Distinct isoform of FABP7 revealed by screening for retroelement-activated genes in diffuse large B-cell lymphoma

Abstract

Significance Sequences derived from transposable elements (TEs) are abundant in the human genome and can influence gene expression. In normal cells, most TEs are silenced by epigenetic mechanisms such as DNA methylation but, in cancer, normally dormant TEs can become active. We hypothesized that cancer-specific release of epigenetic suppression of TEs could result in gene expression perturbations, which could promote oncogenesis. Using a bioinformatics method, we identified many genes expressed in diffuse large B-cell lymphoma (DLBCL) via activation of TE promoters. Further analysis of one, FABP7 , showed it was expressed in some DLBCL samples through use of a TE promoter. The TE-driven FABP7 transcript encodes a novel isoform of the protein, which is required for optimal DLBCL cell line proliferation.

Endogenous retroviral promoter exaptation in human cancer

“…This screen resulted in the detection of 98 such transcripts that were found in at least two DLBCL cases and no normals [138]. One of these involved the gene for fatty acid binding protein 7 ( FABP7 ).…”

LTRs activated by Epstein-Barr virus-induced transformation of B cells alter the transcriptome

“…Hodgkins lymphoma and diffuse large B-cell lymphoma (Lamprecht et al 2010;Lock et al 2014), that express LTR-driven transcripts, have been infected by EBV. We have preliminarily addressed this by examining the cell lines that express the non-canonical isoform of IRF5 and found that it is expressed in both EBV-positive and EBV-negative B cell lymphoma cell lines.…”

“…EBV has long been associated with increased risk of lymphoma (Young et al 2016). Interestingly, analysis of lymphoma cell transcriptomes revealed many TE-driven chimeric transcripts (Lock et al 2014;). However, transformed B cells only express a subset of those described in lymphoma, indicating that perhaps additional events that promote LTR activation occur in the development of lymphoma.…”

“…In the early embryo of both humans and mice, specific ERV groups are transcriptionally active and drive expression of many transcripts in the developing cells Peaston et al 2004;Macfarlan et al 2012;Maksakova et al 2013;Göke et al 2015). Likewise, both embryonic stem cells and induced pluripotent stem cells express LTR-driven transcripts, suggesting that they are important for pluripotency (Leung and Lorincz 2012;Fort et al 2014;Lock et al 2014;Lu et al 2014;Ohnuki et al 2014;Hashimoto et al 2015;. In pathways other than development, LTR-driven transcripts have also been found to be expressed in autoimmune diseases and several types of cancer, including lymphoma, hepatocellular carcinoma, and prostate cancer (Prensner et al 2013;Lock et al 2014;Hashimoto et al 2015;.…”

“…Likewise, both embryonic stem cells and induced pluripotent stem cells express LTR-driven transcripts, suggesting that they are important for pluripotency (Leung and Lorincz 2012;Fort et al 2014;Lock et al 2014;Lu et al 2014;Ohnuki et al 2014;Hashimoto et al 2015;. In pathways other than development, LTR-driven transcripts have also been found to be expressed in autoimmune diseases and several types of cancer, including lymphoma, hepatocellular carcinoma, and prostate cancer (Prensner et al 2013;Lock et al 2014;Hashimoto et al 2015;. While this work has led to an appreciation of the degree of aberrant LTR activation in normal and disease cells, the mechanisms that lead to LTR activation have remained unclear.…”