American Association for Cancer Research
Browse
- No file added yet -

Figure S8 from Oncogenic Transformation Drives DNA Methylation Loss and Transcriptional Activation at Transposable Element Loci

Download (1.21 MB)
figure
posted on 2023-08-01, 08:40 authored by Tomas Kanholm, Uzma Rentia, Melissa Hadley, Jennifer A. Karlow, Olivia L. Cox, Noor Diab, Matthew L. Bendall, Tyson Dawson, James I. McDonald, Wenbing Xie, Keith A. Crandall, Kathleen H. Burns, Stephen B. Baylin, Hari Easwaran, Katherine B. Chiappinelli

Supplemental Figure 8

Funding

National Cancer Institute (NCI)

United States Department of Health and Human Services

Find out more...

National Institute on Aging (NIA)

United States Department of Health and Human Services

Find out more...

G. Harold and Leila Y. Mathers Foundation (Mathers Foundation)

Congressionally Directed Medical Research Programs (CDMRP)

American Cancer Society (ACS)

History

ARTICLE ABSTRACT

Transposable elements (TE) are typically silenced by DNA methylation and repressive histone modifications in differentiated healthy human tissues. However, TE expression increases in a wide range of cancers and is correlated with global hypomethylation of cancer genomes. We assessed expression and DNA methylation of TEs in fibroblast cells that were serially transduced with hTERT, SV40, and HRASR24C to immortalize and then transform them, modeling the different steps of the tumorigenesis process. RNA sequencing and whole-genome bisulfite sequencing were performed at each stage of transformation. TE expression significantly increased as cells progressed through transformation, with the largest increase in expression after the final stage of transformation, consistent with data from human tumors. The upregulated TEs were dominated by endogenous retroviruses [long terminal repeats (LTR)]. Most differentially methylated regions (DMR) in all stages were hypomethylated, with the greatest hypomethylation in the final stage of transformation. A majority of the DMRs overlapped TEs from the RepeatMasker database, indicating that TEs are preferentially demethylated. Many hypomethylated TEs displayed a concordant increase in expression. Demethylation began during immortalization and continued into transformation, while upregulation of TE transcription occurred in transformation. Numerous LTR elements upregulated in the model were also identified in The Cancer Genome Atlas datasets of breast, colon, and prostate cancer. Overall, these findings indicate that TEs, specifically endogenous retroviruses, are demethylated and transcribed during transformation. Analysis of epigenetic and transcriptional changes in a transformation model reveals that transposable element expression and methylation are dysregulated during oncogenic transformation.

Usage metrics

    Cancer Research

    Categories

    Keywords

    Licence

    Exports

    RefWorks
    BibTeX
    Ref. manager
    Endnote
    DataCite
    NLM
    DC