Oncogenic Transformation Drives DNA Methylation Loss and Transcriptional Activation at Transposable Element Loci.
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
Author Information
Tomas Kanholm: The George Washington University Cancer Center (GWCC), Washington, DC. ORCID
Uzma Rentia: The George Washington University Cancer Center (GWCC), Washington, DC. ORCID
Melissa Hadley: The George Washington University Cancer Center (GWCC), Washington, DC. ORCID
Jennifer A Karlow: Department of Pathology, Dana-Farber Cancer Institute/Harvard Medical School, Boston, Massachusetts. ORCID
Olivia L Cox: The George Washington University Cancer Center (GWCC), Washington, DC. ORCID
Noor Diab: The George Washington University Cancer Center (GWCC), Washington, DC. ORCID
Matthew L Bendall: Division of Infectious Diseases, Department of Medicine, Weill Cornell Medicine, New York, New York. ORCID
Tyson Dawson: The Institute for Biomedical Sciences at the George Washington University, Washington, DC. ORCID
James I McDonald: The George Washington University Cancer Center (GWCC), Washington, DC. ORCID
Wenbing Xie: Hefei National Laboratory for Physical Sciences at the Microscale, Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. ORCID
Keith A Crandall: Computational Biology Institute, Department of Biostatistics and Bioinformatics, Milken Institute School of Public Health, The George Washington University, Washington, DC. ORCID
Kathleen H Burns: Department of Pathology, Dana-Farber Cancer Institute/Harvard Medical School, Boston, Massachusetts. ORCID
Stephen B Baylin: Department of Oncology, The Johns Hopkins School of Medicine, The Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland. ORCID
Hari Easwaran: Hefei National Laboratory for Physical Sciences at the Microscale, Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. ORCID
Katherine B Chiappinelli: The George Washington University Cancer Center (GWCC), Washington, DC. ORCID
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. SIGNIFICANCE: Analysis of epigenetic and transcriptional changes in a transformation model reveals that transposable element expression and methylation are dysregulated during oncogenic transformation.
References
Nat Med. 2010 May;16(5):571-9, 1p following 579
[PMID: 20436485]
Nat Commun. 2019 Nov 19;10(1):5228
[PMID: 31745090]
