Transposable elements (TEs) are an abundant source of gene regulatory sequence in the genome. Some TEs have been co-opted by the host genome to serve beneficial regulatory functions, however some TEs have been found to activate disease. Senescence, a pro-inflammatory cell state, is an attractive disease model given its implication in disease. Using an oncogene-induced senescence (OIS) model, I asked whether TEs have any gene regulatory effects that contribute to senescence pro-inflammatory milieu. There were many gene candidates that could potentially be regulated by a TE in the OIS model, however, I settled on Speckled Protein 140 (SP140) from observing a potential novel transcript being produced out of its normal immune modulatory context.

SP140 is a chromatin reader with critical roles regulating immune cell transcriptional programs, and SP140 splice variants are associated with immune diseases including Crohn’s disease, multiple sclerosis, and chronic lymphocytic leukemia. SP140 expression is currently thought to be restricted to immune cells. However, by analyzing human transcriptomic datasets from a wide range of normal and cancer cell types, we found recurrent cancer-specific expression of SP140, driven by an alternative promoter derived from an intronic endogenous retrovirus (ERV). The ERV belongs to the primate-specific LTR8B family and is regulated by oncogenic mitogen-activated protein kinase (MAPK) signaling. The ERV drives expression of multiple cancer-specific isoforms, including a nearly full-length isoform that retains all the functional domains of the full-length canonical isoform and is also localized within the nucleus, consistent with a role in chromatin regulation. In a fibrosarcoma cell line, silencing the cancer-specific ERV promoter of SP140 resulted in phenotypic changes less suited for cancer cells - increased sensitivity to interferon-mediated cytotoxicity and increased regulation of a tumorigenic transcription factor, nuclear factor kappa-B (NF-kB). Our findings implicate aberrant ERV-mediated SP140 expression as a novel mechanism contributing to immune gene dysregulation in a wide range of cancer cells.