYC/Runx2 mouse model. PLoS Pathogens, 15(12), e1008154. (doi: 10.1371/journal.ppat.1008154) (PMID:31815961) (PMCID:PMC6974304)
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Abstract
Murine leukemia virus (MLV) integrase (IN) lacking the C-terminal tail peptide (TP) loses its interaction with the host bromodomain and extraterminal (BET) proteins and displays decreased integration at promoter/enhancers and transcriptional start sites/CpG islands. MLV lacking the IN TP via an altered open reading frame was used to infect tumorigenesis mouse model (MYC/Runx2) animals to observe integration patterns and phenotypic effects, but viral passage resulted in the restoration of the IN TP through small deletions. Mice subsequently infected with an MLV IN lacking the TP coding sequence (TP-) showed an improved median survival by 15 days compared to wild type (WT) MLV infection. Recombination with polytropic endogenous retrovirus (ERV), Pmv20, was identified in seven mice displaying both fast and slow tumorigenesis, highlighting the strong selection within the mouse to maintain the full-length IN protein. Mapping the genomic locations of MLV in tumors from an infected mouse with no observed recombination with ERVs, TP-16, showed fewer integrations at TSS and CpG islands, compared to integrations observed in WT tumors. However, this mouse succumbed to the tumor in relatively rapid fashion (34 days). Analysis of the top copy number integrants in the TP-16 tumor revealed their proximity to known MLV common insertion sites genes while maintaining the MLV IN TP- genotype. Furthermore, integration mapping in K562 cells revealed an insertion preference of MLV IN TP- within chromatin profile states associated with weakly transcribed heterochromatin with fewer integrations at histone marks associated with BET proteins (H3K4me1/2/3, and H3K27Ac). While MLV IN TP- showed a decreased overall rate of tumorigenesis compared to WT virus in the MYC/Runx2 model, MLV integration still occurred at regions associated with oncogenic driver genes independently from the influence of BET proteins, either stochastically or through trans-complementation by functional endogenous Gag-Pol protein.
| Item Type: | Articles |
|---|---|
| Additional Information: | ** From PubMed via Jisc Publications Router ** History: received 25-06-2019; accepted 22-10-2019. |
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Bell, Mrs Margaret and Cameron, Professor Ewan and Kilbey, Dr Anna and Borland, Dr Gillian and Hay, Dr Jodie and Gilroy, Dr Kathryn and Neil, Professor James |
| Creator Roles: | Gilroy, K.Data curation, Formal analysis, Writing – review and editing Borland, G.Investigation Kilbey, A.Investigation Bell, M.Investigation Hay, J.Investigation Cameron, E.Data curation, Funding acquisition, Resources, Supervision Neil, J.Conceptualization, Data curation, Formal analysis, Funding acquisition, Methodology, Project administration, Resources, Supervision, Validation, Visualization |
| Authors: | Loyola, L., Achuthan, V., Gilroy, K., Borland, G., Kilbey, A., Mackay, N., Bell, M., Hay, J., Aiyer, S., Fingerman, D., Villanueva, R. A., Cameron, E., Kozak, C. A., Engelman, A. N., Neil, J., and Roth, M. J. |
| College/School: | College of Medical Veterinary and Life Sciences > School of Cancer Sciences College of Medical Veterinary and Life Sciences > School of Infection & Immunity College of Medical Veterinary and Life Sciences > School of Biodiversity, One Health & Veterinary Medicine |
| Journal Name: | PLoS Pathogens |
| Publisher: | Public Library of Science |
| ISSN: | 1553-7366 |
| ISSN (Online): | 1553-7374 |
| Published Online: | 09 December 2019 |
| Copyright Holders: | This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose |
| First Published: | First published in PLoS Pathogens 15(12): e1008154 |
| Publisher Policy: | Reproduced under a Creative Commons License |
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