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Epigenetic deregulation of transposable elements contributes to Hodgkin lymphoma microenvironment formation

Rita Rebollo Figueiredo Da Sil

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Canadian Institutes of Health Research (CIHR)
Remnants of transposable elements (TEs) or "mobile DNA" make up almost 50% of the human genome and have played an important role in species evolution. TEs are also responsible for several human diseases and "activation" of TE sequences in cancer is often observed. In order to block such harmful events, the host cell has evolved a series of epigenetic mechanisms to inhibit further movement of TEs. These epigenetic mechanisms involve the marking or modification of TEs in the genome so they cannot be expressed. Therefore, global epigenetic abnormalities, which often occur in cancer cells, cause many normally silent TEs to be expressed. We hypothesize that epigenetic alterations of specific TEs may awaken their transcriptional promoters, create host gene transcripts and contribute to the establishment of tumour microenvironments. We have analyzed RNA expression patterns from normal and Hodgkin lymphoma (HL) cell lines in order to find genes differentially expressed due to TE promoters. We have chosen eight genes that are abnormally upregulated in HL compared to normal, and harbor TE derived promoters. Curiously, these genes participate in pathways involved in inflammation, a pathway thought to be responsible for establishment of the HL microenvironment. We will assay for changes in DNA methylation and chromatin modifications, which are epigenetic marks, in the promoters of the eight genes in HL cell lines and normal cells. We will induce epigenetic changes in normal cells to mimic the HL cell lines and hopefully distinguish genes important for HL proliferation and tumour microenvironment. Biological significance of the best gene candidates will be assayed with functional experiments. It is hoped that this work will lend insight into the role of epigenetic abnormalities in HL and how these abnormalities may contribute to the malignant state.

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