Abstract 1708: Transposable element derived enhancers in ovarian cancer

Abstract There is global epigenetic dysregulation during transformation from normal to cancerous cells. One of the many consequences of this global epigenetic dysregulation is the reactivation of transposable elements (TEs). TEs compose roughly half of the human genome and are normally repressed through epigenetic mechanisms such as DNA methylation and histone modifications. Endogenous retroviruses (ERVs) are a class of TEs that contain long terminal repeats (LTRs) with putative gene regulatory motifs. LTRs can be co-opted to be pro-tumorigenic by becoming non-canonical promotors for oncogenic genes. While several examples of TE-derived promotors have been reported in cancer, the potential significance of TE-derived enhancers remains largely unexplored. Here, we utilized publicly available multi-omics datasets (bulk and single-cell ATAC-seq, bulk and single-cell RNA-seq, and chromatin profiling) in the context of ovarian cancer to determine if there are tumor specific, TE-derived-enhancers that have gene regulatory function. We used CRISPRi technology to functionally validate a putative TE-derived enhancer and gene regulatory axis. We discovered that on the bulk tissue level, several TE families are enriched at open chromatin sites and sites marked by H3K27Ac (enhancer mark) of ovarian tumors, suggesting the presence of tumor specific, TE-derived enhancers. On the single-cell level, we discovered that ovarian cells have the highest expression of these TE transcripts compared to stromal and immune cells in the tumor microenvironment, suggesting that the increased TE-derived enhancer activity observed on the bulk level are specific to ovarian cells. Lastly, when we silenced a specific LTR18 locus upstream of a gene, TIPARP, TIPARP gene expression was also repressed, suggesting that these putative TE-derived enhancers have gene regulatory function. Determining the regulatory role of these TE-derived enhancers will provide novel insights into cancer-related transcriptomes. Citation Format: Lily L. Nguyen, Atma Ivancevic, Benjamin G. Bitler, Edward B. Chuong. Transposable element derived enhancers in ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1708.