A novel isoform of IL-33 revealed by screening for transposable element promoted genes in human colorectal cancer.

Frances E Lock,Sabrina Kuah,Liane Gagnier,Mohammad M Karimi,Antonia Weberling,Artem Babaian,Dixie L Mager,Ying Zhang,Jürgen Schmitz

doi:10.1371/journal.pone.0180659

Frances E Lock, Sabrina Kuah + Show 7 more

Open Access

https://doi.org/10.1371/journal.pone.0180659

Copy DOI

Journal: PloS one	Publication Date: Jul 17, 2017
Citations: 18	License type: CC BY 4.0

Affiliation: BC Cancer Agency, University of British Columbia

Abstract

Remnants of ancient transposable elements (TEs) are abundant in mammalian genomes. These sequences contain multiple regulatory motifs and hence are capable of influencing expression of host genes. TEs are known to be released from epigenetic repression and can become transcriptionally active in cancer. Such activation could also lead to lineage-inappropriate activation of oncogenes, as previously described in lymphomas. However, there are few reports of this mechanism occurring in non-blood cancers. Here, we re-analyzed whole transcriptome data from a large cohort of patients with colon cancer, compared to matched normal colon control samples, to detect genes or transcripts ectopically expressed through activation of TE promoters. Among many such transcripts, we identified six where the affected gene has described role in cancer and where the TE-driven gene mRNA is expressed in primary colon cancer, but not normal matched tissue, and confirmed expression in colon cancer-derived cell lines. We further characterized a TE-gene chimeric transcript involving the Interleukin 33 (IL-33) gene (termed LTR-IL-33), that is ectopically expressed in a subset of colon cancer samples through the use of an endogenous retroviral long terminal repeat (LTR) promoter of the MSTD family. The LTR-IL-33 chimeric transcript encodes a novel shorter isoform of the protein, which is missing the initial N-terminus (including many conserved residues) of Native IL-33. In vitro studies showed that LTR-IL-33 expression is required for optimal CRC cell line growth as 3D colonospheres. Taken together, these data demonstrate the significance of TEs as regulators of aberrant gene expression in colon cancer.

Highlights

Gene deregulation is widespread in cancer and can be due to mutations in cis regulatory motifs, disruptions in epigenetic state or dysregulation of other regulatory pathways
We have identified and characterized a novel, shorter isoform of Interleukin 33 (IL-33) driven by an long terminal repeat (LTR) promoter and expressed in a subset of colorectal cancer (CRC) samples
Because highly conserved N-terminal motifs are lacking in this isoform, it is possible that its function may be altered compared to the normal isoform, we were unable to demonstrate a clear functional difference in this study

Summary

Introduction

Gene deregulation is widespread in cancer and can be due to mutations in cis regulatory motifs, disruptions in epigenetic state or dysregulation of other regulatory pathways. While ERV and LINE L1 transcription is generally suppressed in normal cells by epigenetic mechanisms and multiple host factors [19,20,21,22,23,24,25,26], hypomethylation and transcriptional up-regulation of ERVs and L1s is often observed in cancers [27,28,29,30,31], likely a reflection of widespread epigenetic dysregulation [32,33,34] Such deregulation could contribute to somatic L1 retrotransposition events that have been documented in several human tumor types [35,36,37,38,39,40,41]. In recent years a growing number of genes and long non-coding (lnc) RNAs with oncogenic/growth promoting effects have been shown to be ectopically expressed from TEs (mainly ERV LTRs) [3, 45,46,47,48,49,50,51,52,53,54,55,56], a process we have termed “onco-exaptation” [54, 57]

Methods

Results

Conclusion