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Diverse repetitive element RNA expression defines epigenetic and immunologic features of colon cancer
Niyati Desai, … , Vikram Deshpande, David T. Ting
Niyati Desai, … , Vikram Deshpande, David T. Ting
Published February 9, 2017
Citation Information: JCI Insight. 2017;2(3):e91078. https://doi.org/10.1172/jci.insight.91078.
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Research Article Oncology

Diverse repetitive element RNA expression defines epigenetic and immunologic features of colon cancer

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Abstract

There is tremendous excitement for the potential of epigenetic therapies in cancer, but the ability to predict and monitor response to these drugs remains elusive. This is in part due to the inability to differentiate the direct cytotoxic and the immunomodulatory effects of these drugs. The DNA-hypomethylating agent 5-azacitidine (AZA) has shown these distinct effects in colon cancer and appears to be linked to the derepression of repeat RNAs. LINE and HERV are two of the largest classes of repeats in the genome, and despite many commonalities, we found that there is heterogeneity in behavior among repeat subtypes. Specifically, the LINE-1 and HERV-H subtypes detected by RNA sequencing and RNA in situ hybridization in colon cancers had distinct expression patterns, which suggested that these repeats are correlated to transcriptional programs marking different biological states. We found that low LINE-1 expression correlates with global DNA hypermethylation, wild-type TP53 status, and responsiveness to AZA. HERV-H repeats were not concordant with LINE-1 expression but were found to be linked with differences in FOXP3+ Treg tumor infiltrates. Together, distinct repeat RNA expression patterns define new molecular classifications of colon cancer and provide biomarkers that better distinguish cytotoxic from immunomodulatory effects by epigenetic drugs.

Authors

Niyati Desai, Dipti Sajed, Kshitij S. Arora, Alexander Solovyov, Mihir Rajurkar, Jacob R. Bledsoe, Srinjoy Sil, Ramzi Amri, Eric Tai, Olivia C. MacKenzie, Mari Mino-Kenudson, Martin J. Aryee, Cristina R. Ferrone, David L. Berger, Miguel N. Rivera, Benjamin D. Greenbaum, Vikram Deshpande, David T. Ting

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Figure 1

Global repeat RNA expression linked with CpG methylation, but distinct repeat classes had distinct behavior.

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Global repeat RNA expression linked with CpG methylation, but distinct r...
(A) Schema of repeat DNA methylation linked to RNA expression visualized by RNA-ISH (red dots). (B) Total HERV versus LINE-1 CpG methylation fraction in colon cancer cell lines untreated and treated with AZA. (C) Representative images of LINE-1 LOW (HCT116) and LINE-1 HIGH (DLD1) cell lines stained by LINE-1 (green) and GAPDH (red) RNA-ISH. DAPI nuclear stain (blue). Original magnification, ×400. (D) Inverse relationship of LINE-1 RNA expression versus median global CpG methylation in TCGA colon cancer data set. (E) HERV-K versus LINE-1 RNA expression and (F) HERV-H versus LINE-1 RNA expression in TCGA colon cancer mRNA-seq data (log2 read per million [rpm]). Statistical analysis was performed with Pearson correlation.

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