Abstract
Avian leukosis virus (ALV) is a simple retrovirus that can induce B-cell lymphoma in chicken(s) and other birds by insertional mutagenesis. The promoter region of telomerase reverse transcriptase (TERT) has been identified as an important integration site for tumorigenesis. Tumors with TERT promoter integrations are associated with increased TERT expression. The mechanism of this activation is still under investigation. We asked whether insertion of proviral DNA perturbs the epigenome of the integration site and, subsequently, impacts the regulation of neighboring genes. DNA cytosine methylation, which generally acts to suppress transcription, is one major form of epigenetic regulation. In this study, we examine allele-specific methylation patterns of genomic DNA from chicken tumors by bisulfite sequencing. We observed that alleles with TERT promoter integrations are associated with decreased methylation in the host genome near the site of integration. Our observations suggest that insertion of ALV in the TERT promoter region may induce expression of TERT through inhibition of maintenance methylation in the TERT promoter region.
Highlights
Avian leukosis virus (ALV) is a simple retrovirus that can induce B-cell lymphoma in chickens and other fowl by means of insertional mutagenesis
Systematic analysis of the Cancer Genome Atlas database revealed that methylation of the telomerase reverse transcriptase (TERT) promoter region is one of the most prevalent markers associated with TERT expression in human cancers, in addition to the discovery of common somatic point mutations in the TERT promoter [17,18,19]
The we studied the epigenetic state of the ALV provirus and the TERT promoter in chicken lymphomas same subset of tumors was associated with increased TERT expression [7,8]
Summary
Avian leukosis virus (ALV) is a simple retrovirus that can induce B-cell lymphoma in chickens and other fowl by means of insertional mutagenesis. Previous studies have shown common integration sites in ALV-induced lymphomas near MYC, MYB, BIC and, more recently, the telomerase reverse transcriptase (TERT) genes [3,4,5,6,7,8,9]. We found that integrations in the TERT promoter region were one of the most clonally expanded—or most abundant unique—integrations in tumors tested from ALV infected chickens [3,9]. This suggests that TERT promoter integrations occurred early during ALV-infection in tumors with abundant copies of a unique TERT integration, implicating them as important early events in tumorigenesis [3,9]. Systematic analysis of the Cancer Genome Atlas database revealed that methylation of the TERT promoter region is one of the most prevalent markers associated with TERT expression in human cancers, in addition to the discovery of common somatic point mutations in the TERT promoter [17,18,19]
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