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

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:Hay, Dr Jodie and Gilroy, Dr Kathryn and Neil, Professor James and Bell, Mrs Margaret and Kilbey, Dr Anna and Cameron, Professor Ewan and Borland, Dr Gillian
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 > Institute of Biodiversity Animal Health and Comparative Medicine
College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
College of Medical Veterinary and Life Sciences > School of 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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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
190696New Approaches to Modelling Human LeukaemiaEwan CameronBloodwise (BLOODWIS)13046Vets - Veterinary Pathology, Public Health & Disease Investigation
190303New Approaches to Modelling Human LeukaemiaJames NeilCancer Research UK (CRUK)C93/A11951III - Centre for Virus Research