Abstract B012: 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 comprise roughly half of the human genome and are typically repressed through epigenetic mechanisms, including 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 promoters for oncogenic genes. While several examples of TE-derived promoters 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 chromatin profiling and RNA-sequencing) of high-grade serous carcinoma (HGSC) and fallopian tube (FT) tissues to determine if there are tumor-specific, TE-derived enhancers that have gene regulatory function. Once putative enhancers were identified, we used Clustered Regularly Interspaced Short Palindromic Repeats interference (CRISPRi) to functionally validate a putative TE-derived enhancer and gene regulatory axis. We discovered that on the bulk tissue level, several TE families, notably LTR2B, LTR18A, and LTR18B, are enriched at open chromatin sites and sites marked by H3K27Ac (enhancer mark) in HGSC cells compared to FT cells, suggesting the presence of HGSC-specific, TE-derived enhancers. On the single-cell level, we discovered that TE transcripts from the same families are more highly expressed in tumor cells compared to stromal and immune cells in the tumor microenvironment, suggesting that the increased TE-derived enhancer activity observed on the bulk level is specific to tumor cells. Lastly, we discovered that silencing a specific LTR18A locus upstream of the TCDD-Inducible Poly ADP Ribose Polymerase (TIPARP) gene was sufficient to repress TIPARP gene expression suggesting that these putative TE-derived enhancers have a gene regulatory function. TIPARP expression has been shown to be correlated with HGSC, and our studies show a novel mechanism by which TIPARP may be regulated in HGSC. Determining the regulatory role of these TE-derived enhancers will provide novel insights into not only HGSC, but also other cancer-related transcriptomes. Citation Format: Lily Nguyen, Abigail Jeong, Atma Ivancevic, Benjamin Bitler, Edward B. Chuong. Transposable element derived enhancers in ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Ovarian Cancer Research; 2025 Sep 19-21; Denver, CO. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl):Abstract nr B012.